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We examined how long‐term anticholinergic (AC) drug use beginning at midlife affects risk of Alzheimer's disease (AD) and rates of brain atrophy in cognitively normal older adults.    Methods  We followed 723 individuals (mean baseline age 52.3 years; mean follow‐up interval 20.1 years) in the Baltimore Longitudinal Study of Aging. The AC drug exposure was defined using the Anticholinergic Cognitive Burden Scale: Nonusers ( n  = 404), as well as participants exposed to medications with AC activity but without known clinically relevant negative cognitive effects (i.e., “possible AC users”;  n  = 185) and those exposed to AC drugs with established and clinically relevant negative cognitive effects (i.e., “definite AC users”;  n  = 134). The neuroimaging sample included 93 participants who remained cognitively normal through follow‐up and underwent serial magnetic resonance imaging ( n  = 93, 724 brain scans, mean follow‐up interval 8.2 years, and baseline age 68.6 years).    Results  Possible AC users, but not definite AC users, showed increased risk of incident AD compared with nonusers (hazard ratio, 1.63; 95% confidence interval, 1.02–2.61;  P  = .04) and greater rates of atrophy in total cortical gray matter volume compared with nonusers (β = −0.74,  P  = .018). Faster rates of brain atrophy were also observed among possible AC users in the right posterior cingulate, as well as right middle frontal and left superior temporal gyri. Data on frequency and duration of medication use were available in only approximately half of the sample. Among these participants, definite AC users had both shorter duration and lower frequency of medication use relative to possible AC users.    Discussion  Long‐term exposure to medications with mild AC activity during midlife is associated with increased risk of AD and accelerated brain atrophy.

Midlife anticholinergic drug use, risk of Alzheimer's disease, and brain atrophy in community‐dwelling older adults