Sex differences in Alzheimer’s disease and common neuropathologies of aging

Abstract

Alzheimer’s dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer’s disease (AD) and other brain pathologies. We leveraged post mortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two thirds of subjects were women (n=971; 67%), with a mean age-at-death of 89.8 (SD=6.6) years in women and 87.3 (SD=6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate=0.102, SE=0.022, p<0.001), and tau tangle density in particular (estimate=0.334, SE=0.074, p<0.001), and there was a borderline difference between women and men in amyloid-β load (estimate=0.124, SE=0.065, p=0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR=1.28, 95% CI:1.04–1.58, p=0.018), and less likely to have gross infarcts (OR=0.78, 95% CI:0.61–0.98, p=0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of ageing.

Amyloid, Vascular, and Resilience Pathways Associated with Cognitive Aging

“…Sex differences in amyloid deposition have been inconsistent in the literature. Here, we found that females had slightly greater amyloid ( p = 0.045) in comparison to males, which is consistent with the borderline findings in a large postmortem study . Our group and others have shown that amyloid burden at baseline was associated with greater rate of cognitive decline and increased risk of dementia …”

“…Here, we found that females had slightly greater amyloid (p = 0.045) in comparison to males, which is consistent with the borderline findings in a large postmortem study. 43 Our group and others have shown that amyloid burden at baseline was associated with greater rate of cognitive decline and increased risk of dementia. 2,3,[44][45][46][47] The growth curve modeling approach allowed us to observe 2 phenomena with respect to the amyloid pathway and cognitive decline.…”

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

“…Sex difference is becoming focused in AD research field. 25,26 A new cohort with increased samples will help us to understand the effects of sex on outcomes. We could not measure blood glucose levels during the course of our study until 18 months of age, because any stressful or invasive procedure might have impacts on lifespan of our mice.…”

Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease

“… Abstract Sex differences in the manifestations of Alzheimer’s disease (AD) are under intense investigations 1,2 . Despite the emerging importance of polygenic predictions for AD 3–8 , the sex-dependent polygenic effects have not been demonstrated.…”

“…Evidence on sex-dependent clinicopathological progressions of Alzheimer’s disease (AD) is just beginning to emerge 2 . Compared to men, women show later manifestation of verbal memory deficits 10 , faster decline after disease onset 11 , and some differences in neuropathological characteristics, such as tau tangle density 1,12 . Results from studies on incidence rate and prevalence are less consistent 13,14 , yet women are often reported to have increased incidence of AD in older ages 15 and higher prevalence 16 .…”