Investigational Therapies For Treatment Of Alzheimer's Disease

From Anvita Health Wiki

Contents 1 Introduction 2 More General Terms 3 Additional Terms 4 References

Introduction

• in vitro studies

• certain NSAIDS diminish formation of Abeta42 [6,13,14]

• flurbiprofen, ibuprofen, mecofenamate indomethacin, sulindac, fenoprofen, & diclofenac do
• aspirin, naproxen, celecoxib don't
• inhibition via direct interaction with gamma-secretase [13,14]
• inhibition of Abeta42 formation in favor of Abeta38

• simvastatin alledgedly diminishes formation of Abeta42 formation [17] (also see statins & Alzheimer's disease)
• acetylcholinesterase may act as a nucleating factor to promote conversion of soluble amyloid peptide into insoluble amyloid fibrils [11]

• a peripheral site rather than the active site of the enzyme is though to mediate the interaction (based on X-ray crystallography)
• inhibition of this interaction is proposed as a target for pharmaceutical intervention

• disruption of amyloid beta-pleated sheets [12]
• linking Abeta with chaperone using a small bivalent molecule prevents aggregation of Abeta & eliminates Abeta toxicity [19]
• resveratrol promotes intracellular degradation of Abeta via a mechanisms involving the proteasome [24]
• 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]
• calorie restriction & resveratrol activate SIRT1, SIRT1 inhibits ROCK1, which in turn, increases APP alpha-secretase activity [34]

• studies in rodents

• immunization with Abeta42 or passive immunization with A-beta(1-42) antibodies

• protected mice genetically engineered to overproduce Abeta42 from developing amyloid plaques [1,2]
• attenuated learning defects associated with plaques [3]

• an inhibitor of acyl-cholesterol acyltransferase ( ACAT) reduces accumulation of amyloid plaques & Abeta levels in a mouse-model for Alzheimer's disease [20]
• inhibitors of diacylglycerol O-acyltransferase 1 ( DGAT1) enhance beta peptide & amyloid plaque removal in a mouse model for Alzheimer's disease
• curcumin diminishes amyloid in a mouse model for AD [27]
• DHA (omega-3) diminishes amyloid in a mouse model for AD [7]
• anti- oxidant 'cocktails' have been proposed [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]
• inositol 30 mg/kg/day reduces amyloid pathology & improves behavioral manifestations of Abeta aggregation in a transgenic mouse model for Alzheimer's disease [29]
• muscarinic M1 receptor agonist AF267B reduced Abeta & tau pathology in a 3xTg (transgenic) mouse model for AD, selective activation of ADAM17 reduced Abeta pathology & diminished GSK3beta diminished tau pathology [30]
• caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease [37]
• pomegranate juice decreases amyloid load & improves behavior in a mouse model of Alzheimer's disease [32]
• Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease [33]
• LRP-IV (an LRP1 fragment) clears amyloid in a mouse-model of Alzheimer's disease [35], no adverse effects reported
• valsartan clears beta-amyloid & improves spatial learning in a mouse model for AD [36], <not a feature of ARBs>
• BACE1 inhibitor tethered to sterol via polyglycol diminishes pathology in APP transgenic mice [38]
• electromagnetic field treatment at standard cell phone frequencies protects against & reverses cognitiv decline in a mouse model for AD (AbetaPPsw) [42]

• studies in humans

• HMG CoA reductase inhibitors (statins) [4]

• Alzheimer's Disease Cooperative Study ( ADCS)
• Sun Health Research Institute

• atorvastatin may be of some clinical benefit in mild to moderate Alzheimer's disease [21]

• PROSPER
• statins reduce 24-OH cholesterol, but < than reduction in LDL [16]
• also see statins & Alzheimer's disease statins & the risk of dementia (data NOT supportive)

• non-steroidal anti-inflammatory agents ( NSAIDs)

• epidemiologic studies associate NSAID use with diminished risk of AD [5]

• RR 0.27 for long-term users > 24 months [10]
• RR < 0.76 for long-terms users > 5 years [39]

• risk may be attenuated with certain NSAIDs, but not others [6,9] (see studies in rodents above)

• rofecoxib 25 mg/day of no benefit [9]
• naproxen 220 mg BID of no benefit [9,31]
• celecoxib 200 mg BID of no benefit [31]
• risk reduction greatest with ibuprofen & indomethacin [39], although inhibition of Abeta42 formation allegedly does not play a role [39]

• direct interaction of certain NSAIDs with gamma-secretase [13,14]

• see in vitro studies above
• no benefit of tarenflurbil (R-flubiprofen), a drug that inhibits gamma-secretase & formation of Abeta42 [41]

• no dose information available for NSAIDs that may be of benefit

• vitamins:

• combination of vitamin E & vitamin C may reduce the risk of Alzheimer's disease; RR = 0.22 for users > 5 years [18]
• combination of folate (5 mg), vitamin B6 (25 mg), & vitamin B12 (1 mg) of not benefit [40]
• vitamin B12 without folate or vitamin B6 might be of benefit [44]
• 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]

• antioxidant combination associated with greater cognitive decline than placebo ( MMSE, -2.8 vs. -0.9 points) & showed a trend toward greater functional deterioration
• no between-group differences or changes in Abeta-42, tau, or phosphorylated tau
• F2- isoprostanes decreased by 19% in the antioxidant combination group [46]

• clioquinol (metal chelator) in phase II clinical trial 3/02

• alledgedly withdrawn due to toxicity [7]

• Alzhemed in Phase 3 clinical trials (07/04)
• LY450139 in clinical trials (07/04)
• dimebon in Phase 3 trials (08/08)
• immunization with A-beta(1-42) [22,23]

• associated with meningoencephalitis (6%) [22]
• candidate biomarkers associated with risk of immunotherapy identified from microarray analysis using peripheral blood [22]

• nicotine & its analogs may diminish deposition of Abeta in the entorhinal cortex [26]
• cerebrolysin, a neuropeptide isolated from brain extracts, & its derivative N-PEP-12 may have benefit
• docosahexaenoic acid ( omega-3 fatty acid) does not slow decline of mild to moderate AD (2 g/day for 18 months) [43]
• intranasal insulin, promising phase 2 study [45]

• herbal therapy

• Huperzine A (Chinese traditional herb)

• contains cholinesterase inhibitor(s) {not FDA approved, no published studies} [8]

More General Terms

• investigational/experimental therapy

Additional Terms

• prevention of Alzheimer's disease

References

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investigational therapies for treatment of Alzheimer's disease