Men’s brains shrink faster with age, deepening an Alzheimer’s mystery

A new large-scale brain imaging study suggests that the normal process of aging does not affect female brains more severely than male brains. In fact, the findings indicate that men tend to experience slightly greater age-related decline in brain structure, a result that challenges the idea that brain aging patterns explain the higher prevalence of Alzheimer’s disease in women. The research was published in the Proceedings of the National Academy of Sciences.

Alzheimer’s disease is a progressive neurodegenerative condition that impairs memory and other essential cognitive functions. It is the most common cause of dementia, and women account for a significant majority of cases worldwide. Because advancing age is the single greatest risk factor for developing Alzheimer’s, researchers have long wondered if sex-based differences in how the brain ages might contribute to this disparity.

Previous studies on this topic have produced mixed results, with some suggesting men’s brains decline faster and others indicating the opposite. To provide a clearer picture, an international team of researchers led by scientists at the University of Oslo set out to investigate this question using an exceptionally large and diverse dataset. They aimed to determine if structural changes in the brain during healthy aging differ between men and women, and if any such differences become more pronounced with age.

“Women are diagnosed with Alzheimer’s disease more often than men, and since aging is the main risk factor, we wanted to test whether men’s and women’s brains change differently with age. If women’s brains declined more, that could have helped explain their higher Alzheimer’s prevalence,” said study author Anne Ravndal, a PhD candidate at the University of Oslo.

To conduct their investigation, the researchers combined data from 14 separate long-term studies, creating a massive dataset of 12,638 magnetic resonance imaging (MRI) scans from 4,726 cognitively healthy participants. The individuals ranged in age from 17 to 95 years old. The longitudinal nature of the data, with each person being scanned at least twice over an average interval of about three years, allowed the team to track brain changes within individuals over time.

Using this information, they measured changes in several key brain structures, including the thickness and surface area of the cortex, which is the brain’s outer layer responsible for higher-level thought.

The analysis began by examining the raw changes in brain structure without any adjustments. In this initial step, the team found that men experienced a steeper decline than women in 17 different brain measures. These included reductions in total brain volume, gray matter, white matter, and the volume of all major brain lobes. Men also showed a faster thinning of the cortex in visual and memory-related areas and a quicker reduction in surface area in other regions.

Recognizing that men typically have larger heads and brains than women, the researchers performed a second, more nuanced analysis that corrected for differences in head size. After this adjustment, the general pattern held, though some specifics changed. Men still showed a greater rate of decline in the occipital lobe volume and in the surface area of the fusiform and postcentral regions of the cortex. In contrast, women only exhibited a faster decline in the surface area of a small region within the temporal lobe.

The findings were in line with the researchers expectations: “Although earlier studies have shown mixed findings, especially for cortical regions, our results align with the overall pattern that men show slightly steeper age-related brain decline,” Ravndal told PsyPost. “Still, it was important to demonstrate this clearly in a large longitudinal multi-cohort sample covering the full adult lifespan.”

The study also revealed age-dependent effects, especially in older adults over 60. In this age group, men showed a more rapid decline in several deep brain structures, including the caudate, nucleus accumbens, putamen, and pallidum, which are involved in motor control and reward. Women in this age group, on the other hand, showed a greater rate of ventricular expansion, meaning the fluid-filled cavities within the brain enlarged more quickly.

Notably, after correcting for head size, there were no significant sex differences in the rate of decline of the hippocampus, a brain structure central to memory formation that is heavily affected by Alzheimer’s disease.

The researchers also conducted additional analyses to test the robustness of their findings. When they accounted for the participants’ years of education, some of the regions showing faster decline in men were no longer statistically significant.

Another analysis adjusted for life expectancy. Since women tend to live longer than men, a man of any given age is, on average, closer to the end of his life. After accounting for this “proximity to death,” several of the cortical regions showing faster decline in men became non-significant, while some areas in women, including the hippocampus in older adults, began to show a faster rate of decline. This suggests that differences in longevity and overall biological aging may influence the observed patterns.

“Our findings add support to the idea that normal brain aging doesn’t explain why women are more often diagnosed with Alzheimer’s,” Ravndal said. “The results instead point toward other possible explanations, such as differences in longevity and survival bias, detection and diagnosis patterns, or biological factors like APOE-related vulnerability and differential susceptibility to pathological processes, though these remain speculative.”

The study, like all research, has some caveats to consider. The data were collected from many different sites, which can introduce variability. The follow-up intervals for the brain scans were also relatively short in the context of a human lifespan. A key consideration is that the participants were all cognitively healthy, so these findings on normal brain aging may not apply to the changes that occur in the pre-clinical or early stages of Alzheimer’s disease.

It is also important to that although the study identified several statistically significant differences in brain aging between the sexes, the researchers characterized the magnitude of these effects as modest. For example, in the pericalcarine cortex, men showed an annual rate of decline of 0.24% compared to 0.14% for women, a difference of just one-tenth of a percentage point per year.

“The sex differences we found were few and small,” Ravndal told PsyPost. “Importantly, we found no evidence of greater decline in women that could help explain their higher Alzheimer’s disease prevalence. Hence, if corroborated in other studies, the practical significance is that women don’t need to think that their brain declines faster, but that other reasons underlie this difference in prevalence.”

Future research could explore factors such as differences in longevity, potential biases in how the disease is detected and diagnosed, or biological variables like the APOE gene, a known genetic risk factor that may affect men and women differently.

“We are now examining whether similar structural brain changes relate differently to memory function in men and women,” Ravndal said. “This could help reveal whether the same degree of brain change has different cognitive implications across sexes.”

The study, “Sex differences in healthy brain aging are unlikely to explain higher Alzheimer’s disease prevalence in women,” was authored by Anne Ravndal, Anders M. Fjell, Didac Vidal-Piñeiro, Øystein Sørensen, Emilie S. Falch, Julia Kropiunig, Pablo F. Garrido, James M. Roe, José-Luis Alatorre-Warren, Markus H. Sneve, David Bartrés-Faz, Alvaro Pascual-Leone, Andreas M. Brandmaier, Sandra Düzel, Simone Kühn, Ulman Lindenberger, Lars Nyberg, Leiv Otto Watne, Richard N. Henson, for the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (AIBL), the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Kristine B. Walhovd, and Håkon Grydeland.