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investigational therapies for treatment of Alzheimer's disease

Comparative biology: === in vitro studies === 1) certain NSAIDS diminish formation of Abeta42 [6,13,14] a) flurbiprofen, ibuprofen, mecofenamate indomethacin, sulindac, fenoprofen, & diclofenac do b) aspirin, naproxen, celecoxib don't c) inhibition via direct interaction with gamma-secretase [13,14] d) inhibition of Abeta42 formation in favor of Abeta38 2) simvastatin allegedly diminishes formation of Abeta42 formation [17] (also see statins & Alzheimer's disease) 3) acetylcholinesterase may act as a nucleating factor to promote conversion of soluble amyloid peptide into insoluble amyloid fibrils [11] a) a peripheral site rather than the active site of the enzyme is thought to mediate the interaction (based on X-ray crystallography) b) inhibition of this interaction is proposed as a target for pharmaceutical intervention 4) disruption of amyloid beta-pleated sheets [12] 5) linking Abeta with chaperone using a small bivalent molecule prevents aggregation of Abeta & eliminates Abeta toxicity [19] 6) resveratrol promotes intracellular degradation of Abeta via a mechanism involving the proteasome [24] 7) docosahexaenoic acid (DHA)-derived 10,17S-docosatriene NPD1 promotes neuron survival via the induction of antiapoptotic & neuroprotective gene-expression programs that suppress Abeta42-induced neurotoxicity [25] 8) calorie restriction & resveratrol activate SIRT1, SIRT1 inhibits ROCK1, which in turn, increases APP alpha-secretase activity [34] === studies in rodents === 1) immunization with Abeta42 or passive immunization with A-beta(1-42) antibodies a) protected mice genetically engineered to overproduce Abeta42 from developing amyloid plaques [1,2] b) attenuated learning defects associated with plaques [3] 2) an inhibitor of acyl-cholesterol acyltransferase (ACAT) reduces accumulation of amyloid plaques & Abeta levels in a mouse-model for Alzheimer's disease [20] 3) inhibitors of diacylglycerol O-acyltransferase 1 (DGAT1) enhance beta peptide & amyloid plaque removal in a mouse model for Alzheimer's disease 4) curcumin diminishes amyloid in a mouse model for AD [27] 5) DHA (omega-3) diminishes amyloid in a mouse model for AD [7] 6) anti-oxidant 'cocktails' have been proposed [7] 7) doxycyline beginning at 6 months of age diminished APP expression & Abeta production & stopped progression of amyloid pathology in APP transgenic mice, but resulted in little clearance of preexisting amyloid plaques [28] 8) inositol 30 mg/kg/day reduces amyloid pathology & improves behavioral manifestations of Abeta aggregation in a transgenic mouse model for Alzheimer's disease [29] 9) muscarinic M1 receptor agonist AF267B reduced Abeta & tau pathology in hippocampus & cerebral cortex, but not amygadla in a transgenic mouse model for AD [30] - selective activation of ADAM17 reduced Abeta pathology - diminished GSK3beta activity diminished tau pathology [30] 10) caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease [37] 11) pomegranate juice decreases amyloid load & improves behavior in a mouse model of Alzheimer's disease [32] 12) Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease [33] 13) LRP-IV (an LRP1 fragment) clears amyloid in a mouse-model of Alzheimer's disease [35], no adverse effects reported 14) valsartan clears beta-amyloid & improves spatial learning in a mouse model for AD [36], ARBs> 15) BACE1 inhibitor tethered to sterol via polyglycol diminishes pathology in APP transgenic mice [38] 16) electromagnetic field treatment at standard cell phone frequencies protects against & reverses cognitive decline in a mouse model for AD (AbetaPPsw) [42] 17) intravascular administration of a high-affinity humanized anti-PrP antibody to rats prevents the plasticity-disrupting effects induced by exposure to soluble AD brain extracts (Abeta oligomers) [49] 18) inhibitor of PTPN5/STEP improves cognitive function in a mouse model with no change in beta amyloid or phospho-tau levels [50] 19) scanning ultrasound in conjunction with intravenously administered microbubbles (ultrasound/microbubble therapy) reduced amyloid plaque & improved memory in a mouse model of Alzheimer's disease [51] 20) 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-beta oligomers & amyloid plaques [53] 21) noninvasive, multisensory stimulation in a mouse model of Alzheimer disease helped to clear amyloid & tau & restored at least some cognitive function - a 40-Hz tone use to entrain firing rate of neurons in the auditory cortex, the hippocampal CA1 region, & the medial prefrontal cortex [61] - after a week, the tone - reduced amyloid-beta in the auditory cortex & hippocampal CA1 region - decreased plaque & phosphorylated tau in CA1 region & auditory cortex - increased amyloid uptake by microglia - upregulated astrocytes - improved spatial & recognition memory (impaired in the experimental mice) - combining the tone with a 40-Hz light flicker - augmented entrainment of neuronal activity in all 3 regions - reduced amyloid plaque throughout the neocortex [61] 22) low-dose lithium rescues functional deficits in object recognition, reduces loss of cholinergic boutons in hippocampus, reduces levels of soluble & insoluble cortical Abeta-42, reduces reduces hippocampal Abeta plaque number in McGill-R-Thy1-APP transgenic rats [63] === studies in humans === 1) HMG CoA reductase inhibitors (statins) [4] a) Alzheimer's Disease Cooperative Study (ADCS) b) Sun Health Research Institute - atorvastatin may be of some clinical benefit in mild to moderate Alzheimer's disease [21] c) PROSPER d) statins reduce 24-OH cholesterol, but < than reduction in LDL [16] e) also see statins & Alzheimer's disease, statins & the risk of dementia (data NOT supportive) 2) non-steroidal anti-inflammatory agents (NSAIDs) a) epidemiologic studies associate NSAID use with diminished risk of AD [5] 1] RR=0.27 for long-term users > 24 months [10] 2] RR < 0.76 for long-terms users > 5 years [39] b) risk may be attenuated with certain NSAIDs, but not others [6,9] (see studies in rodents above) 1] rofecoxib 25 mg/day of no benefit [9] 2] naproxen 220 mg BID of no benefit [9,31] 3] celecoxib 200 mg BID of no benefit [31] 4] risk reduction greatest with ibuprofen & indomethacin [39], although inhibition of Abeta42 formation allegedly does not play a role [39] c) direct interaction of certain NSAIDs with gamma-secretase [13,14] 1] see in vitro studies above 2] no benefit of tarenflurbil (R-flubiprofen), a drug that inhibits gamma-secretase & formation of Abeta42 [41] d) no dose information available for NSAIDs that may be of benefit 3) vitamins: a) combination of vitamin E & vitamin C may reduce the risk of Alzheimer's disease; RR = 0.22 for users > 5 years [18] b) combination of folate (5 mg), vitamin B6 (25 mg), & vitamin B12 (1 mg) of no benefit [40] c) vitamin B12 without folate or vitamin B6 might be of benefit [44] d) antioxidant combination (vitamin E 800 IU/day, vitamin C 500 mg/day, alpha-lipoic acid (component of pantothenic acid) 900 mg/day, coenzyme Q 400 mg/day [46] 1] antioxidant combination associated with greater cognitive decline than placebo (MMSE, -2.8 vs. -0.9 points) & showed a trend toward greater functional deterioration 2] no between-group differences or changes in Abeta-42, tau, or phosphorylated tau 3] F2-isoprostanes decreased by 19% in the antioxidant combination group [46] 4) clioquinol (metal chelator) in phase II clinical trial 3/02 - allegedly withdrawn due to toxicity [7] 5) Alzhemed in Phase 3 clinical trials (07/04) 6) LY450139 in clinical trials (07/04) 7) dimebon in Phase 3 trials (08/08) 8) immunization with A-beta(1-42) [22,23] a) associated with meningoencephalitis (6%) [22] b) candidate biomarkers associated with risk of immunotherapy identified from microarray analysis using peripheral blood [22] 9) monoclonal antibodies - 2 monoclonal antibodies against beta-amyloid failed to produce meaningful clinical results [48] - crenezumab lowers amyloid-beta oligomers in CSF [71] - aducanumab, a monoclonal Ab that removes beta-amyloid reduces Abeta plaques in Alzheimer's disease [55] - FDA-approved in 2021 - donanemab targets beta-amyloid (small phase 2 trial) - lecanemab (BAN2401) also targets beta-amyloid (small phase 2b trial) [77] - in phase II trial shows clearance of amyloid from the brain of Alzheimer's patients & cognitive benefits [60] - FDA-approved Jan 6, 2022 - gantenerumab targets A-beta (beta-amyloid) [70] - reduces amyldoid plaques & lowers CSF total tau & phosphorylated tau - no evidence of cognitive benefit - solanezumab targets A-beta [70] - does not slow cognitive decline in symptomatic patients or show benefit in Alzheimer markers - semorinemab targets microtubule-associated protein tau - does not slow progression of Alzheimer's disease [83] - anti-tau agents not likely to meaningfully slow cognitive impairment [85] 10) tau aggregation inhibitors - tau aggregation inhibitor hydromethylthionine mesylate (HMTM) improves cognition over 18 months in elderly with mild cognitive impairment [88] - tau aggregation inhibitor (LMTM) of no benefit in patients with mild-to-moderate Alzheimer's disease [56] 11) no benefit of intravenous immunoglobulin on cognition or function in patients with AD [57] 12) nicotine & its analogs may diminish deposition of Abeta in the entorhinal cortex [26] 13) cerebrolysin, a neuropeptide isolated from brain extracts, & its derivative N-PEP-12 may have benefit 14) docosahexaenoic acid (omega-3 fatty acid) does not slow decline of mild to moderate AD (2 g/day for 18 months) [43] 15) intranasal insulin not effective for AD or MCI [45] 16) phase 2A proof-of-concept clinical trial of bexarotene at Cleveland clinic Dec 2013, to treat patients with Alzheimer's disease (BEAT-AD) [5] 17) tramiprosate blocks aggregation of beta-amyloid monomers into toxic oligomers - gene-dose effect for APOE4 carriers - phase 4 trial [54] 18) edonerpic (T-817) of no benefit in patients with mild-to-moderate Alzheimer's disease 19) bryostatin (parenteral) tolerated in safety studies may show some cognitive benefits 20) 5HT6 receptor antagonist idalopirdine of no benefit alone or added to a cholinesterase inhibitor 21) ib drugs - nilotinib reduces CSF tau - safe & well-tolerated in patients with Alzheimer's disease - masitinib 22) sumifilam, a compound that binds to filamin improves biomarkers of AD, & may improve episodic memory & spatial working memory [65] 23) plasma exchange with albumin replacement may slow symptoms of AD [66] - plasmapheresis 2.5 to 3 liters of plasma weekly with fresh commercial albumin replacement - thought to remove amyloid beta bound to albumin from plasma [66] 24) sodium benzoate reported to have a 3 point benefit in the 70 point ADAS-Cog score but no change in behavior in women [69] - no cognitive or behavioral benefit in men [69] 25) hyperbaric oxygen therapy - 100% oxygen via a mask at twice atmospheric pressure for 90 min session reportedly improved global cognition & memory (although the improvement less than the sum of the standard deviations) [74] 26) bumetanide (Bumex) may have benefit in prevention & treatment of apoE4- related Alzheimer's disease [75] 27) sildenafil may reduce risk of Alzheimer's disease (RR=0.31) [78] 28) SAGE-718 reported to improve Montreal Cognitive Assessment scores (+2.3) within 4 weeks in patients with AD 29) drugs with noradrenergic activity used to treat ADHD may show a small positive effect on global cognition in patients with AD & a much larger effect on apathy [84] 30) suvorexant acutely decreases tau phosphorylation & amyloid-beta in human CNS [6] 31) intranasal empagliflozin/insulin ==== gene transfer studies in humans ==== - sterotactic injections of adenovirus vector (serotype 2) nerve growth factor (AAV2-NGF) into the nucleus basalis is safe & well-tolerated for 24 months but without affect on clinical outcomes or selected biomarkers (PET scan, MRI) [58] - greater but statistically insignificant worsening of cognition in gene transfer group vs sham control [58] ==== genomic analysis of the human proteome ==== - genomic analysis of the proteome from brain, CSF & plasma may identify drug targets for Alzheimer's disease [72] ==== sensory stimulation ==== - a device that delivers a combination of auditory & visual stimulations at a frequency of 40 Hertz (Hz) elicits gamma oscillation in the brain as recorded by EEG - beneficial effects in cognitive & functional abilities & a reduction in brain atrophy [79] ==== transcranial electromagnetic stimulation ==== - in-home bioengineered head device emitting electromagnetic waves worn for two 1-hour periods each day - allegedly reverses memory impairment in AD after 2 months [62] - 4+ point improvement in ADAS-cog score (70 point scale) - MRI evidence of changes in the cingulate cortex - CSF-tau & CSF-A-beta apparently changed - disaggregates both A-beta phospho-tau oligomers - induces brain mitochondrial enhancement - none of the 8 patients wanted to return their head device [62] - a specially designed helmet delivering near-infrared light to the brain may improve memory, motor function, & processing skills in cognitively intact healthy older adults [81] - 24 weeks of precuneus repetitive transcranial magnetic stimulation may slow down cognitive and functional decline in Alzheimer's disease [86] ==== low-intensity focused ultrasound ==== - MRI-guided low-intensity focused ultrasound with injected microbubbles to temporarily open the blood-brain barrier reduces beta-amyloid plaques & cognitive impairment in patients with mild Alzheimer's disease [73] - ability to transiently open the blood-brain barrier on demand safely facilitates new therapeutic strategies for treating brain disease - patients wear a helmet that has ultrasound probes - MRI is used to visualize areas of the brain with amyloid plaques. - ultrasound waves travel through the scalp & skull converging on the locations in the brain targeted with MRI with a high degree of plaques - tiny spherical microbubbles injected into the bloodstream oscillate in areas targeted with ultrasound, resulting in a transient opening of the blood-brain barrier - treatment takes ~2 hours - patients undergo 3 treatments, each 2 weeks apart. ==== plasma exchange ==== - plasma exchange with albumin replacement in patients with mild Alzheimer's disease showed improvement in memory, language abilities, processing speed, & quality of life [76] ==== other agents ==== - etanercept a recombinant protein that inhibits TNF-alpha of no benefit [52] - rationale: elevated TNF in CSF of patients with AD - elevated CSF TNF may lead to synaptic dysfunction - issue of blood-brain barrier (etanercept given SC) not addressed [52] - BACE1 inhibitor verubecestat does not reduce cognitive or functional decline in patients with mild-moderate AD [59] - sargramostim (GM-CSF) shows potential in small phase II trial [68] - cilostazol may help to preserve general cognitive function, including preservation in category fluency [87] ==== herbal therapy ==== - Huperzine A (Chinese traditional herb) - contains cholinesterase inhibitor(s) {not FDA approved, no published studies} [8] ==== gum disease ==== - Porphyromonas gingivalis is suggested as a potential pathogen of AD [80] === in silico === - machine learning to evaluate gene involvement in AD pathology produced a list of 15 FDA-approved drugs that might be repurposed to treat Alzheimer's disease; 5 are Janus kinase inhibitors [67]

Related

Alzheimer's disease (AD) guidelines for Alzheimer's disease management prevention of Alzheimer's disease/dementia

General

investigational/experimental therapy

References

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