Alzheimer's Disease: Experimental, Investigational, or Unproven Treatments

Number: 0788

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses experimental treatments for Alzheimer's disease.

1. Experimental, Investigational, or Unproven

   Aetna considers the following treatments for Alzheimer's disease (AD) experimental, investigational, or unproven because their effectiveness for this indication has not been established (not an all-inclusive list).

   1. Acupuncture
   2. Adoptive immunotherapy (see CPB 0641 - Adoptive Immunotherapy and and Cellular Therapy)
   3. Amytrap (a conjugate containing a retro-inverso peptide, polyethylene glycol, and human serum albumin)
   4. Applied behavior analysis
   5. Bapineuzumab
   6. Berberine
   7. Beta-amyloid degrading enzymes including cathepsin B, neprilysin, and neprilysin-2
   8. Bosutinib
   9. Celecoxib (Celebrex)
   10. Continuous drainage of cerebral spinal fluid
   11. Crenezumab
   12. Deep brain stimulation (see CPB 0208 - Deep Brain Stimulation)
   13. Drugs that improve insulin sensitivity (e.g., dipeptidyl peptidase IV inhibitors, incretins, metformin, and thiazolidinediones)
   14. Edonerpic maleate
   15. Etanercept (Enbrel) (see CPB 0315 - Etanercept)
   16. Fecal microbiota transplantation
   17. Focused ultrasound
   18. Gamma band neural stimulation
   19. Gemfibrozil
   20. Gene therapy
   21. Glucagon-like peptide 1 (GLP-1) receptor agonists (e.g., liraglutide)
   22. Growth hormone secretagogues (see CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists)
   23. Histamine H3 receptor antagonists
   24. Hormone replacement therapy/estrogen replacement therapy (for women with AD)
   25. Huperzine A
   26. Hyperbaric oxygen therapy (HBOT) (see CPB 0172 - Hyperbaric Oxygen Therapy (HBOT))
   27. Indomethacin
   28. Insulin (nasal spray)
   29. Intra-nasal interferon beta
   30. Intravenous immunoglobulins (IVIG) (see CPB 0206 - Parenteral Immunoglobulins)
   31. Lanabecestat
   32. Leuprolide (CPB 0501 - Gonadotropin-Releasing Hormone Analogs and Antagonists)
   33. Levetiracetam
   34. Light therapy
   35. Lithium
   36. Medium-chain fatty acids
   37. Melissa oil aromatherapy
   38. Metal protein attenuating compounds (e.g., clioquinol)
   39. Methylthioninium chloride
   40. Mifepristone (RU 486)
   41. Mitotherapy (mitochondria transplantation)
   42. Music therapy
   43. Naproxen
   44. Nilotinib
   45. Noradrenergic pharmacotherapy
   46. PBT2 (a metal-protein attenuating compound)
   47. Peroxisome proliferators activated receptor-gamma agonists (e.g., pioglitazone and rosiglitazone)
   48. Plasma exchange and hemapheresis
   49. Photobiomodulation
   50. Probiotic therapy
   51. Raloxifene
   52. Resveratrol
   53. Selegiline
   54. Semagacestat
   55. Semorinemab
   56. Serotonin receptor antagonists (e.g., idalopirdine)
   57. Solanezumab
   58. Statins
   59. Stem cell therapy (including adipose tissue-derived stem cells, and bone marrow derived mesenchymal stem cells)
   60. Tarenflurbil
   61. Therapeutic touch
   62. Transcranial magnetic stimulation/direct current stimulation (see CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation)
   63. Tumor necrosis factor-alpha inhibitors
   64. Vaccine therapy (e.g., active and passive amyloid vaccines)
   65. Vagus nerve stimulation (see CPB 0191 - Vagus Nerve Stimulation)
   66. Verubecestat.

2. Related Policies

   • CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists
   • CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)
   • CPB 0191 - Vagus Nerve Stimulation
   • CPB 0206 - Parenteral Immunoglobulins
   • CPB 0208 - Deep Brain Stimulation
   • CPB 0315 - Etanercept
   • CPB 0349 - Alzheimer's Disease Tests
   • CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation
   • CPB 0501 - Gonadotropin-REleasing Hormone Analogs and Antagonists
   • CPB 0641 - Adoptive Immunotherapy and and Cellular Therapy
   • CPB 0996 - Aducanumab-avwa (Aduhelm)
   • CPB 1026 - Lecanemab-irmb (Leqembi)

Background

Alzheimer disease (AD) is the most common form of dementia. It is a neurologic condition characterized by loss of mental ability severe enough to interfere with normal activities of daily living, lasting at least six months and not present from birth. AD usually occurs in adulthood and is marked by a decline in cognitive functions such as remembering, reasoning and planning. 

Alzheimer's disease (AD) is characterized by progressive neuro-degeneration.  The treatment of patients with AD has been an intensive research topic in the past several decades.  Current treatments mainly target towards cholinergic deficiency.  Cholinesterase inhibitors (e.g., donepezil, rivastigmine, and galantamine) remain the preferred therapy for early and intermediate AD, while memantine (a glutamate antagonist) is also approved for advanced AD.  Advances in knowledge of the pathogenesis of the disease as well as an increase in disease burden have resulted in research on innovative therapies.  Epidemiological studies have suggested that non-steroidal anti-inflammatory drugs, estrogen, HMG-CoA reductase inhibitors (statins) or tocopherol (vitamin E) can prevent AD.  However, prospective, randomized studies have not convincingly been able to demonstrate clinical effectiveness.  Other experimental approaches include adoptive immunotherapy, continuous drainage of cerebral spinal fluid (CSF), deep brain stimulation, hormone replacement therapy, hyperzine A, hyperbaric oxygen therapy, intra-nasal insulin, intravenous immunoglobulins (IVIG), leuprolide, metal protein attenuating compounds (e.g., clioquinol), mifepristone (RU 486), stem cell therapy, transcranial magnetic stimulation/direct current stimulation, vaccine therapy, and vagus nerve stimulation (VNS).  However, data on these experimental therapies remain equivocal at best.

In a review on AD, Ballard et al (2011) listed several proposed disease-modifying treatments for AD -- methylthioninium chloride (a tau aggregation inhibitor), PBT2 (a copper or zinc modulator), and semagacestat (a secretase inhibitor).  The clinical value of these agents in the treatment of patients with AD needs to be validated by well-designed studies.

Semagacestat

Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for AD.  Doody et al (2013) conducted a double-blind, placebo-controlled trial in which 1,537 patients with probable AD underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily.  Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-Cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning.  A mixed-model repeated-measures analysis was used.  The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board.  At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat.  The ADAS-Cog scores worsened in all 3 groups (mean change of 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; p = 0.15 and p = 0.07, respectively, for the comparison with placebo).  The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; p = 0.14 and p < 0.001, respectively, for the comparison with placebo).  Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (p < 0.001 for all comparisons with placebo).  Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.  The authors concluded that as compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability.  Semagacestat was associated with more adverse events, including skin cancers and infections.

Vagus Nerve Stimulation

In a open-label, pilot study (n = 10), Sjogren and colleagues (2002) examined the effect of VNS on cognition in patients with AD.  Before implantation of the vagus stimulator, patients underwent neuropsychological tests such as Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE), computerized tomography of the brain, medical/neurological and psychological examinations (status evaluation), and lumbar puncture with investigation of the CSF.  The presence of depression was rated using the Montgomery-Asberg Depression Rating Scale.  Vagus nerve stimulation commenced 2 weeks after the implantation, and patients were followed-up with regular investigations and tests over 6 months.  Response was defined as improvement or absence of impairment in ADAS-Cog and MMSE scores after 3 and 6 months.  After 3 months of treatment, 7 of 10 patients were responders according to the ADAS-Cog (median improvement of 3.0 points), and 9 of 10 patients were responders according to the MMSE (median improvement of 1.5 points).  After 6 months of treatment, 7 patients were responders on the ADAS-Cog (median improvement of 2.5 points), and 7 patients were responders on the MMSE (median improvement of 2.5 points).  Vagus nerve stimulation was well-tolerated, and its side effects were mild and transient.  The authors concluded that the findings of this pilot study suggested a positive effect of VNS on cognition in patients with AD.  They stated that further studies are needed. 

In a follow-up report of the afore-mentioned study, Merrill and co-workers (2006) presented data through 1 year of VNS.  Responder rates for ADAS-Cog and MMSE were measured as improvement or absence of decline from baseline.  Global change, depression, as well as quality of life (QOL) were also assessed.  Cerebrospinal fluid levels for total tau, tau phosphorylated at Thr181 (phosphotau), and beta amyloid 42 (Abeta 42) were measured by standardized enzyme-linked immunosorbent assay.  After 1 year, 7 (41.2 %) of 17 patients and 12 (70.6 %) of 17 patients improved or did not decline from baseline on the ADAS-Cog and MMSE, respectively.  Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC).  No significant decline in mood, behavior, or QOL occurred during 1 year of treatment.  The median change in CSF tau at 1 year was a reduction of 4.8 % (p = 0.057), with a 5.0 % increase in phosphotau (p= 0.040; n = 14).  The authors concluded that the findings of this study supported long-term tolerability of VNS among patients with AD and warranted further investigation.  In this regard, Ansari et al (2007) noted that clinical trials are ongoing to examine VNS as a potential treatment for cognitive deficits in AD.

Intravenous Immunoglobulins

Active or passive immunization has been reported to mitigate plaque pathology in murine models of AD.  It has been shown that antibodies against Abeta are present in human IVIG preparations, which specifically recognize and inhibit the neurotoxic effects of Abeta.  In a pilot study, Dodel and colleagues (2004) reported the findings of treatment with IVIG in patients with AD.  A total of 5 patients with AD were enrolled and received monthly IVIG over a 6-month period.  Effectiveness assessment included total Abeta/Abeta (1-42) measured in the CSF/serum as well as effects on cognition (ADAS-Cog; Consortium to Establish a Registry for Alzheimer’s Disease [CERAD]) at baseline and at 6 months following IVIG.  Following IVIG treatment, total Abeta levels in the CSF decreased by 30.1 % (17.3 % to 43.5 %) compared to baseline (p < 0.05).  Total Abeta increased in the serum by 233 % (p < 0.05).  No significant change was found in Abeta (1-42) levels in the CSF/serum.  Using ADAS-Cog, an improvement of 3.7 +/- 2.9 points was detected.  Scores in MMSE were essentially unchanged (improved in 4 patients, stable in 1 patient) following IVIG treatment compared to baseline.  The authors concluded that although the sample size of this pilot study was too small to draw a clear conclusion, the results provided evidence for a more detailed investigation of IVIG for the treatment of AD.  Furthermore, Solomon (2007) noted that preliminary results indicated that IVIG warrants further study into its potential to deliver a controlled immune attack on Abeta, avoiding the immune toxicities that have had a negative impact on the first clinical trials of vaccine against the peptide.

Mifepristone

DeBattista and Belanoff (2005) noted that AD is often associated with abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis.  Elevated cortisol levels in AD may in turn be associated with a more rapid progression of the illness.  Furthermore, elevated cortisol levels may directly contribute to cognitive deficits in patients with AD.  Mifepristone (RU 486) is a potent antagonist of the glucocorticoid receptor and blocks the central actions of cortisol.  These researchers noted that given the limited options for the treatment of AD, mifepristone represents an innovative and promising therapeutic approach for this disease.  However, there is currently a lack of well-designed studies to support this approach in treating AD. 

In a pilot study, Pomara et al (2006) examined the cortisol response to RU 486 in patients with AD.  A total of 9 AD subjects were randomized in a placebo-controlled parallel study: 4 in the placebo group and 5 in the RU 486 group.  Subjects received oral doses of RU 486 (200 mg) or placebo daily for 6 weeks.  Morning plasma cortisol was determined at baseline, at 12 hours following the first study drug dose, and weekly thereafter.  Mifepristone resulted in a significant increase in cortisol levels [F(1,6) = 65.32; p < 0.001].  The magnitude of this increase grew over the course of the study [F(1,6) = 63.17; p < 0.001], was not related to cortisol suppression after dexamethasone and appeared greater than that reported in the literature in younger populations in response to the same drug regimen.  The authors concluded that further studies with age-matched controls should be done to determine possible AD-related changes in this response.

Dhikav and Anand (2007) stated that mifepristone has intrinsic neuroprotective and antioxidant potential which could provide benefits to patients with mild AD or with milder cognitive impairment.  Moreover, appropriate dose, duration, safety and effectiveness need to be worked out.

Leuprolide

Estrogen and other sex hormones have received much attention for their speculative role in AD, however a direct connection between estrogen and the pathogenesis of AD remains elusive and somewhat contradictory.  While there is a large body of evidence suggesting that estrogen is neuro-protective, and that hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later, studies such as the Women's Health Initiative showed that HRT initiated in elderly women increases the risk of dementia.  Although estrogen continues to be examined, the disparity of findings involving HRT has resulted in investigation of other hormones of the HPA axis such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  Casadesus and associates (2006) proposed that LH, rather than estrogen, is the critical player in the pathogenesis of AD since both men and women experience a 3- to 4-fold increase in LH with aging, and LH receptors are found throughout the brain following a regional pattern similar to that exhibited by neurons affected in AD.  With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD.  The authors proposed that elevated levels of LH may be an instigator responsible for the aberrant re-activation of the cell cycle that is observed in AD.  Wilson et al (2007) stated that leuprolide acetate, a synthetic nonapeptide that suppresses gonadotrope secretion of LH and FSH, which subsequently suppresses gonadal sex steroid production, is presently being tested for the treatment of AD.

Hormone Replacement Therapy

In a Cochrane review on HRT to maintain cognitive function in women with dementia, Hogervorst and colleagues (2009) examined the effects of HRT (estrogens combined with a progestagen) or estrogen replacement therapy (ERT; estrogens only) compared with placebo in randomized controlled trials (RCTs) on cognitive function of post-menopausal women with dementia.  All double-blind RCTs into the effect of ERT or HRT for cognitive function with a treatment period of at least 2 weeks in post-menopausal women with AD or other types of dementia were selected.  Abstracts of the references retrieved by the searches were read by two reviewers independently in order to discard those that were clearly not eligible for inclusion.  The two reviewers studied the full text of the remaining references and independently selected studies for inclusion.  Any disparity in the ensuing lists was resolved by discussion with all reviewers in order to arrive at the final list of included studies.  The selection criteria ensured that the blinding and randomization of the included studies was adequate.  The 2 reviewers also assessed the quality of other aspects of the included trials.  A total of 7 trials including 351 women with AD were analyzed.  Because different drugs were used at different studies it was not possible to combine more than 2 studies in any analysis.  On a clinical global rating, clinicians scored patients taking conjugated equine estrogens (CEE) as significantly worse compared with the placebo group on the Clinical Dementia Rating scale after 12 months (overall WMD = 0.35, 95 % confidence interval [CI]: 0.01 to 0.69, z = 1.99, p < 0.05).  Patients taking CEE had a worse performance on the delayed recall of the Paragraph Test (overall WMD = -0.45, 95 % CI: -0.79 to -0.11, z = 2.60, p < 0.01) after 1 month than those taking placebo.  They had a worse performance on Finger Tapping after 12 months (WMD = -3.90, 95 % CI: -7.85 to 0.05, z = 1.93, p < 0.05).  Limited positive effects were found for the lower dosage of CEE (0.625 mg/day) which showed a significant improvement in MMSE score only when assessed at 2 months, and disappeared after correction for multiple testing.  No significant effects for MMSE were found at longer end points (3, 6 and 12 months of treatment).  With a dosage of 1.25 mg/d CEE, short-term significant effects were found for Trial-Making test B at 1 month and Digit Span backward at 4 months.  After 2 months of transdermal diestradiol (E2) treatment, a highly significant effect was observed for the word recall test (WMD = 6.50, 95 % CI: 4.04 to 8.96, z = 5.19, p < 0.0001).  No other significant effects were found for other outcomes measured.  The authors concluded that currently, HRT or ERT for cognitive improvement or maintenance is not indicated for women with AD.

Statins

Zhou and associates (2007) performed a meta-analysis to evaluate the preventive and treatment effects of statins on dementia and AD onset.  Relevant studies were systematically identified, and data were abstracted according to pre-defined criteria.  These investigators used a fixed-effects model and a random-effects model to compute pooled relative risks and to assess statistical heterogeneity.  The pooled crude odds ratios in statin users as compared with non-users were 0.67 (95 % CI: 0.54 to 0.82) in the dementia group and 0.81 (95 % CI: 0.64 to 1.02) in the AD group.  The pooled adjusted relative risks calculated by random-effects model were 0.77 (95 % CI: 0.45 to 1.30) in the dementia group and 0.81 (95 % CI: 0.56 to 1.16) in the AD group.  The authors concluded that the use of statins did not show a beneficial effect on the risk of dementia or AD.  They noted that further study and independent confirmation of the association between the use of statin and dementia/AD in larger clinical trials are warranted.

Bifulco et al (2008) noted that statins are currently among the most commonly prescribed agents for the prevention of cardiovascular disease.  It is well established that statins reduce cholesterol levels and prevent coronary heart disease.  Moreover, evidence suggests that statins have additional properties such as endothelial protection via actions on the nitric oxide synthetase system as well as anti-oxidant, anti-inflammatory and anti-platelet effects.  There is evidence that all these actions might have potential therapeutic implications not only in stroke, but also in various neurological disorders, such as AD, Parkinson's disease, multiple sclerosis and primary brain tumors.  The authors stated that currently available data suggest that statins are safe and effective in the treatment of these neurological disorders, although more research and new data are needed.

A Cochrane systematic evidence review (McGuinness et al, 2010) identified trials of statins for dementia involving 748 participants, and found that "there is insufficient evidence to recommend statins for the treatment of dementia."  Analysis from the studies available, including 1 large RCT, indicate statins have no benefit on the outcome measures (Alzheimer's Disease Assessment Scale- cognitive subscale (ADAS-Cog) or Mini Mental State Examination (MMSE)).  The authors stated that we need to await full results from the CLASP (Cholesterol lowering agent to slow progression of AD) study before we can be certain.

A systematic evidence review in BMJ Clinical Evidence (Warner et al, 2008) found statins to be of "unknown effectiveness" in treating the cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular).

In a randomized, double-blind, placebo-controlled trial, Sano et al (2011) examined if simvastatin slows the progression of symptoms in patients with mild-to-moderate AD and normal lipid levels.  Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo.  The primary outcome was the rate of change in the ADAS-Cog portion.  Secondary outcomes measured clinical global change, cognition, function, and behavior.  A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo.  Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures.  There was no evidence of increased adverse events with simvastatin treatment.  The authors concluded that simvastatin had no benefit on the progression of symptoms in individuals with mild-to-moderate AD despite significant lowering of cholesterol.

Indomethacin

In a double-blind, randomized, placebo-controlled study, de Jong and colleagues (2008) examined if treatment with the indomethacin slows cognitive decline in patients with AD.  A total of 51 patients with mild-to-moderate AD were enrolled in this trial.  Patients received 100 mg indomethacin or placebo daily for 12 months.  Additionally, all patients received omeprazole.  The primary outcome measure was the change from baseline after 1 year of treatment on ADAS-Cog.  Secondary outcome measures included MMSE, CIBIC with caregiver input, ADAS-non-Cog, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily Life in Dementia.  Considerable recruitment problems of participants were encountered, leading to an under-powered study.  A total of 19 out of 25 patients in the placebo group; and a total of 19 out of 26 patients in the indomethacin group completed the study.  The deterioration on the ADAS-Cog was less in the indomethacin group (7.8 +/- 7.6), than in the placebo group (9.3 +/- 10.0).  However, this difference (1.5 points; CI -4.5 to 7.5) was not statistically significant, and neither was any of the secondary outcome measures.  The authors concluded that the results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD.

Huperzine A

In a Cochrane review, Li et al (2008) stated that the degeneration of acetylcholine-containing neurons in the basal forebrain has been implicated in the symptoms of AD.  Thus, cholinesterase inhibitors may block the degradation of acetylcholine, increasing the effectiveness of the remaining cholinergic neurons.  Huperzine A is a competitive, reversible inhibitor of acetyl cholinesterase that has both central and peripheral activity with the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis.  These properties might qualify huperzine A as a promising agent for treating dementia (including AD).  These researchers assessed the safety and effectiveness of huperzine A for the treatment of patients with AD.  A total of 6 trials (454 patients) met the inclusion criteria.  The methodological quality of most included trials was not high.  It was shown that compared to placebo, huperzine A had beneficial effects on the improvement of general cognitive function measured by MMSE (WMD 2.81; 95 % CI: 1.87 to 3.76; p < 0.00001) and ADAS-Cog at 6 weeks (WMD 1.91; 95 % CI: 1.27 to 2.55) and at 12 weeks (WMD 2.51; 95 % CI: 1.74 to 3.28), global clinical assessment measured by Clinical Dementia Rating (CDR) (WMD -0.80; 95 % CI: -0.95 to -0.65) and CIBIC-plus (OR 4.32, 95 % CI: 2.37 to 7.90), behavioral disturbance measured by ADAS-non-Cog at 6 weeks (WMD -1.33, 95 % CI: -2.12 to -0.54) and at 12 weeks (WMD -1.52, 95 % CI: -2.39 to -0.65), and functional performance measured by activities of daily living (WMD = -7.17; 95 % CI: -9.13 to -5.22; p < 0.00001).  However, huperzine A was not superior to placebo in the improvement of general cognitive function measured by Hasegawa Dementia Scale (HDS) (WMD: 2.78; 95 % CI: -0.17 to 5.73, p = 0.06) and specific cognitive function measured by Weshler Memory Scale (WMS) (WMD = 6.64; 95 % CI: -3.22 to 16.50; p = 0.19).  No data were available on QOL and caregiver burden.  The adverse events of huperzine A were mild and there were no significant differences of adverse events between huperzine A groups and control groups.  The authors concluded that huperzine A appears to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD.  However, only 1 study was of adequate quality and size.  Thus, there is insufficient evidence to make any recommendation about its use.  Rigorous design, randomized, multi-center, large-sample trials of huperzine A for AD are needed to further evaluate the effects.

In a multi-center, phase II clinical trial, Rafii et al (2011) evaluated the safety, tolerability, and efficacy of huperzine A in mild-to-moderate AD.  A total of 210 subjects were randomized to receive placebo (n = 70) or huperzine A (200 μg BID [n = 70] or 400 μg BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase.  The primary analysis assessed the cognitive effects of huperzine A 200 μg BID (change in ADAS-Cog at week 16 at 200 μg BID compared to placebo).  Secondary analyses assessed the effect of huperzine A 400 μg BID, as well as effect on other outcomes including MMSE, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI).  Huperzine A 200 μg BID did not influence change in ADAS-Cog at 16 weeks.  In secondary analyses, huperzine A 400 μg BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks versus 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement versus 0.34-point improvement in the placebo arm (p = 0.07) at week 16.  Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose.  The authors concluded that the primary efficacy analysis did not show cognitive benefit with huperzine A 200 μg BID.

Naproxen and Celecoxib

In a randomized, double-masked trial, the ADAPT Research Group (2008) evaluated the effects of naproxen sodium and celecoxib on cognitive function in older adults.  Men and women aged 70 years and older with a family history of AD enrolled in this study; 2,117 of 2,528 enrolled had follow-up cognitive assessment.  Patients were randomly assigned to receive celecoxib (200 mg twice-daily), naproxen sodium (220 mg twice-daily), or placebo in a ratio of 1:1:1.5, respectively.  Seven tests of cognitive function and a global summary score were measured annually.  Longitudinal analyses showed lower global summary scores over time for naproxen compared with placebo (- 0.05 SDs; p = 0.02) and lower scores on the modified MMSE over time for both treatment groups compared with placebo (- 0.33 points for celecoxib [p = 0.04] and - 0.36 points for naproxen [p = 0.02]).  Restriction of analyses to measures collected from persons without dementia attenuated the treatment group differences.  Analyses limited to measures obtained while subjects were being issued study drugs produced results similar to the intention-to-treat analyses.  The authors concluded that the use of naproxen or celecoxib did not improve cognitive function.  Furthermore, there was weak evidence for a detrimental effect of naproxen.

A systematic evidence review from BMJ Clinical Evidence (Warner et al, 2008) found non-steroidal anti-inflammatory drugs, including naproxen and celecoxib, of "unknown effectiveness" in the treatment of cognitive symptoms of dementia.

Metal Protein Attenuating Compounds

In a Cochrane review, Sampson and colleagues (2008) assessed the effectiveness of metal protein attenuating compounds for the treatment of cognitive impairment due to AD.  Randomized double-blind trials in which treatment with clioquinol was administered to patients with AD in parallel group comparison with placebo are included.  Three reviewers independently evaluated the quality of trials according to the Cochrane Collaboration Handbook. The primary outcome measures of interest were cognitive function (as measured by psychometric tests).  The secondary outcome measures of interest were in the following areas: QOL, functional performance, effect on caregiver, safety and adverse effects, and death.  There was one included trial of clioquinol compared with placebo in 36 patients.  There was no statistically significant difference in cognition (as measured on the ADAS-Cog) between active treatment and placebo groups at 36 weeks.  One subject in the active treatment group developed neurological symptoms (impaired visual acuity and color vision) that resolved on cessation of treatment and was thought to be possibly attributable to the drug.  The authors concluded that there is an absence of evidence as to whether clioquinol has any positive clinical benefit for patients with AD, or whether the drug is safe.  These researchers have some concerns regarding the quality of the study methodology, especially the randomization (subjects in the active treatment group had higher mean pre-morbid IQ as measured by the National Adult Reading Test (NART) and this may have biased the results), the secondary analyses of results stratified by baseline disease severity and whether the study was adequately powered for the analysis of the other data collected on zinc and copper levels.

Intra-Nasal Insulin

In a pilot study, Reger et al (2008) tested the hypothesis that daily intra-nasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnesic mild cognitive impairment.  The proportion of verbal information retained after a delay period was the planned primary outcome measure.  Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta amyloid, and cortisol.  A total of 25 subjects were randomly assigned to receive either placebo (n = 12) or 20 IU b.i.d. intra-nasal insulin treatment (n = 13) using an electronic atomizer, and 24 subjects completed the study.  Participants, caregivers, and all clinical evaluators were blinded to treatment assignment.  Cognitive measures and blood were obtained at baseline and after 21 days of treatment.  Fasting plasma glucose and insulin were unchanged with treatment.  The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374).  Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410).  Insulin treatment raised fasting plasma concentrations of the short form of the beta amyloid peptide (Abeta 40; p = 0.0471) without affecting the longer isoform (Abeta 42), resulting in an increased Abeta 40/42 ratio (p = 0.0207).  The authors concluded that the findings of this study supported further investigation of the benefits of intra-nasal insulin for patients with AD, and suggested that intra-nasal peptide administration may be a novel approach to the treatment of neuro-degenerative disorders.

In a pilot study, Craft and colleagues (2012) examined the effects of intra-nasal insulin administration on cognition, function, cerebral glucose metabolism, and CSF biomarkers in adults with amnestic mild cognitive impairment or AD.  The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild-to-moderate AD (n = 40).  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, WA).  Primary outcome measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the ADAS-cog score and the ADCS-ADL scale.  A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.  Outcome measures were analyzed using repeated-measures analysis of covariance.  Treatment with 20 IU of insulin improved delayed memory (p < 0.05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (p < 0.01).  Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (p < 0.05).  Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in CSF.  Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parieto-temporal, frontal, pre-cuneus, and cuneus regions and insulin-minimized progression.  No treatment-related severe adverse events occurred.  The authors concluded that these findings support longer trials of intra-nasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD.  Drawbacks of this study included the availability of data on biomarkers and brain metabolism for only a subset of patients, and the short duration of treatment.

Continuous Drainage of Cerebral Spinal Fluid

Alzheimer's disease has been associated with abnormal cerebral clearance of macromolecules such as amyloid and microtubule-associated-protein tau (MAP-tau).  It has been hypothesized that improving clearance of macromolecules from the central nervous system (CNS) might slow the progression of dementia.  In a prospective, randomized, double-blinded, placebo-controlled trial, Silverberg and co-workers (2008) evaluated the safety and effectiveness of a surgically implanted shunt in subjects with probable AD.  A total of 215 subjects with probable AD received either a low-flow ventriculo-peritoneal shunt or a sham (occluded) shunt for 9 months.  Longitudinal CSF sampling was performed in both active and control subjects.  Primary outcome measures were the Mattis Dementia Rating Scale and the Global Deterioration Scale.  Cerebral spinal fluid Abeta (1-42) and MAP-tau also were assayed.  After a planned interim analysis, the study was halted for futility.  Using the intent-to-treat population, no between-group differences were observed in the primary outcome measures.  The surgical procedure and device were associated with 12 CNS infections, some temporally associated with CSF sampling.  All were treated successfully.  The authors concluded that there is no benefit to low-flow CSF shunting in subjects with mild-to-severe AD.  Cerebral spinal fluid infections, while treatable, occurred more frequently than expected, in some cases likely related to CSF sampling.

Transcranial Direct Current Stimulation

Vaccine Therapy

Okura and Matsumoto (2008) noted that clinical trials of active vaccine for AD were halted as a consequence of the development of meningoencephalitis in some patients.  However, vaccine therapy is thought to be effective based on the clinical and pathological findings of the vaccinated patients.  Based on this information, active and passive vaccines have been developed, some of which are now undergoing clinical trials in Europe and the United States.  However, there are still some problems for general application of such drugs for patients with AD.  Salloway and Correia (2009) stated that in the active vaccine approach, a small fragment of beta-amyloid is injected to stimulate the production of beta amyloid antibodies to lower brain amyloid levels.  However, although active vaccines are designed primarily to stimulate a B-cell response, they can cause adverse effects via unplanned stimulation of T-cells.  Thus, passive immunization with a monoclonal antibody against beta amyloid may be a safer approach; and several compounds are undergoing clinical trials.

Yu et al (2023) noted that anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating AD.  UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase-I clinical trial.  In a 78-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center phase-IIa clinical trial, these researchers examined the safety, immunogenicity, and preliminary effectiveness of UB-311 in subjects with mild AD.  This study was carried out in Taiwan.  Subjects were randomized in a 1:1:1 ratio to receive 7 intra-muscular injections of UB-311 (Q3M arm), or 5 doses of U311 with 2 doses of placebo (Q6M arm), or 7 doses of placebo (placebo arm).  The primary endpoints were safety, tolerability, and immunogenicity of UB-311.  Safety was assessed in all subjects who received at least 1 dose of investigational product.  Between December 7, 2015 and August 28, 2018, a total of 43 subjects were randomized.  UB-311 was safe, well-tolerated, and generated a robust immune response.  The 3 TEAEs with the highest incidence were injection-site pain (14 TEAEs in 7 [16 %] subjects), amyloid-related imaging abnormality with micro-hemorrhages and hemosiderin deposits (12 TEAEs in 6 [14 %] subjects), and diarrhea (5 TEAEs in 5 [12 %] subjects).  A 97 % antibody response rate was observed and maintained at 93 % by the end of the study across both UB-311 arms.  The authors concluded that these findings supported the continued development of UB-311.

Stem Cell Therapy

Alzheimer's disease is characterized by degeneration and dysfunction of synapses and neurons in brain regions that are critical for learning as well as memory functions.  The endogenous generation of new neurons in certain areas of the mature brain, derived from neural stem cells, has raised hope that stem cells may be employed for structural brain repair.  Stem cell therapy has been suggested as a possible strategy for replacing damaged circuitry and restoring learning and memory abilities in patients with AD (Feng et al, 2009).  However, there is a lack of evidence regarding the effectiveness of this approach.

Neishaboori et al (2022) noted that in recent years, numerous investigations have evaluated the effectiveness of adipose tissue-derived stem cells (ADSCs) and their exosome transplantation in managing AD in different animal models; however, there are still many contradictions among the studies that hinder reaching a reliable conclusion.  In a systematic review, these researchers examined the available evidence regarding the effectiveness of ADSCs administration in treatment of AD.  They carried out a systematic search in the databases of Medline (via PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in Google and Google scholar, to find articles published until March 13, 2021.  Pre-clinical studies were included; and 2 independent reviewers summarized the eligible papers.  A total of 10 articles were included in this review.  The treatment strategies varied between isolated ADSC, ADSCs exosomes, ADSCs conditioned medium, and combination therapy (ADSCs plus conditioned medium in 1 study, and ADSCs plus melatonin in another study).  Overview of the included articles showed promising results of ADSCs and its conditioned medium/exosome administration in animal models of AD.  These studies showed significant learning and memory improvements through ADSCs and their conditioned medium/exosome administration in animal models of AD.  Furthermore, the use of ADSCs reduced the amyloid-beta plaque deposits in the hippocampus and neocortex of these animals.  The authors concluded that based on the afore-mentioned evidence, studies have suggested potential beneficial effects of ADSCs in the treatment of AD, especially via decreasing the size of Aβ plaques and improvement of cognitive deficits.  These researchers stated that further investigations regarding the subject are encouraged to achieve more accurate conclusions.

Bapineuzumab

In a phase II clinical trial, Salloway and colleagues (2009) examined the effectiveness of bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody, for the potential treatment of AD.  The study enrolled 234 patients, randomly assigned to intravenous bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg).  Patients received 6 infusions, 13 weeks apart, with final assessments at week 78.  The pre-specified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia.  Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.  No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and apolipoprotein E (APOE) epsilon4 non-carriers.  Reversible vasogenic edema, detected on brain magnetic resonance imaging (MRI) in 12/124 (9.7 %) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers.  A total of 6 vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.  The authors concluded that primary efficacy outcomes in this phase II trial were not significant.  Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase III with special attention to APOE epsilon4 carrier status.  Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provided insufficient evidence to support or refute a benefit of bapineuzumab.

Kerchner and Boxer (2010) stated that bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with AD.  However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema, a dose-limiting and potentially severe adverse reaction, may limit its clinical applicability.

Salloway et al (2014) conducted 2 double-blind, randomized, placebo-controlled, phase III trials involving patients with mild-to-moderate AD -- one involving 1,121 carriers of the APOE ε4 allele and the other involving 1,331 non-carriers.  Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks.  The primary outcome measures were scores on 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11), with scores ranging from 0 to 70 and higher scores indicating greater impairment and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment).  A total of 1,090 carriers and 1,114 non-carriers were included in the efficacy analysis.  Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and CSF phosphorylated tau (phospho-tau) concentrations.  There were no significant between-group differences in the primary outcomes.  At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (p = 0.80) and -1.2 (p = 0.34), respectively, in the carrier study; the corresponding differences in the non-carrier study were -0.3 (p = 0.64) and 2.8 (p = 0.07) with the 0.5 mg/kg dose of bapineuzumab and 0.4 (p = 0.62) and 0.9 (p = 0.55) with the 1.0 mg/kg dose.  The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0 mg/kg dose.  Between-group differences were observed with respect to PIB-PET and CSF phospho-tau concentrations in APOE ε4 allele carriers but not in non-carriers.  The authors concluded that bapineuzumab did not improve clinical outcomes in patients with AD, despite treatment differences in biomarkers observed in APOE ε4 carriers.

Gao et al (2024) stated that AD affects millions of people worldwide, and very few drugs are available for its treatment.  Monoclonal antibodies have shown promising effects in the treatment of various types of diseases.  Bapineuzumab is one of the humanized monoclonal antibodies, which have shown promising effects in AD patients.  Bapineuzumab has shown effectiveness in the treatment of mild-to-moderate AD; however, its safety is still unclear.  In a systematic review and meta-analysis, these investigators examined the exact safety profile of bapineuzumab in the treatment of mild-to-moderate AD.  They carried out a web-based literature search of PubMed and clinical trial websites using the relevant keywords.  Data were extracted from eligible records, and the RR was calculated with a 95 % CI.  All the analyses were carried out using Review Manager software (version 5.3 for windows).  Heterogeneity was measured by Chi-square and I-square tests.  Non-significant association of bapineuzumab with serious treatment-emergent AEs (TEAEs) [RR: 1.11 (0.92 to 1.35)], headache [RR: 1.03 (0.81 to 1.32)], delirium [RR: 2.21 (0.36 to 13.53)], vomiting [RR: 0.92 (0.55 to 1.55)], hypertension [RR: 0.49 (0.12 to 2.12)], convulsions [RR:2.23 (0.42 to 11.71)], falls [RR: 0.98 (0.80 to 1.21)], fatal AEs [RR: 1.18 (0.59 to 2.39)], and neoplasms [RR:1.81 (0.07 to 49.52)] was reported; however, a significant association was found with vasogenic edema [RR: 22.58 (3.48 to 146.44)].  The authors concluded that based on available evidence, bapineuzumab is found to be safe in the treatment of AD patients; however, vasogenic edema should be considered.

Etanercept

Tobinick (2009) stated that tumor necrosis factor (TNF) is an immune signaling molecule produced by glia, neurons, macrophages and other immune cells.  In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons.  The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord and in a variety of experimental models.  Excess TNF is present in the CSF of individuals with AD, and has been implicated as a mediator of the synaptic dysfunction that is hypothesized to play a central role in the pathogenesis of AD.  Tumor necrosis factor may also play a role in endothelial and microvascular dysfunction in AD, and in amyloidogenesis and amyloid-induced memory dysfunction in AD.  Genetic and epidemiological evidence has implicated increased TNF production as a risk factor for AD.  Peri-spinal administration of etanercept produced sustained clinical improvement in a 6-month, open-label pilot study in patients with AD ranging from mild to severe.  Subsequent case studies have documented rapid clinical improvement following peri-spinal etanercept in both AD and primary progressive aphasia, providing evidence of rapidly reversible, TNF-dependent, pathophysiological mechanisms in AD and related disorders.  The author state that peri-spinal etanercept for AD merits further study in randomized clinical trials.

Andrade and Radhakrishnan (2009) stated that experimental treatments potentially useful for AD include dimebon (an anti-inflammatory agent), PBT2 (a metal-protein attenuating compound) and etanercept; the safety and effectiveness of the Alzheimer's vaccine remains to be proven, and growth hormone secretagogue and tarenflurbil (a gamma-secretase inhibitor) are likely ineffective.

In a double-blind study, Butchart et al (2015) examined if etanercept is well-tolerated and obtained preliminary data on its safety in AD dementia. Patients with mild-to-moderate AD dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once-weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. A total of 41 participants (mean age of 72.4 years; 61 % men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well-tolerated; 90 % of participants (18/20) completed the study compared with 71 % (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. The authors concluded that this study showed that subcutaneous etanercept (50 mg/week) was well-tolerated in this small group of patients; however, a larger more heterogeneous AD dementia group is needed to fully assess the long-term safety and clinical effects of this approach before recommending its use for broader groups of patients.

Applied Behavior Analysis

Bakke (1997) noted that while psychoactive drugs are the usual treatment choice for problem behaviors in individuals with AD, non-drug treatments are increasingly sought.  This investigator described applied behavior analysis, the predominant non-drug treatment approach for behavior problems in people with cognitive impairments associated with developmental disabilities.  Applied behavior analysis identifies the causes of an individual's problem behavior through "functional assessment" and then employs treatment methods that address those causes.  Functional assessment seeks information on environmental and internal factors influencing a problem behavior, emphasizing the function or purpose the problem behavior serves for the individual.  The author concluded that applied behavior analysis merits further investigation as a treatment approach to behavior problems in AD.  Furthermore, in a review on the etiology and management of psychiatric and behavioral symptoms in AD and other dementias, Aarsland et al (2005) stated that more studies are needed to clarify the role of cholinergic and other psychotropic agents as well as non-pharmacologic interventions for psychiatric and behavioral symptoms in patients with dementia.  Also, in a review on AD, Ballard et al (2011) did not mention the use of applied behavior analysis for the treatment of neuropsychiatric symptoms in AD patients.

Beta-Amyloid Degrading Enzymes

Miners and colleagues 2011) stated that there is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset AD.  Several Aβ-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce Aβ levels and protect against cognitive impairment in mouse models of AD.  The activity of several Aβ-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the build-up of Aβ.  The age- and disease-related changes in expression of more recently recognized Aβ-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy.  Regardless of the role of Aβ-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge.  The most promising current approaches include the peripheral administration of agents that enhance the activity of Aβ-degrading enzymes and the direct intra-cerebral delivery of NEP by convection-enhanced delivery.  In the longer term, genetic approaches to increasing the intra-cerebral expression of NEP or other Aβ-degrading enzymes may offer advantages.

Light Therapy

Nowak and Davis (2011) examined the effect as well as duration of effect of therapeutic light on sleep, rest-activity, and global function in women with AD using mixed methods in a 2-group experimental design with repeated measures on 1 factor.  A total of 20 women with AD were randomized to experimental or control conditions.  Blue-green or dim red light was delivered via cap visor in the morning.  Results of the qualitative analysis of serial interviews with family and facility care-givers regarding perceived effect of light on global function were presented.  Themes emerged in both groups with respect to cognition and psychosocial function.  The authors concluded that future studies with larger samples using quantitative measures of global function are needed to verify these preliminary findings.

Mitolo and colleagues (2018) noted that bright light treatment is a therapeutic intervention mainly used to treat sleep and circadian disturbances in AD patients.  Recently, a handful of studies also focused on the effect on cognition and behavior.  Conflicting findings have been reported in the literature, and no definite conclusions have been drawn regarding its specific therapeutic effect.  These researchers provided a critical evaluation of available evidence in this field, highlighting the specific characteristics of effective bright light treatment.  Eligible studies were required to assess at least one of the following outcome measures: sleep, cognition, mood, and/or behavior (e.g., depression, agitation).  A total of 32 articles were included in this systematic review and identified as research intervention studies about light treatment in AD.  The quality of the publications was evaluated based on the U.S. Preventive Service Task Force (USPSTF) guidelines.  The authors concluded that the current literature suggested that the effects of light treatment in AD patients were mixed and may be influenced by several factors, but with a general trend toward a positive effect.  These investigators stated that bright light appeared to be a promising therapy without significant adverse effects.  They stated that further well-designed RCTs are needed taking into account the highlighted recommendations.

Solanezumab

Plasma Exchange and Hemapheresis

Boada et al (2016) stated that there is a growing interest in new therapeutic strategies for the treatment of AD that focus on reducing the beta-amyloid peptide (Aβ) burden in the brain by sequestering plasma Aβ, a large proportion of which is bound to albumin and other proteins.  These researchers discussed the concepts of interaction between Aβ and albumin that have given rise to AMBAR (Alzheimer's Disease Management by Albumin Replacement) project, a new multi-center, RCT for the treatment of AD.  Results from preliminary research suggested that Albutein^® (therapeutic albumin, Grifols) contains no quantifiable levels of Aβ.  Studies also showed that Albutein^® has Aβ binding capacity.  On the other hand, AD entails a high level of nitro-oxidative stress associated with fibrillar aggregates of Aβ that can induce albumin modification, thus affecting its biological functions.  Results from the phase II study confirmed that using therapeutic apheresis to replace endogenous albumin with Albutein^® 5 % is feasible and safe in patients with AD.  This process resulted in mobilization of Aβ and cognitive improvement in treated patients.  The AMBAR study will test combination therapy with therapeutic apheresis and hemapheresis with the possible leverage effect of Albutein^® with IVIG replacement (Flebogamma^® DIF).  Cognitive, functional, and behavioral changes in patients with mild-to-moderate AD will be assessed.

Bosutinib and Nilotinib

Lonskaya et al (2015) noted that AD brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex ELISA. Plaque Aβ was detected at 4 months in TgAPP and pre-plaque intracellular Aβ accumulation (2.5 months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, vascular endothelial growth factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2 months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6 months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. The authors concluded that taken together these data suggested that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.

Drugs that Improve Insulin Sensitivity (e.g., Dipeptidyl Peptidase IV Inhibitors, Incretins, Metformin, and Thiazolidinediones)

Chen and associates (2016) noted that sporadic AD is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the past 30 years have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. These investigators reviewed recent studies that target brain insulin signaling, especially those investigations on intra-nasal insulin administration and drugs that improve insulin sensitivity, including dipeptidyl peptidase IV inhibitors, incretins, metformin, and thiazolidinediones. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. The authors concluded that although larger RCTs are needed for validating their effectiveness for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to-date are encouraging.

Levetiracetam

Xiao (2016) stated that levetiracetam (a homolog of piracetam with an a-ethyl side-chain substitution) is a Food and Drug Administration (FDA)-approved anti-epileptic drug. Recently, several studies have found that levetiracetam was able to reduce seizure frequency in epileptic seizures patients without affecting their cognitive functions. These investigators summarized the effects of levetiracetam on cognitive improvement in epileptic seizures patients with or without AD, high-grade glioma (HGG) patients and amnestic mild cognitive impairment (aMCI) patients. In addition, levetiracetam was observed to improve the cognitive deficits in normal aged animals and the transgenic animal models with AD, suggesting that levetiracetam may be a better choice for the prevention or treatment of AD.

Selegiline

An UpToDate review on “Treatment of dementia” (Press and alexander, 2015) states that “In addition to the ADCS trial above, a number of smaller studies have also investigated the use of selegiline with varying results. A meta-analysis of 12 trials found that eight of the studies suggested some beneficial effect of selegiline in the treatment of cognitive benefits and, in three trials, in the treatment of behavior and mood. Three studies that were longer than one year reported significant delays in time to the primary outcome (death, institutionalization, loss of ability to perform ADLs, or severe dementia). However, the magnitude of the benefits in the meta-analysis was small and largely dependent on the ADCS study described above. Thus, the clinical importance for the population at large is unclear”.

Serotonin (5-HT) Receptor Antagonists (e.g., Idalopirdine)

Benhamu et al (2014) noted that in the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. These investigators reviewed the evidence for the implication of this receptor in learning and memory processes. They summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging pre-clinical findings that demonstrated their significant pro-cognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The authors concluded that the results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

Ramirez et al (2014) explained the rationale behind testing serotonergic therapies for AD in terms of current knowledge about the pathophysiology of the disease. Based on pre-clinical studies, certain 5-HT receptor ligands have been suggested to have the ability to modify or improve memory/cognition, specifically 5-HT receptors acting at 5-HT1A, 5-HT4 and 5-HT6 receptors. The authors summarized the pharmacology, efficacy, safety and tolerability data for the various serotonergic agents currently in clinical development for AD.

Galimberti and Scarpini (2015) stated that AD is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the 5-HT6R, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT6 receptors induces acetylcholine release, it became reasonable to consider that 5-HT6 antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system. This review discussed the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT6 antagonists. The article was also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine. The authors concluded that idalopirdine is safe and well-tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs.

Wicke et al (2015) summarized the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized pre-clinically and is now undergoing critical phases of clinical development.  The article covered the current status of 5-HT6 receptor antagonists in clinical development.  It also discussed the underlying mechanisms for the observed pro-cognitive effects.  The article was based on a search for investigational drugs using the key words “5-HT6”, “cognition”, “dementia”, “Alzheimer's disease”, “Phase II” and “Phase III” in various databases and from conference abstracts.  After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with 3 companies (GSK, Lundbeck, and Pfizer) confirming aggressive development plans and initiating pivotal phase II and III studies.  These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine).  Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.

Atri and associates (2018) examined if idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild-to-moderate AD.  A total of 3 RCTs that included 2,525 patients aged 50 years or older with mild-to-moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites) were included in this analysis.  The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017.  Idalopirdine (10, 30, or 60 mg/day) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3).  Primary end-point in all 3 studies: change in cognition total score (range of 0 to 70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the ADAS-Cog; key secondary end-points: ADCS-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores.  Dose group efficacy required a significant benefit over placebo for the primary end-point and 1 or more key secondary end-points.  Safety data and adverse event (AE) profiles were recorded.  Among 2,525 patients randomized in the 3 trials (mean age of 74 years; mean baseline ADAS-Cog total score, 26; between 62 % and 65 % of participants were women), 2,254 (89 %) completed the studies.  In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference [MD] versus placebo, 0.05 [95 % CI: -0.88 to 0.98] for the 60-mg dose group and 0.33 [95 % CI: -0.59 to 1.26] for the 30-mg dose group).  In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted MD versus placebo, 0.63 [95 % CI: -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed).  In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted MD versus placebo, -0.55 [95 % CI: -1.45 to 0.36]).  Treatment-emergent AEs occurred in between 55.4 % and 69.7 % of participants in the idalopirdine groups versus between 56.7 % and 61.4 % of participants in the placebo groups.  The authors concluded that in patients with mild-to-moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment.  These findings did not support the use of idalopirdine for the treatment of AD.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist (e.g., Liraglutide)

Hansen et al (2016) stated that pre-clinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD.  GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD.  Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds.  In this study, effects of long-term liraglutide treatment were therefore determined in 2 double APP/PS1 transgenic mouse models of AD carrying different clinical APP/PS1 mutations, i.e., the “London” (hAPPLon/PS1A246E) and “Swedish” mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants.  Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.).  In both models, regional plaque load was quantified throughout the brain using stereological methods.  Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice.  Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice.  The authors concluded that long-term liraglutide treatment exhibited no effect on cerebral plaque load in 2 transgenic mouse models of low- and high-grade amyloidosis, which suggested differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

Histamine H3 Receptor Antagonists

Kubo et al (2015) performed a systematic review and meta-analysis of double-blind RCTs of histamine H3 receptor antagonists (H3R-ANTs) for AD.  Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to June 19, 2015.  The primary outcome was a change in the MMSE scores.  Secondary outcomes were NPI scores, discontinuation rate, and individual adverse events/side effects.  Risk ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated based on a random effects model.  The computerized search initially yielded 33 studies after excluding duplicates.  These researchers excluded 29 of these articles following a review of titles and abstracts and 1 RCT including healthy subjects after full-text review.  They identified 3 RCTs (2 on GSK239512 and one on ABT-288) including 402 patients.  Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores.  Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups.  The authors concluded that the findings of this systematic review and meta-analysis suggested that H3R-ANTs are not effective in treating cognitive dysfunction in AD.  However, they stated that further studies with larger samples are needed for definitive conclusions regarding responsive subpopulations.

Peroxisome Proliferators Activated Receptor-Gamma Agonists

Cheng et al (2016) stated that peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now.  To clarify this point, a meta-analysis was performed.  These investigators searched Medline, Embase, Cochrane Central database, PubMed, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014.  Standardized mean difference (SMD), relative risk (RR) and 95 % CI were calculated to evaluate the strength of the novel therapeutics for AD and mild-to-moderate AD.  A total of 9 studies comprising 1,314 patients and 1,311 controls were included in the final meta-analysis.  These researchers found the effect of PPAR-γ agonists on ADAS-Cog scores by using STATA software.  There was no evidence for obvious publication bias in the overall meta-analysis.  The authors concluded that there is insufficient evidence that PPAR-γ agonists improved cognition of AD and mild-to-moderate AD patients.  However, they stated that PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale RCTs to confirm.

Raloxifene

In a randomized, double-blind, placebo-controlled, pilot trial, Henderson et al (2015) examined if raloxifene, a selective estrogen receptor modulator, improves cognitive function compared with placebo in women with AD and provided an estimate of cognitive effect.  This pilot study was conducted with a planned treatment of 12 months.  Women with late-onset AD of mild-to-moderate severity were randomly allocated to high-dose (120 mg) oral raloxifene or identical placebo provided once-daily.  The primary outcome compared between treatment groups at 12 months was change in the ADAS-Cog.  A total of 42 women were randomized to receive raloxifene or placebo, and were included in intent-to-treat analyses (mean age of 76 years, range of 68 to 84), and 39 women contributed 12-month outcomes; ADAS-Cog change scores at 12 months did not differ significantly between treatment groups (standardized difference 0.03, 95 % CI: -0.39 to 0.44, 2-tailed p = 0.89).  Raloxifene and placebo groups did not differ significantly on secondary analyses of dementia rating, activities of daily living, behavior, or a global cognition composite score.  Caregiver burden and caregiver distress were similar in both groups.  The authors concluded that results on the primary outcome showed no cognitive benefits in the raloxifene-treated group.  This study provided Class I evidence that for women with AD, raloxifene did not have a significant cognitive effect.  The study lacked the precision to exclude a small effect.

Resveratrol

In a randomized, placebo-controlled, double-blind, multi-center, 52-week phase II clinical trial, Turner et al (2015) examined the safety and tolerability of resveratrol in individuals with mild-to-moderate AD and its effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).  Participants (n = 119) were randomized to receive placebo or resveratrol 500 mg orally once-daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice-daily).  Brain MRI and CSF collection were performed at baseline and after completion of treatment.  Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.  Resveratrol and its major metabolites were measurable in plasma and CSF.  The most common adverse events were nausea, diarrhea, and weight loss; CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52.  Brain volume loss was increased by resveratrol treatment compared to placebo.  The authors concluded that resveratrol was safe and well-tolerated; resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects.  They stated that further studies are needed to interpret the biomarker changes associated with resveratrol treatment.  This study provided Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and altered some AD biomarker trajectories.  The study was rated Class II because more than 2 primary outcomes were designated.

Acupuncture

Peng and colleagues (2017) described the study protocol for a RCT to examine the effect of electro-acupuncture combined with donepezil on cognitive function in AD patients.  A total of 334 patients with AD will be randomly assigned to either an electro-acupuncture combined with donepezil group or a donepezil group with a ratio of 1:1.  Subjects in the electro-acupuncture combined with donepezil group will receive electro-acupuncture in addition to donepezil for 12 weeks and will keep taking donepezil for the following 24 weeks.  Subjects in the control group will take donepezil only.  The primary outcome is the change from baseline in the total score of the ADAS-Cog at week 12.  A follow-up will be conducted 24 weeks after the treatment.  The authors expect to verify the hypothesis that acupuncture in addition to donepezil is better than donepezil in improving the cognitive function of patients with AD.

Home-Based Occupational Therapy

In a randomized, controlled clinical trial, Callahan and colleagues (2017) examined if collaborative care plus 2 years of home-based occupational therapy (OT0 would delay functional decline.  Subjects were 180 community-dwelling participants with AD and their informal care-givers.  All participants received collaborative care for dementia.  Patients in the intervention group also received in-home OT delivered in 24 sessions over 2 years.  The primary outcome measure was the ADCS ADL score; performance-based measures included the Short Physical Performance Battery (SPPB) and Short Portable Sarcopenia Measure (SPSM).  At baseline, clinical characteristics did not differ significantly between groups; the mean MMSE score for both groups was 19 (SD = 7).  The intervention group received a median of 18 home visits from the study occupational therapists.  In both groups, ADCS ADL scores declined over 24 months.  At the primary end-point of 24 months, ADCS ADL scores did not differ between groups (mean difference, 2.34 [95 % CI: -5.27 to 9.96]).  These researchers also could not definitively demonstrate between-group differences in mean SPPB or SPSM values.  The authors could not definitively demonstrate whether the addition of 2 years of in-home OT to a collaborative care management model slowed the rate of functional decline among persons with AD.

Non-Pharmacological Management of Alzheimer’s Disease-Associated Agitation

Millan-Calenti and colleagues (2016) stated that many patients with AD will develop agitation at later stages of the disease, which constitutes one of the most challenging and distressing aspects of dementia.  Recently, non-pharmacological therapies have become increasingly popular and have been proven to be effective in managing the behavioral symptoms (including agitation) that are common in the middle or later stages of dementia.  These therapies appear to be an alternative to pharmacological treatment to avoid unpleasant side effects.  These investigators presented a systematic review of RCTs focused on the non-pharmacological management of agitation in Alzheimer's disease (AD) patients aged 65 years and above.  Of the 754 studies found, 8 met the inclusion criteria.  These researchers found that music therapy is an effective non-pharmacological intervention for reducing agitation in institutionalized AD patients, particularly when the intervention implies individualized and interactive music.  However, more evidence regarding the long-term effects of this therapy is needed.  Bright light therapy has little and potentially no clinically significant effects on agitation levels.  Therapeutic touch is effective for reducing physical non-aggressive behaviors but is not superior to simulated therapeutic touch or usual care in reducing physically aggressive and verbally agitated behaviors.  Melissa aromatherapy and behavioral management techniques do not appear to be superior to pharmacological therapies or placebo in managing agitation in AD patients; more evidence about their effects on agitation is needed to make definitive clinical recommendations.  The authors concluded that there is a severe paucity of research into the effects of non-pharmacological therapies in managing agitation in AD patients.

Crenezumab

In a phase-II clinical trial, cummings and colleagues (2018) evaluated the safety and efficacy of crenezumab in patients with mild-to-moderate AD.  A total of 431 patients with mild-to-moderate AD aged 50 to 80 years were randomized 2:1 (crenezumab:placebo).  Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks.  Primary outcome measures were change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating-Sum of Boxes scores from baseline to week 73.  The primary and secondary end-points were not met.  In an exploratory post-hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group.  Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with MMSE scores of 22 to 26.  In both groups, there was a significant increase in CSF β-amyloid1-42 levels that correlated with crenezumab CSF levels.  The overall rate of adverse events (AEs) was balanced between groups; 1 case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported.  The authors concluded that although pre-specified criteria for testing treatment effects were not met, these data suggested a potential therapeutic effect in patients with mild AD treated with high-dose crenezumab.  They stated that together with the safety profile for crenezumab, these data supported the exploration of crenezumab treatment at even higher doses in patients with early AD.

Gamma Band Neural Stimulation

McDermott and colleagues (2018) stated that existing treatments for AD have questionable efficacy with a need for research into new and more effective therapies to both treat and possibly prevent the condition.  These researchers  examined a novel therapeutic modality that showed promise for treating AD based on modulating neuronal activity in the gamma frequency band through external brain stimulation.  The gamma frequency band is roughly defined as being between 30 Hz to 100 Hz, with the 40 Hz point being of particular significance.  The epidemiology, diagnostics, existing pathological models, and related current treatment targets were initially briefly reviewed.  Next, the concept of external simulation triggering brain activity in the gamma band with potential demonstration of benefit in AD was introduced with reference to a recent important study using a mouse model of the disease.  These investigators presented a selection of relevant studies that described the neurophysiology involved in brain stimulation by external sources, followed by studies involving application of the modality to clinical scenarios.  A table summarizing the results of clinical studies applied to AD patients was also reported and may aid future development of the modality.  The authors concluded that the use of a therapy based on modulation of gamma neuronal activity represents a novel non-invasive, non-pharmacological approach to AD.  They stated that although its use in clinical setting is still a relatively recent area of research, the technique shows good signs of efficacy and may represent an important option for treating AD in the future.

Lanabecestat

Sakamoto and colleagues (2017) noted that lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of AD.  In this 1st Japanese clinical study for an AD intervention to include CSF sampling in Japanese elderly healthy subjects, these investigators reported the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase-I clinical trial involving 40 healthy Japanese subjects.  No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which was consistent with observations in a U.S. phase-I study of lanabecestat.  Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner.  For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14).  Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63 % and 79 % in the 15- and 50-mg lanabecestat groups, respectively; CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment.  Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and U.S. patients with mild-to-moderate AD.  The authors concluded that lanabecestat is a promising potentially disease-modifying treatment in phase-III development for patients with early AD.

Cebers and co-workers (2017) stated that AZD3293 (LY3314814) is a promising new potentially disease-modifying human Aβ precursor protein-cleaving enzyme 1 (BACE1) (β-secretase) inhibitor in phase-III clinical development for the treatment of AD.  These researchers reported the first 2 phase-I studies: A single ascending dose study evaluating doses of 1 to 750 mg with a food-effect component (n = 72), and a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once-daily (QD) or 70 mg once-weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild-to-moderate AD (Part 2, n = 16).  AZD3293 was generally well-tolerated up to the highest doses given.  No notable food effects were observed.  Pharmacokinetic following multiple doses (Part 2) were tmax of 1 to 3 hours and mean t1/2 of 16 to 21 hours across the 15 to 150 mg dose range.  For single doses of greater than or equal to 5 mg, a greater than or equal to 70 % reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied.  Following multiple doses, robust reductions in plasma (greater than or equal to 64 % at 15 mg and greater than or equal to 78 % at greater than or equal to 50 mg) and CSF (greater than or equal to 51 % at 15 mg and greater than or equal to 76 % at greater than or equal to 50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen.  The authors concluded that AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported; and 2 phase-III clinical trials of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

Sim and associates (2017) noted that several ongoing clinical development programs are investigating potential disease-modifying treatments for AD, including lanabecestat, which is a brain-permeable oral inhibitor of BACE1 that reduces Aβ production.  As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner.  Significant reductions in plasma and CSF Aβ1-40 and Aβ1-42 were observed in phase-I studies of healthy subjects and AD patients treated with lanabecestat.  Currently, 3 lanabecestat trials are ongoing and intended to support registration in early AD: First  -- phase II/III study in patients with MCI due to AD and mild AD dementia (AMARANTH, NCT02245737).  Second -- delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study.  Third -- phase III study in mild AD dementia (DAYBREAK-ALZ, NCT02783573).

On June 13, 2018, Eli Lilly (IN, USA) and AstraZeneca (Cambridge, UK) announced that they are discontinuing the global phase-III clinical trials of lanabecestat, an oral β-secretase cleaving enzyme (BACE) inhibitor, for AD. (Salt, 2018).

Tumor Necrosis Factor-Alpha Inhibitors

In a systematic review, Ekert and colleagues (2018) examined the effect of tumor necrosis factor-alpha inhibitors (TNF-αI) on AD-associated pathology.  These researchers carried out a literature search of PubMed, Embase, PsychINFO, Web of Science, Scopus, and the Cochrane Library databases for human and animal studies that evaluated the use of TNF-αI on October 26, 2016.  The main outcomes assessed were cognition and behavior, reduction in brain tissue mass, presence of plaques and tangles, and synaptic function.  Risk of bias was assessed regarding blinding, statistical model, outcome reporting, and other biases.  A total of 16 studies were included, 13 of which were animal studies and 3 of which were human.  All animal studies found that treatment with TNF-αI led to an improvement in cognition and behavior.  None of the studies measured change in brain tissue mass.  The majority of studies documented a beneficial effect in other areas, including the presence of plaques and tangles and synaptic function.  The amount of data from human studies was limited; 2 of 3 studies concluded that TNF-αI were beneficial in AD patients, with 1 being an observational study and the latter being a small pilot study, with a high risk of bias.  The authors concluded that a large-scale RCT evaluating the effectiveness of TNF-αI on humans is needed.

Verubecestat

In a randomized, double-blind, placebo-controlled, 78-week study, Egan and colleagues (2018) examined the effects of verubecestat (an oral BACE-1 inhibitor) at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate AD.  The co-primary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function.  A total of 1,958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo.  The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1,958 patients was complete.  The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (p = 0.63 for the comparison between the 12-mg group and the placebo group and p = 0.46 for the comparison between the 40-mg group and the placebo group).  The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (p = 0.49 for the comparison between the 12-mg group and the placebo group and p = 0.32 for the comparison between the 40-mg group and the placebo group); AEs, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group.  The authors concluded that verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate AD and was associated with treatment-related AEs.

Amytrap

Gandbhir and Sundaram (2019) noted that amyloid-β (Aβ42) is implicated in AD pathogenesis.  These researchers have designed a non-immune based proprietary therapeutic, called Amytrap, a conjugate containing a retro-inverso peptide, polyethylene glycol, and human serum albumin.  Amytrap not only binds Aβ42 but also prevents and dissociates aggregated Aβ42.  Amytrap binds to the region in Aβ42 known to trigger its self-aggregation, thus disrupting aggregation.  These investigators have obtained proof-of-concept on AmyTrap in a clinically relevant murine model, namely, AD-APPSWE/Tg2576.  They synthesized and characterized Amytrap and confirmed its authenticity.  Efficacy evaluations were performed on young (5 months) and old (9 months) model mice.  Amytrap was injected bi-weekly for a period of 5 months.  Pharmacokinetics and safety toxicology were assessed in normal mice and rats, respectively.  Post-treatment, younger mice showed significant improvements in cognition and Aβ42 levels in plasma, brain, and CSF, while older mice showed less significant benefits.  Immunohistochemistry of brain sections showed similar differences between young and old mice.  They all had diminished size and number of plaques in the brain of Amytrap-treated mice.  Further, Amytrap-treated mice did not develop antibodies to Amytrap, suggesting Amytrap is non-immunogenic.  Safety toxicological studies in rats showed that Amytrap was well-tolerated and therefore safe (even at 50 X the efficacy dose).  Stability tests showed Amytrap is stable at 4°C for up to 1 year.  The authors concluded that the safety and efficacy features make Amytrap a promising candidate for treating or modulating AD.

Combined Therapy of Acetylcholinesterase Inhibitors and Memantine

Glinz and colleagues (2019) stated that the safety and efficacy of combination therapy with AChEI and memantine compared to AChEI or memantine alone in patients with AD is inconclusive.  These researchers conducted a systematic review and meta-analysis of RCTs comparing the safety and efficacy of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate-to-severe AD (MMSE score was 20).  They searched Embase, Medline and CENTRAL until February 2018 for eligible RCTs.  These investigators pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE).  They included 9 RCTs (2,604 patients).  At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (SMD 0.20, 95 % CI: 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD 0.15, 95 % CI: -0.28 to -0.01, 4 RCTs, moderate QoE), but not on ADL (SMD 0.09, 95 % CI: -0.01 to 0.18, 5 RCTs, moderate QoE) or behavioral and psychological symptoms of dementia (MD -3.07, 95 % CI: -6.53 to 0.38, 6 RCT, low QoE).  There was no significant difference in AEs (RR 1.05, 95 % CI: 0.98 to 1.12, 4 RCTs, low QoE).  Evidence for long-term follow-up (greater than or equal to 9 months) or nursing home placement was sparse.  Only 2 studies compared combination therapy with memantine monotherapy.  The authors concluded that combination therapy had statistically significant effects on cognition and clinical global impression.  The clinical relevance of these effects was uncertain.  The overall QoE was very low.  These researchers stated that with the current evidence, it remains unclear whether combination therapy adds any benefit.  They stated that large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and AEs are needed.

Combined Therapy of Cholinesterase and Phosphodiesterase 4D Inhibitors

Pan and colleagues (2019) reported that a series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesized and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of AD.  Compound 10j, which is tacrine linked with pyrazolo[3,4-b]pyridine moiety by a 6-carbon spacer, was the most potent AChE with IC50 value of 0.125 μM.  Moreover, compound 10j provided a desired balance of AChE and butylcholinesterase (BuChE) and PDE4D inhibition activities, with IC50 value of 0.449 and 0.271 μM, respectively.  The authors concluded that these findings indicated that this hybrid is a promising dual functional agent for the treatment of AD.

Edonerpic Maleate

Schneider and colleagues (2019) noted that edonerpic maleate (T-817MA) protects against Aβ40-induced neurotoxic effects and memory deficits, promotes neurite outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice.  These effects may be mediated via sigma-1 receptor activation, delivery of synaptic AMPA receptors, or modulation of microglial function and may benefit patients with AD.  In a randomized, double-blind, placebo-controlled, parallel-group, phase-II clinical trial, these researchers examined the safety, tolerability, and efficacy of edonerpic for patients with mild-to-moderate AD.  This trial was conducted over 52 weeks from June 2, 2014 to December 14, 2016 at 52 U.S. clinical and academic centers.  Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable AD, MMSE scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine.  Random assignment (1:1:1 allocation) to placebo or 224 mg or 448 mg of edonerpic maleate, once-daily.  Co-primary outcomes were scores on the ADAS-Cog and ADCS-Clinical Impression of Change (ADCS-CGIC) at week 52.  Biomarkers were brain, lateral ventricular, and hippocampal volumes, as determined on MRI, and CSF Aβ40, Aβ42, total tau, and phospho-tau181.  The primary efficacy analysis was performed on the co-primary end-points for the modified intention-to-treat (ITT) population.  Of 482 subjects in the safety population, 140 of 158 participants (88.6 %) assigned to placebo, 117 of 166 participants (70.5 %) to 224-mg of edonerpic maleate, and 120 of 158 participants (76.0 %) to 448-mg of edonerpic maleate completed the trial.  The mean ADAS-Cog score change at week 52 was 7.91 for the placebo group, 7.45 for the 224-mg group, and 7.08 for the 448-mg group.  Mean differences from placebo were -0.47 (95 % CI: -2.36 to 1.43; p = 0.63) for the 224-mg group and -0.84 (95 % CI: -2.75 to 1.08; p = 0.39) for the 448-mg group.  Mean ADCS-CGIC scores were 5.22 for the placebo group, 5.24 for the 224-mg group, and 5.25 for the 448-mg group, with mean differences from placebo of 0.03 (95 % CI: -0.20 to 0.25; p = 0.81) for the 224-mg group and 0.04 (95 % CI: -0.19 to 0.26; p = 0.76) for the 448-mg group.  In the safety population, a total of 7 of 158 participants (4.4 %) in the placebo group, 23 of 166 participants (13.9 %) in the 224-mg group, and 23 of 158 participants (14.6 %) in the 448-mg group discontinued because of AEs; and the most frequent AEs were diarrhea and vomiting.  The authors concluded that beyond the pre-clinical data, the clinical outcomes of 3 phase-II clinical trials and the use of maximal doses did not provide evidence of clinical proof-of-concept for edonerpic maleate for patients with mild-to-moderate AD.

Gemfibrozil

Chandra and Pahan (2019) noted that deposition of extracellular senile plaques containing amyloid-β is one of the major neuropathological characteristics of AD; thus, targeting amyloid-β dyshomeostasis is an important therapeutic strategy for treatment of AD.  These researchers demonstrated that gemfibrozil, an FDA-approved drug for hyperlipidemia, can lower the amyloid plaque burden in the hippocampus and cortex of the 5XFAD murine model of AD.  Additionally, gemfibrozil reduced microgliosis and astrogliosis associated with plaque in these mice.  Administration of gemfibrozil also improved spatial learning and memory of the 5XFAD mice.  Finally, the authors delineated that gemfibrozil requires the transcription factor peroxisome proliferator-activated receptor alpha (PPARα) to exhibit its amyloid lowering and memory enhancing effects in 5XFAD mice.  They stated that these findings highlighted a new therapeutic property of gemfibrozil and suggested that this drug may be re-purposed for treatment of AD.

Intra-Nasal Interferon Beta

Chavoshinezhad and colleagues (2019) stated that according to the critical role of inflammation in pathogenesis of AD and memory deficits, a cytokine with anti-inflammatory properties like interferon beta (IFNβ), currently used to slow down disease progression and protect against cognitive disturbance in multiple sclerosis, might be also an effective treatment in AD condition.  These researchers examined if intra-nasal (IN) administration of IFNβ with high CNS accessibility can alleviate memory impairments in a mutant APP-overexpressing rat model of AD through modulating inflammatory responses.  To address this question, the lentiviruses carrying human amyloid protein precursor (APP) with the Swedish and Indiana mutations (LV-APPSw/Ind) were bilaterally injected in the hippocampus of adult rats.  Memory performance was assessed using passive avoidance task on days 49 and 50 after injection.  Moreover, the expression of glial markers (GFAP and Iba1) and pro-inflammatory (TNF-α, IL-1β and IL-6) and anti-inflammatory cytokines (IL-10) were evaluated in the hippocampus.  Therapeutic effects of IN-administered IFNβ (0.5 μg/kg and 1 μg/kg doses, every other day from day 23 to 50 after lentivirus injection) were examined in the LV-APP-injected rats.  The results showed that over-expression of mutant human APP gene in the hippocampus led to learning and memory deficits concomitant with gliosis and pro-inflammatory responses.  Interestingly, treatment of AD-modeled rats with IFNβ ameliorated memory impairments possibly through suppressing gliosis and shifting from pro-inflammatory toward anti-inflammatory status, suggesting that IFNβ may be a promising therapeutic agent to improve cognitive functions and modulate inflammatory responses in an AD-like neurodegenerative context.

Berberine

Yuan and colleagues (2019) stated that berberine is an isoquinoline alkaloid extracted from various Berberis species that is widely used in East Asia for a wide range of symptoms.  Recently, neuro-protective effects of berberine in AD animal models are being extensively reported.  To-date, no clinical trial has been conducted on the neuro-protective effects of berberine.  However, a review of the experimental data is needed before choosing berberine as a candidate drug for clinical experiments.  These researchers conducted a systematic review on AD rodent models to analyze the drug effects with minimal selection bias.  A total of 5 online literature data-bases were searched to find publications reporting studies of the effect of berberine treatment on animal models of AD.  Up to March 2018, 15 papers were identified to describe the efficacy of berberine.  The included 15 studies met inclusion criteria with different quality ranging from 3 to 5.  These investigators analyzed data extracted from full texts with regard to pharmacological effects and potential anti-Alzheimer's properties.  The analysis revealed that in multiple memory defects animal models, berberine showed significant memory-improving activities with multiple mechanisms, such as anti-inflammation, anti-oxidative stress, ChE inhibition and anti-amyloid effects.  The authors concluded that AD is likely to be a complex disease driven by multiple factors.  Yet, many therapeutic strategies based on lowering β-amyloid have failed in clinical trials.  This suggested that the therapy should not base on a single cause of AD but rather a number of different pathways that lead to the disease.  These researchers think that berberine could be a promising multi-potent agent to treat AD.  These researchers stated that considering the positive results from animal studies and the relatively low toxicity of berberine, the performance of clinical trials to evaluate the anti-AD effect of berberine on human patients appears justified.

Lithium

Matsunaga and associates (2015) carried out the 1st meta-analysis of randomized, placebo-controlled trials examining if lithium (Li) as a treatment for patients with AD and individuals with MCI.  The primary outcome measure was efficacy on cognitive performance as measured through the ADAS-Cog subscale or the MMSE.  Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-β42) in the CSF.  A total of 3 clinical trials including 232 patients who met the study's inclusion criteria were identified.  Lithium significantly decreased cognitive decline as compared to placebo (SMD = -0.41, 95 % CI: -0.81 to -0.02, p = 0.04, I2 = 47 %, 3 studies, n = 199).  There were no significant differences in the rate of attrition, discontinuation due to all causes or AEs, or CSF biomarkers between treatment groups.  The authors concluded that these findings indicated that Li treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia.

Forlenza and colleagues (2019) stated that experimental studies indicated that Li may facilitate neurotrophic/protective responses in the brain.  Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in AD support the clinical translation of these findings.  Nonetheless, there is limited controlled data regarding the potential use of Li for the treatment or prevention of  dementia.  These researchers examined the benefits of Li treatment in patients with amnestic MCI, a clinical condition associated with high risk for AD.  A total of 61 community-dwelling, physically healthy, older adults with MCI were randomized to receive Li or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase).  Lithium carbonate was prescribed to yield sub-therapeutic concentrations (0.25 to 0.5 mEq/L).  Primary outcome variables were the cognitive (ADAS-Cog subscale) and functional (CDR - Sum of Boxes) parameters obtained at baseline and after 12 and 24 months.  Secondary outcomes were neuropsychological test scores; CSF concentrations of AD-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0 to 48 months).  Subjects in the placebo group displayed cognitive and functional decline, whereas Li-treated patients remained stable over 2 years.  Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1-42) after 36 months.  Th authors concluded that long-term lithium attenuated cognitive and functional decline in amnestic MCI, and modified AD-related CSF biomarkers.  These researchers stated that these findings reinforced the disease-modifying properties of Li in the MCI-AD continuum.

Baethge (2020) observed that the study by Forlenza et al (2019) was the first low-dose Li (0.25 to 0.5 mmol/L) trial in MCI. The authors stated that the effect sizes presented by Forlenza et al (2019) are substantial, but noted that, “[g]iven the uncertainties in this study and the fact that effect sizes could be larger in early and small studies, it is unclear whether the results will hold . . . .“ The authors noted that a large clinical trial of Li for MCI is ongoing and scheduled for completion in 2022 (Lithium As a Treatment to Prevent Impairment of Cognition in Elders).

Bone Marrow Mesenchymal Stem Cells Transplantation

Qin and colleagues (2020) stated that AD is a neurodegenerative disorder.  Therapeutically, a transplantation of bone marrow mesenchymal stem cells (BMMSCs) could play a beneficial role in animal models of AD; however, the relevant mechanism remains to be fully elucidated.  Subsequent to the transplantation of BMMSCs, memory loss and cognitive impairment were significantly improved in animal models with AD.  Potential mechanisms involved neurogenesis, apoptosis, angiogenesis, inflammation, immunomodulation, etc.  The above mechanisms might play different roles at certain stages.  It was revealed that the transplantation of BMMSCs could alter some gene levels.  Moreover, the differential expression of representative genes was responsible for neuropathological phenotypes in AD, which could be used to construct gene-specific patterns.  The authors concluded that multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improved cognitive and behavioral deficits in AD models.  Gene expression profile can be used to establish statistical regression model for the evaluation of therapeutic effect.  These researchers stated that there is a great possibility for the clinical application of autologous BMMSCs in patients with AD.

Mitotherapy / Mitochondria Transplantation

Nascimento-Dos-Santos and colleagues (2021) stated that mitochondria are key players of aerobic respiration and the production of adenosine triphosphate (ATP) and constitute the energetic core of eukaryotic cells.  In addition, cells rely on mitochondria homeostasis, the disruption of which has been reported in pathological processes such as cancer, chronic inflammation, liver hepatotoxicity, muscular dystrophy, as well as in neurological conditions (e.g., AD, depression, and schizophrenia).  In addition to the well-known spontaneous cell-to-cell transfer of mitochondria, a therapeutic potential of the transplant of isolated, metabolically active mitochondria has been demonstrated in several in-vitro and in-vivo experimental models of disease.  These investigators examined the striking outcomes achieved by mitotherapy thus far, and the most relevant underlying data regarding isolated mitochondria transplantation, including mechanisms of mitochondria intake, the balance between administration and therapy effectiveness, the relevance of mitochondrial source and purity and the mechanisms by which mitotherapy is gaining ground as a promising therapeutic approach.

These researchers stated that mitotherapy holds promise from a therapeutic point of view, since most of the studies of diverse diseases and conditions showed positive results.  However, important limitations still need to be overcome.  They noted that the stability of mitochondria in serum was tested for up to 4 hours and the mitochondria remained functional; however, this issue must be further examined.  These investigators stated that further studies are needed to examine the possibility of chronic treatment, and clinical trials may be on the horizon, pending every ethical and security issue.  Overall, mitotherapy remains a promising treatment, in need of more information to reach its full potential.

Photobiomodulation

Dos Santos Cardoso and colleagues (2020) noted that AD is characterized by the decline of cognitive functions such as learning and memory.  Scientific society has proposed some non-pharmacological interventions, among which photobiomodulation has gained prominence for its beneficial effects.  In a systematic review, these researchers examined the therapeutic potential of photobiomodulation in AD.  They carried out a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: "photobiomodulation therapy" or "low-level laser therapy" or "LLLT" or "light emitting diode" and "amyloid" or "Alzheimer".  The data search was performed from 2008 to 2019.  These investigators followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.  The search strategy included experimental in-vivo and in-vitro studies in the English language and photobiomodulation as a non-pharmacological intervention.  They included 10 studies -- 5 in vivo and 4 in-vitro and 1 study using both in-vivo and in-vitro.  To evaluate the quality of the studies, these researchers employed the Rob tool of the Systematic Review Center for Laboratory Animal Experimentation (SYRLE).  The studies showed that photobiomodulation is able to reduce inflammatory response, oxidative stress and apoptotic effects generated by amyloid beta (Aβ) and restore mitochondrial function and cognitive behavior.  The authors concluded that both in-vivo and in-vitro studies provided promising findings on the effects of photobiomodulation in AD indicating that this approach may be a useful tool for treating AD.

Focused Ultrasound

Liu et al (2022) stated that AD affects the basic ability to function and has imposed an immense burden on the community and health care system.  Focused ultrasound (FUS) has recently been proposed as a novel non-invasive therapeutic approach for AD; however, systematic reviews on the FUS application in AD treatment have not been forthcoming.  These investigators followed the PRISMA criteria to summarize the techniques associated with safety and effectiveness, as well as possible underlying mechanisms of FUS effects on AD in animal and human studies.  Animal studies demonstrated FUS with micro-bubbles (FUS-MB) induced blood-brain-barrier (BBB) opening that could facilitate various therapeutic agents entering the brain.  Repeated FUS-MB and FUS stimulation could relieve AD pathology and improve cognitive and memory function.  Human studies showed repeated FUS-MB were well-tolerated with few AEs and FUS stimulation could enhance local perfusion and neural function, which correlated with cognitive improvement.  The authors concluded that FUS is a feasible and safe therapeutic and drug delivery strategy for AD.  However, FUS treatment on humans is still in the early stages and requires further optimization and standardization.

Gene Therapy

Tedeschi et al (2021) stated that AD is the main cause of dementia and it is a progressive neurogenerative disease characterized by the accumulation of neurofibrillary tangles and senile plaques.  There is currently no cure; however, some treatments are available to slow down the progression of the disease, including gene therapy, which has been examined to have great potential for the treatment of AD.  These researchers determined the effectiveness of gene therapy to restore cognition in AD.  They carried out a systematic review using papers published up to May 2020 and available in the Web of Science, Scopus, and Medline/PubMed databases.  Studies were considered for inclusion if they were original research that examined the effects of gene therapy on cognition in AD.  The methodological quality of the selected studies was evaluated using the Risk of Bias Tool for Animal Intervention Studies (SYRCLE's Rob tool) and the Jadad Scale.  Most pre-clinical studies obtained positive results in improving memory and learning in mice that underwent treatment with gene therapy.  On the other hand, clinical studies have obtained inconclusive results related to the delivery methods of the viral vector used in gene therapy.  The authors concluded that gene therapy has shown a great potential for the treatment of AD in pre-clinical trials; however, results should be interpreted with caution since pre-clinical studies presented limitations to predict the effectiveness of the treatment outcome in humans.

Noradrenergic Pharmacotherapy

David et al (2022) stated that dysfunction of the locus coeruleus-noradrenergic system occurs early in AD, contributing to cognitive and neuropsychiatric symptoms in some patients.  This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice.  In a systematic review and meta-analysis, these researchers examined the effectiveness of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in patients with AD.  The Medline, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021.  These investigators generated pooled estimates using random effects meta-analyses.  They included 19 RCTs (1,811 patients), of which 6 were judged as “good” quality, 7 as “fair” and 6 as “poor”.  Meta-analysis of 10 of these studies (1,300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the MMSE or ADAS-Cog (SMD: 0.14, 95 % CI: 0.03 to 0.25, p = 0.01; I2 = 0 %).  No significant effect was observed on measures of attention (SMD: 0.01, 95 % CI: -0.17 to 0.19, p = 0.91; I2 = 0).  The apathy meta-analysis included 8 trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95 % CI: 0.16 to 0.73, p = 0.002; I2 = 58 %).  This positive effect was still present following removal of outliers to account for heterogeneity across studies.  The authors concluded that re-purposing of established noradrenergic drugs is most likely to offer effective treatment in patients with AD for general cognition and apathy; however, several factors should be considered before designing future clinical trials.  These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimize risks and maximize therapeutic effects.

Probiotic Therapy

Xiang et al (2022) stated that AD and Parkinson's disease (PD) are 2 of the most common neurodegenerative diseases, and mild cognitive impairment (MCI) is considered a prodromal stage of clinical AD.  Animal studies have shown that probiotics can improve cognitive function and mitigate inflammatory response; however, results from RCTs in humans are still unclear.  In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of probiotic therapy on cognitive function, oxidative stress, and gastro-intestinal (GI) function in patients with AD, MCI, and PD.  They searched the electronic databases such as PubMed, Embase, Cochrane Library until October 2020 for the eligible RCTs, as well as the unpublished and ongoing trials.  The primary endpoints were cognitive function, inflammatory and oxidative stress biomarkers, GI function, and AEs.  After screening 2,459 titles and abstracts on AD or MCI, these investigators selected 6 eligible studies (n = 499 patients).  After screening 1,923 titles and abstracts about PD, they selected 5 eligible studies (n = 342 patients).  Compared with the control group, treatment with probiotics improved the cognitive function of patients with AD in the intervention group (p = 0.023).  Cognitive function also improved in MCI patients (p = 0.000).  Inflammation-related indicators: Malondialdehyde (MDA) was significantly reduced (p = 0.000); and hs-CRP decreased (p = 0.003).  Lipid-related indicators: VLDL decreased (p = 0.026); triglyceride decreased (p = 0.009); and insulin resistance level improved: decreased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.019).  The authors concluded that the findings of these analyses suggested that probiotic therapy could improve cognitive and GI symptoms in patients with AD, MCI, and PD, which is possibly via reducing inflammatory response and improving lipid metabolism; and the safety has also been proven.  Moreover, these researchers stated that, larger RCTs with longer follow-up are needed to support these findings.

The authors stated that this study had several drawbacks.  First, the strains, dosage and intervention time of probiotics were not the same, which would have a certain influence on the outcome.  Second, the criteria for recruiting MCI subjects were different.  Third, among the 3 AD studies, 2 of them used MMSE as the evaluation criterion of cognition, and 1evaluated cognition according to test your memory (TYM), which may have affected the results of the meta-analysis.

Fecal Microbiota Transplantation

Nassar et al (2022) noted that AD, a neurodegenerative disease that starts slowly and worsens progressively, is the leading cause of dementia worldwide.  Recent studies have linked the brain with the gut and its microbiota via the microbiota-gut-brain axis, opening the door for gut-modifying agents (e.g., prebiotics and probiotics) to influence the brain's cognitive function.  In a systematic review, these investigators examined the effects of fecal microbiota transplantation (FMT) as a gut-microbiota-modifying agent on the progressive symptoms of AD.  This systematic review was based on PRISMA 2020 guidelines.  They carried out a systematic search using Google Scholar, PubMed, PubMed Central, and ScienceDirect databases in June 2022.  The pre-defined criteria upon which the studies were selected were English language, past 10 years of narrative reviews, observational studies, case reports, and animal studies involving Alzheimer's subjects as no previous meta-analysis or systematic reviews were carried out on this subject.  Later, a quality evaluation was performed using the available assessment tool based on each study type.  The initial search generated 4,302 studies, yielding 13 studies to be included in the final selection: 1 cohort, 2 case reports, 2 animal studies, and 8 narrative reviews.  The authors concluded that these findings showed that FMT positively affected AD subjects (whether mice or humans).  In humans, the FMT effect was measured by the Mini-Mental State Examination (MMSE), showing improvement in Alzheimer's symptoms of mood, memory, and cognition.  Moreover, these researchers stated that randomized and non-randomized clinical trials are needed for more conclusive results.

Matheson and Holsinger (2023) stated that neurodegenerative diseases are highly prevalent but poorly understood, and with few therapeutic options despite decades of intense research, attention has recently shifted toward other mediators of neurological disease that may present future targets for therapeutic research.  One such mediator is the gut microbiome, which communicates with the brain via the gut-brain axis and has been implicated in various neurological disorders.  Alterations in the gut microbiome have been associated with numerous neurological and other diseases, and restoration of the dysbiotic gut has been shown to improve disease conditions.  One method of restoring a dysbiotic gut is via FMT, re-colonizing the "diseased" gut with normal microbiome.  Fecal microbiota transplantation is a treatment traditionally used for Clostridium difficile infections; however, it has recently been used in neurodegenerative disease research as a potential treatment method.  The authors concluded that the available evidence suggests that gut microbiome modification via FMT may be a novel treatment for AD, PD, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) that should be examined in more depth.  At the very least, it appears to provide some relief from symptoms with minimal (if any) adverse side effects; this is incredibly valuable in an area where treatments are either missing or limited in their long-term effectiveness.  These researchers eagerly await the emergence of further research, especially, clinical trials.

Medium-Chain Fatty Acids for the Prevention/Treatment of Alzheimer's Disease

Castro et al (2023) noted that in pre-clinical AD, the brain gradually becomes insulin resistant.  As a result, brain glucose utilization is compromised, causing a cellular energy deficit that results in the accumulation of free radicals, which increases inflammation and damages neurons.  When glucose utilization is impaired, ketone bodies offer an alternative energy source.  Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue.  Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy.  In a systematic review and meta-analysis, these investigators examined the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD.  They carried out a comprehensive search of electronic databases on August 12, 2019, to retrieve all publications meeting the inclusion criteria.  Alerts were then set to identify any publications after the search date up until January 31, 2021.  Data were extracted by 2 authors and evaluated by a 3^rd author.  A total of 410 articles were identified, of which 16 (n = 17 studies) met the inclusion criteria.  All studies examining change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase.  Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) non-carriers (n = 2 studies); 1 study reported an increase in regional cerebral blood flow (CBF) in APOE ε4 non-carriers and another reported an increase in energy metabolism in the brain.  The authors concluded MCFA supplementation increased circulating ketone body levels, resulting in increased brain energy metabolism.  Moreover, these researchers stated that further investigation is needed to examine if this MCFA-mediated increase in brain energy metabolism would improve cognition.

Music Therapy

Bleibel et al (2023) noted that the use of music interventions as a non-pharmacological therapy to improve cognitive and behavioral symptoms in AD patients has gained popularity in recent years; however, the evidence for their effectiveness remains inconsistent.  In a systematic review, these investigators examined the evidence of the effect of music therapy (alone or in combination with pharmacological therapies) on cognitive functions in AD patients compared to those without the intervention.  They carried out a systematic literature search in PubMed, Cochrane library, and HINARI for papers published from January 1, 2012 to June 25, 2022.  All RCTs that compared music therapy with standard care or other non-musical intervention and evaluation of cognitive functions are included.  Cognitive outcomes included: global cognition, memory, language, speed of information processing, verbal fluency, and attention.  Quality assessment and narrative synthesis of the studies were performed.  A total of 8 studies out of 144 met the inclusion criteria (689 participants, mean age range of 60.47 to 87.1 years).  Of the total studies, 4 were conducted in Europe (2 in France, 2 in Spain), 3 in Asia (2 in China, 1 in Japan), and 1 in the U.S.  Quality assessment of the retrieved studies revealed that 6 out of 8 studies were of high quality.  The results showed that compared to different control groups, there was an improvement in cognitive functions following music therapy application.  A greater effect was shown when patients were involved in the music-making when using active music intervention (AMI).  The authors concluded that the findings of this review highlighted the potential benefits of music therapy as a complementary therapeutic option for individuals with AD and the importance of continued investigation in this field.  These researchers stated that more investigation is needed to examine the effects of music therapy, to determine the optimal intervention strategy, and to evaluate the long-term effects of music therapy on cognitive functions.  The authors stated that this review had several drawbacks including differences in subject characteristics (age/severity of illness/cognitive ability…), outcome measures, and intervention methods, that may have influenced the results.  Furthermore, the music therapy interventions used in the studies differed, with activities ranging from singing to playing instruments.  These factors, combined with the small number of studies included in the review, limited the power of these findings.  Furthermore, the heterogeneity of the interventions and outcome measures used in the studies made it difficult to carry out a meta-analysis and combine the data in a meaningful way.  The varying methods of music selection and exposure also posed challenges in synthesizing the results.

Semorinemab

Teng et al (2022) stated that neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of AD, and correlate with clinical disease severity.  Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau.  In a randomized, double-blind, placebo-controlled, parallel-group, phase-II clinical trial, these researchers examined the safety and effectiveness of the monoclonal anti-tau antibody semorinemab in prodromal-to-mild AD.  This study was carried out between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia.  Patients aged 50 to 80 years (inclusive) with prodromal-to-mild AD, MMSE scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by PET or CSF) were included.  During the 73-week blinded study period, subjects received intravenous (IV) infusions of placebo or semorinemab (1,500 mg, 4,500 mg, or 8,100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter.  The primary outcomes were change from baseline on the CDR-SB score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo.  In the modified ITT (mITT) cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7 %]), similar increases were observed on the CDR-SB score in the placebo (n = 126; Δ = 2.19 [95 % CI: 1.74 to 2.63]) and semorinemab (1,500 mg: n = 86; Δ = 2.36 [95 % CI: 1.83 to 2.89]; 4,500 mg: n = 126; Δ = 2.36 [95 % CI: 1.92 to 2.79]; 8,100 mg: n = 84; Δ = 2.41 [95 % CI: 1.88 to 2.94]) arms.  In the safety-evaluable cohort (n = 441), similar proportions of participants experienced AEs in the placebo (130 [93.1 %]) and semorinemab (1,500 mg: 89 [88.8 %]; 4,500 mg: 132 [94.7 %]; 8,100 mg: 90 [92.2 %]) arms.  The authors concluded that in patients with prodromal-to-mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period; but did demonstrate an acceptable and well-tolerated safety profile.  These researchers stated that additional studies of anti-tau antibodies may be needed to examine the clinical use of this therapeutic approach.

Monteiro et al (2023) noted that accumulation of tau pathology in AD correlates with cognitive decline; anti-tau immunotherapies were proposed as potential interventions in AD.  While antibodies targeting N-terminal tau failed to show clinical effectiveness in prodromal-to-mild AD, their use at other disease stages was not examined in previous studies.  Lauriet is a randomized, placebo-controlled, double-blind, phase-II clinical trial of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD.  Participants were patients with mild-to-moderate AD who received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks.  Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks.  Co-primary effectiveness endpoints were change from baseline to week 49 or 61 on the ADAS-Cog11 and the ADCS-ADL scale.  Secondary effectiveness endpoints included change from baseline on the MMSE and CDR-SB.  Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated.  Between December 3, 2018, and February 27, 2020, a total of 624 individuals were screened, 272 participants were randomized, and 238 were included in the mITT population (received 1 or more dose(s) of study medication and underwent baseline and 1 or more post-baseline assessment(s)).  Baseline characteristics were well-balanced.  At week 49, the semorinemab arm showd a 42.2 % reduction (-2.89 points, 95 % CI: -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (co-primary endpoint) relative to the placebo arm.  However, no treatment effects were observed on the ADCS-ADL scale (co-primary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95 % CI: -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints).  Semorinemab was safe and well-tolerated.  The authors concluded that based on the findings of the pre-specified co-primary endpoints, this study was negative.  While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes.  These results may warrant further investigations of semorinemab or other anti-tau therapies in mild-to-moderate AD.  This study provided Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD; combining semorinemab or other anti-tau therapies with other disease-modifying drugs such as anti-Aβ antibodies may be of particular interest.

The authors stated that there were 2 main drawbacks that may limit the interpretation of these findings.  First, the COVID-19 pandemic contributed to missed doses and/or remote or missed clinical assessments for some participants.  The blinded treatment period was extended to account for missed doses, and pre-specified analysis of a restricted modified ITT (mITT) population yielded results that were very similar to those observed in the mITT population.  However, there might be unknown effects of the pandemic on these findings that were not assessed by these pre-planned sensitivity analyses.  Second, the relatively small sample size and lack of racial and ethnic diversity in the study cohort may also restrict the generalizability of these findings.

Thangwaritorn et al (2024) AD is the most common neurodegenerative condition and a form of dementia encountered in medical practice.  Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide.  The initial part of this article provided an overview and illustration of the primary mechanisms responsible for neuronal damage in AD.  Subsequently, it offered a critical evaluation of the most noteworthy studies on pharmacotherapy for AD and outlined recent advancements and novel approaches to managing this condition.  Main properties, categorization, FDA status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacotherapies for AD were described.  The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone.  The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab.  Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene were also revised.  Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers.  Anti-diabetic and anti-neuroinflammation drugs recently proposed for AD treatment were discussed.  The anti-diabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin.  The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with IVIG aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells.  Additional anti-inflammatory agents being currently tested in phase-II clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed.  Finally, drugs targeting AD-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, were reviewed.  As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising therapeutic option for AD in the future.

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