Brain inflammation and activation of microglia are early pathological events in AD, and epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs: cyclooxygenase (COX)-1 and -2 inhibitors) may slow disease onset. Initial retrospective studies of patients with AD using indomethacin 42 showed a positive effect in reducing AD progress.54 However, prospective trials with NSAIDs, e.g., rofecoxib 43, celecoxib 44, and naproxen, failed to demonstrate efficacy in AD. Nonetheless, the COX-1 inhibitor, (R)-flurbiprofen 45, is in Phase III AD trials, despite limited benefit in a Phase II study. Nitroflurbiprofen (NCX-2216; 46), an NO-donating flurbiprofen derivative, with reduced gastrointestinal side effects, is also in Phase II trials in AD. In preclinical studies, nitroflurbiprofen reduced lipopolysaccharide-induced microglial activation and decreased both the microglial activation and the amount of Ab deposits in the brains of transgenic mice with familial AD mutations in the APP gene.55
In addition to their anti-inflammatory effects, NSAIDs may modulate amyloidogenic processing of APP via interactions with the peroxisome proliferator-activated receptor-g (PPAR-g).20 NSAIDs, e.g., indomethacin 42, activate PPAR-g, hence the interest in evaluating this target in AD. Pioglitazone 47, a PPAR-g agonist used in the treatment of type 2 diabetes, showed equivocal effects on Ab pathology in AD mouse models but clinical improvement was demonstrated with another PPAR-g agonist, rosiglitazone 48, in patients with mild AD or amnestic MCI.56
Dietary cholesterol affects the formation of Ab and accelerates the appearance of AD pathology in mouse models; high serum cholesterol and low high-density lipoprotein cholesterol levels are AD risk factors.57 Cholesterol-lowering agents, e.g., statins, are of interest as treatments for AD. These agents inhibit b-hydroxy-b-methyl glutaryl-CoA reductase, a key regulatory enzyme in the cholesterol biosynthetic pathway. Atorvastatin 49, evaluated in an intention-to-treat clinical trial, showed positive benefit in ADAS-cog performance at 6 months.58 An observational study of AD patients treated with lipid-lowering agents, 47% of which were statins, showed a positive benefit (i.e., slower decline) on the MMSE.59 Thus, with further study statins may become standard therapy.
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