Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition

Abstract

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy. Another element of uncertainty is that the majority of studies have lacked neuropathological confirmation of the AD diagnosis. We compared clinical and pathological AD severity in 1028 deceased subjects with full neuropathological examinations. The age of dementia onset did not differ by gender but females were more likely to proceed to very severe clinical and pathological disease, with significantly higher proportions having a Mini-Mental State Examination score of 5 or less and Braak stage VI neurofibrillary degeneration. Median neuritic plaque densities were similar in females and males with AD but females had significantly greater tangle density scores. In addition, we found that AD-control brain weight differences were significantly greater for females, even after adjustment for age, disease duration, and comorbid conditions. These findings suggest that when they are affected by AD, females progress more often to severe cognitive dysfunction, due to more severe neurofibrillary degeneration, and greater loss of brain parenchyma.

Keywords: Amyloid plaque; Brain weight; Cognition; Neuritic plaque; Neurofibrillary tangle; Phosphorylated tau.

FIGURE 1

Distribution of neurofibrillary degeneration severity by Braak stage. A higher proportion of females (black) were classified as having the highest (stage VI) Braak neurofibrillary stage (**p < 0.001). A higher proportion of males (gray) were classified as having the lowest (stage I) nonzero stage (*p < 0.05).

FIGURE 2

Brain weights in males and females, subdivided by having Alzheimer disease (AD) or no dementia, by age. The differences between AD and control brain weights, within females and males, are maintained in a fairly uniform way across different ages. There is no suggestion of an increasing gap between AD and controls with increasing age, as might be expected if there were an AD-aging synergy acting upon brain atrophy.

FIGURE 3

Mini-Mental State Examination (MMSE) scores distribution. A higher proportion of females (black) had very severe cognitive impairment as defined by MMSE scores of 5 or less (*p < 0.05). All other paired comparisons are not significantly different.