Sex differences in the clinical manifestations of Alzheimer disease pathology

Context: Sex differences in risk of clinically diagnosed Alzheimer disease (AD) have been studied extensively, but little is known about the relation of the pathologic indices of AD to the clinical manifestations of the disease in men compared with women. Objective: To test whether the relation of AD pathology to the clinical manifestations of the disease differs in men and women. Design: Longitudinal, clinicopathologic cohort study Participants and Setting: Analyses were conducted on 141 older Catholic clergy members who underwent detailed annual clinical evaluations and brain autopsy at death. The number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm(2) area sampled from 4 cortical regions was counted, and a global measure of AD pathology (range, 0-2.98 U) and specific measures of each pathology were derived. Main Outcome Measures: Clinical diagnosis of probable AD and level of global cognitive function at the last evaluation before death. Results: Women had more global AD pathology than did men (P=.04), due primarily to more neurofibrillary tangles (P=.02). At the last evaluation before death, 57 persons met clinical criteria for probable AD (34 [60%] of them women). In logistic regression models, sex was not related to odds of clinical AD (odds ratio [OR], 1.35; 95% confidence interval [CI], 0.56-3.25), but the relation of global AD pathology to clinical diagnosis differed for men and women. Each additional unit of AD pathology was associated with a nearly 3-fold increase in the odds of clinical AD in men (OR, 2.82; 95% CI, 1.03-7.65) compared with a more than 20-fold increase in the odds of clinical AD in women (OR, 22.67; 95% Cl, 5.11-100.53). Results were unchanged after controlling for potential confounders or using level of cognition as the outcome. Conclusion: These data suggest that AD pathology is more likely to be clinically expressed as dementia in women than in men.