Your brain could be affected in different ways, depending on which of your parents had Alzheimer's. (Sergii Gnatiuk/Shutterstock)
Research shows men’s brains hit harder by memory-robbing disease, even with less tau protein
In a nutshell
- Women showed higher levels of tau, a toxic Alzheimer’s protein, but experienced less brain shrinkage over time, suggesting they may have biological resilience against some Alzheimer’s-related damage.
- People whose fathers had Alzheimer’s showed a stronger link between the brain’s amyloid and tau buildup, while those with a mother who had the disease appeared to maintain better memory despite similar protein levels.
- Your sex and whether your mother or father had Alzheimer’s may influence not just your risk, but how your brain responds to early signs of the disease, pointing to the need for more personalized prevention and treatment strategies.
MONTREAL — When it comes to Alzheimer’s disease, your family tree matters, but not in the way scientists thought. Your brain is keeping score of two crucial factors that might determine your Alzheimer’s risk: whether you’re a man or woman, and whether it was your mother or father who had the disease. Results from a decade-long Canadian study reveal women accumulate more of the toxic tau protein associated with Alzheimer’s yet show greater resistance to brain shrinkage, while paternal inheritance may pose greater risks than previously thought.
The study, published in Neurology, was conducted by a research team from McGill University. While the higher prevalence of Alzheimer’s in women has been previously documented, these new findings suggest much more complex biological mechanisms are at play.
The study followed 243 cognitively normal older adults with a family history of Alzheimer’s disease for 10 years, using advanced brain scanning techniques to track the buildup of two key proteins, beta-amyloid and tau, along with changes in brain volume and cognitive abilities. All participants had at least one parent with Alzheimer’s, making them all high-risk.
Women Show Greater Brain Resilience
Nearly 70% of participants were women, with an average age of 68. While researchers found no significant differences between men and women in amyloid buildup, the sticky plaques long considered the hallmark of Alzheimer’s, they observed major differences in tau accumulation.
Women had significantly higher levels of tau protein in their brains, particularly in frontoparietal regions affected in later stages of Alzheimer’s disease. Tau forms toxic tangles that directly damage neurons, and higher tau levels typically correlate with more severe cognitive decline.
Despite having more tau, women showed greater resistance to amyloid-related brain shrinkage over time. The hippocampus, crucial for memory, shrank less rapidly in women with high amyloid levels compared to men with similar amyloid burden.
This suggests women may possess some protective mechanisms that help preserve brain structure even as disease-related proteins accumulate. Scientists speculate hormonal differences or brain network variations might play a role, though the exact reason is still unclear.
Paternal History
Previous studies suggest that maternal Alzheimer’s inheritance carries greater risk than paternal. However, this study shows that individuals whose fathers had Alzheimer’s showed a stronger association between amyloid and tau accumulation than those whose mothers had the disease. In other words, having a father with Alzheimer’s might make you more vulnerable to the cascade of protein buildup that leads to neurodegeneration.
The study also found that people with maternal Alzheimer’s history showed greater cognitive resilience, maintaining memory function better despite amyloid buildup compared to those with paternal history. Different inheritance pathways might influence separate aspects of disease progression, with paternal history affecting protein accumulation while maternal history impacts how well the brain copes with those proteins.
Biological sex and parental history should be considered when developing personalized Alzheimer’s treatments, especially because clinical trials have historically struggled to show consistent effectiveness. Different responses between men and women, or between those with maternal versus paternal inheritance, might help explain why some treatments work better in for certain people.
For example, women might benefit from interventions focused on reducing tau accumulation, while those with paternal Alzheimer’s history might need earlier interventions to prevent the amyloid-tau cascade.
Alzheimer’s is not a one-size-fits-all disease. Factors like menopause, hormonal changes, and genetic inheritance patterns create different risk profiles that may require tailored approaches to prevention and treatment. Your sex and your parents’ medical history matter in ways we’re only beginning to understand.
Paper Summary
Methodology
The study examined 243 cognitively normal older adults (69.4% female, average age 68.3 years) from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) cohort in Canada. All participants had at least one parent with Alzheimer’s disease, making them at higher risk. Researchers used PET scans to measure beta-amyloid and tau protein in participants’ brains, along with MRI scans to assess hippocampal volume and cognitive tests to track memory and other cognitive functions. Participants were followed for up to 10 years, with 115 receiving follow-up PET scans approximately 4.4 years after baseline, 238 receiving follow-up MRI scans about 6.5 years after baseline, and 242 receiving follow-up cognitive assessments about 6.7 years after baseline. During the study period, 71 participants progressed to mild cognitive impairment.
Results
Women showed higher tau protein levels in frontoparietal brain regions but did not differ from men in amyloid levels. Women demonstrated a stronger association between amyloid and tau accumulation, suggesting greater vulnerability to Alzheimer’s-related protein spreading. However, women also showed less amyloid-related hippocampal shrinkage over time, indicating greater brain resilience. Contrary to expectations, individuals with a father with Alzheimer’s showed a stronger association between amyloid and tau accumulation than those with a mother with Alzheimer’s. However, individuals with maternal Alzheimer’s history demonstrated greater cognitive resilience, maintaining better memory function despite high amyloid levels compared to those with paternal history.
Limitations
The researchers acknowledge several limitations, including the reduced sample size for analyses comparing maternal versus paternal Alzheimer’s history, as they excluded participants with both parents affected (36 individuals) or those with multiple siblings with Alzheimer’s (10 individuals). The PREVENT-AD cohort also lacks diversity, with 98.8% of participants being White and having relatively high education levels, potentially limiting generalizability to broader populations. The study couldn’t fully explore the influence of vascular risk factors, which might contribute to Alzheimer’s pathology. The researchers also note that potential nonspecific binding in PET scanning might have influenced some sex-based differences observed.
Funding and Disclosures
The study was supported by the Canadian Institutes of Health Research, the Fonds de Recherche du Québec—Santé, the J.-Louis Lévesque Foundation, Brain Canada Foundation, and a joint Alzheimer’s Society Canada and Brain Canada Research grant. Lead author Valentin Ourry received support from a postdoctoral fellowship from the Fonds de Recherche du Québec—Santé. The authors reported no relevant financial disclosures.
Publication Information
The paper, titled “Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease: Role of Sex and Parent’s Sex,” was published in Neurology (Volume 104, Number 9) on May 13, 2025. The principal investigators were Valentin Ourry, Alfonso Fajardo-Valdez, Jean-Paul Soucy, Judes Poirier, John C.S. Breitner, and Sylvia Villeneuve, representing McGill University and the Douglas Mental Health University Institute in Montreal, Quebec, Canada.
