A large-scale analysis of brain scans taken over time has found that men’s brains shrink faster than women’s across a broader range of regions during healthy aging yet the researchers concluded this pattern is unlikely to account for why women develop Alzheimer’s disease at nearly twice the rate of men.
The sex disparity in Alzheimer’s diagnosis has long puzzled researchers. Women make up roughly two-thirds of Alzheimer’s patients worldwide. One prominent hypothesis has been that women’s brains age structurally faster, leaving them more vulnerable to neurodegeneration. Testing that hypothesis required a study large enough, and long enough, to track real brain changes across the full adult lifespan in both sexes under comparable conditions.
Prior research had established that the brain loses volume and cortical thickness gradually across adulthood, with the pace accelerating in later decades. But most earlier work was limited either by sample size, by relying on single time-point scans rather than tracking the same individuals over time, or by failing to account for the considerable difference in average head size between men and women โ a factor that can distort volume comparisons if left unadjusted.
Researchers led by Anne Ravndal at the University of Oslo pooled MRI data from 14 international research cohorts, ultimately analyzing 12,638 longitudinal scans from 4,726 cognitively healthy participants ranging in age from 17 to 95. Because participants were scanned more than once, the team could measure actual change within individuals rather than inferring change by comparing different people at different ages.
The analysis examined 85 separate structural brain measures including cortical thickness, surface area, and subcortical volumes โ covering regions distributed across the whole brain. Statistical models controlled for intracranial volume (head size), education level, and other relevant variables. In a separate set of analyses, the team additionally adjusted for estimated remaining life expectancy, to account for the fact that women live longer on average.
Of the 85 brain measures examined, 17 โ or roughly 20% โ showed significantly steeper rates of decline in men compared to women. No comparable cluster of measures showed faster decline in women.
Cortical thickness: Men showed greater annual reductions in cortical thickness in four regions: the cuneus, lingual gyrus, parahippocampal cortex, and pericalcarine cortex. These areas are involved in visual processing, memory, and spatial orientation. The pericalcarine cortex โ the brain’s primary visual area โ declined at approximately 0.24% per year in men versus 0.14% per year in women. The postcentral cortex, associated with touch and body sensation, declined at about 0.20% per year in men compared to 0.12% in women.
Surface area: Men showed greater surface area loss in the fusiform and postcentral regions. Women showed greater surface area decline in one region only: the banks of the superior temporal sulcus.
Subcortical volumes: Among adults over 60, men experienced more pronounced volume loss in four subcortical structures โ the caudate, nucleus accumbens, putamen, and pallidum โ which are involved in movement, motivation, and reward processing.
Global measures: Total brain volume, overall gray matter, and white matter each declined more steeply in men. Women showed greater ventricular expansion in older age, meaning the fluid-filled spaces within the brain enlarged more in women โ a pattern that typically accompanies surrounding tissue loss.
Brain changes occurred gradually across adulthood in both sexes, but the pace of decline accelerated noticeably after age 60.
Despite finding that men’s brains decline faster across more regions, the team concluded that these sex differences in healthy structural aging do not support the hypothesis that faster female brain aging underlies women’s higher rates of Alzheimer’s disease. The pattern runs in the opposite direction: if anything, men’s brains showed the steeper structural decline.
The researchers pointed instead to several other possible explanations for women’s greater Alzheimer’s risk. These include hormonal changes associated with menopause, genetic factors โ particularly differing sensitivities to the APOE ฮต4 allele, a known Alzheimer’s risk gene โ greater female vulnerability to tau tangles and amyloid plaques (the hallmark proteins of Alzheimer’s pathology), and women’s longer average lifespan, which allows more time for disease to develop and be diagnosed.
The study was restricted to cognitively healthy individuals, so it does not directly measure what happens in the brain during or before the onset of Alzheimer’s disease. The adjustments made for life expectancy shifted some findings: when life expectancy was factored in, certain male disadvantages in cortical decline diminished, and greater hippocampal volume decline became more apparent in women โ a pattern potentially more relevant to Alzheimer’s risk. The study also cannot establish that any of the observed structural changes cause cognitive decline; the relationship between brain structure and cognition requires separate investigation. While pooling 14 international cohorts provides breadth, demographic and lifestyle variation across those cohorts may introduce heterogeneity the models did not fully capture.
Reference:
Ravndal, A., Fjell, A. M., et al. (2025). Sex differences in healthy brain aging are unlikely to explain higher Alzheimerโs disease prevalence in women. Proceedings of the National Academy of Sciences (PNAS), 122(41), e2510486122.
