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Background: Statin use and serum cholesterol reduction have been proposed as preventions for dementia and mild cognitive impairment (MCI). Methods: 1604 and 1345 eligible participants from the Baltimore Longitudinal Study of Aging (BLSA) were followed after age 50 for a median time of around 25 years, to examine the incidence of dementia (n = 259) and MCI (n = 138), respectively. Statin use (ever-use and time-dependent use), total cholesterol levels (TC; first visit and time-dependent), TC change trajectory from first visit and high-density lipoprotein (HDL-C):TC ratio (first visit and time-dependent) were the main exposures of interest. Cox proportional hazards models were used. Results: Participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI, while first-visit TC was higher among statin ever-users compared with never-users (age-unadjusted associations). Statin users had a two-to threefold lower risk of developing dementia (HR = 0.41; 95% Cl 0.18 to 0.92), but not MCI, when considering time-dependent ‘statin use’ with propensity score model adjustment. This association remained significant independently of serum cholesterol exposures. An elevated first-visit TC was associated with reduced MCI risk (upper quartile (Q₄) vs Q₁: HR = 0.51; 95% Cl 0.29 to 0.90). Compared with the lowest quartile (Q₁: 0.00-0.19), HDL-C:TC (time-dependent) in (Q₂: 0.19-0.24) was associated with reduced MCI risk (HR = 0.58; 95% Cl 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR = 4.21; 95% Cl 1,28 to 13.85). Conclusions: Statins may have multifactorial effects on dementia but not MCI risk. Future interventions may be warranted, and research should focus on optimal serum TC, HDL-C:TC ratio and TC change trajectories. (PsycINFO Database Record (c) 2012 APA, all rights reserved). (journal abstract)

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