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% CI 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% CI 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% CI 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR=4.21; 95% CI 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.