EVALUATION OF HOW CIGARETTE SMOKE IS A DIRECT RISK FACTOR FOR ALZHEIMER'S DISEASE.

Cigarette smoking is a risk for Alzheimer's disease (AD), the pathological hallmark of which is amyloid-β (Aβ) brain deposits. We found the adjusted risk of AD was significantly increased among medium level smokers (RR = 2.56; 95% CI = 1.65-5.52), with an even higher risk in the heavy smoking group (RR = 3.03; 95% CI = 1.25-4.02). This systematic review and original data further support this association. We searched Pubmed, Google scholar, and PsyINFO for original population study articles, meta-analyses, and reviews published between 1987 and 2011. Some studies were excluded due to design flaws including survivor bias. We performed analyses of: 1) amyloid precursor protein (APP) processing in N2a cells overexpressing Swedish mutant APP (SweAPP N2a) exposed to cigarette smoke condensate (CSC), 2) microglial inflammatory response to CSC, and 3) CSC exposed microglial phagocytosis of Aβ(1-42). CSC significantly promotes neuronal Aβ generation, increases microglial IL-1β and TNF-α production, and decreases microglial Aβ(1-42) phagocytosis. The mechanism underlying the epidemiological association of cigarette smoking with AD might involve the effect of cigarette smoke on APP processing, a reduction of Aβ clearance by microglia, and/or an increased microglial proinflammatory response. In vivo studies are required to fully elucidate how cigarette smoke promotes AD.