A team from the Sant Pau Research Institute (IR Sant Pau) has conducted a comprehensive review of the impact of sex on the progression of genetically determined Alzheimer’s disease, including autosomal dominant Alzheimer’s disease (ADAD), Down syndrome-associated Alzheimer’s disease (DSAD), and APOE4 homozygosity. The study, published in Frontiers in Aging Neuroscience and led by Dr Laura del Hoyo, a Miguel Servet researcher in the Neurobiology of Dementia group at IR Sant Pau, concludes that while sex influences certain cognitive and structural aspects of the brain, its effects on disease progression are far less pronounced than in sporadic Alzheimer’s.
According to Dr del Hoyo, “Sexual dimorphism is one thing, but how sex impacts Alzheimer’s disease progression is another. In genetically determined Alzheimer’s, genetics play such a significant role that we do not see major differences between men and women in disease progression, unlike in the sporadic form.” However, the study identifies some exceptions that may be linked to differences in cognitive reserve.
The review examined studies analysing the impact of sex on three fundamental aspects defining genetically determined Alzheimer’s: disease penetrance (i.e., the proportion of individuals with a specific genetic mutation who develop the associated clinical symptoms), the age of symptom onset, and the clinical progression and evolution of key biomarkers such as amyloid accumulation, tau pathology, and neurodegeneration.
The results showed that in all forms of genetic Alzheimer’s, sex differences in these three aspects were subtle or non-existent, although some specific patterns emerged. In ADAD, the reviewed studies indicated that women in advanced disease stages exhibited greater neurodegeneration, with more pronounced cortical thinning and a reduction in hippocampal and amygdala volume compared to men. Despite these structural changes, their cognitive performance remained similar, suggesting that they may have greater cognitive reserve, which helps protect against pathological progression.
In the case of DSAD, the results were relatively different. Women carrying the APOE4 gene tended to develop dementia symptoms earlier than men with the same genetic predisposition. Additionally, this group showed higher amyloid accumulation and increased neurodegeneration compared to men. These findings contrast with observations in ADAD and APOE4 homozygosity, where no significant sex differences were found in disease progression.
“In Down syndrome, carrying APOE4 seems to have a greater impact on women than on men in terms of amyloid accumulation and neurodegeneration,” explains the researcher. However, she clarifies, “We cannot say that the effect of this gene is generally more detrimental in women than in men because we have not consistently observed this.”
One of the key findings of this review is that, unlike sporadic Alzheimer’s, where women show higher prevalence and faster disease progression, genetic Alzheimer’s follows more predictable patterns and is less influenced by sex. As Dr del Hoyo explains, “Genetics creates so much noise that the role of sex becomes diluted.” However, this does not mean that underlying differences do not influence how the disease manifests in each individual.
Sexual dimorphism is evident in aspects such as cognitive performance before disease onset. Women are generally better at verbal memory tasks, while men tend to perform better in visuospatial tasks. This is significant because it may mask early signs of decline in women, making early detection more challenging, as most diagnostic tools rely on language-dependent tests.
“If all the assessment tools we use rely heavily on language, we might be underestimating early deficits in women, as they have a pre-existing advantage in this domain,” warns the researcher. This testing bias could lead to later detection of symptoms in women, posing a challenge for research and clinical practice. In this regard, the study highlights the need to develop more balanced assessment tools that account for sex differences and enable more accurate and equitable detection of cognitive decline in the early stages of the disease.
Beyond the findings on genetic Alzheimer’s progression, the study emphasises the importance of continuing to investigate these differences using more refined methodologies. Longitudinal studies, which follow patients over time, are essential tools for better understanding the effects of sex on the disease. The need to diversify cognitive assessment methods is also highlighted, incorporating tests that do not rely solely on skills where one sex may have an initial advantage. Additionally, a new line of research is emerging on the role of hormones, particularly in Alzheimer’s in people with Down syndrome, as early menopause in women with this condition may influence disease progression.
One of the study’s key points is the importance of communicating results rigorously and avoiding bias in data interpretation. “There has been some ‘cherry-picking’ in gender studies, highlighting only findings where differences are observed and overlooking ‘null results’. But it is just as important to report when we do not find differences. Communicating ‘null results’ well is crucial for gender-sensitive research that is based on solid scientific evidence,” emphasises Dr del Hoyo.
This study represents a significant step forward in understanding the impact of sex on genetic Alzheimer’s and raises new questions about how to tailor diagnostic and treatment strategies to the individual characteristics of each patient. Although sex differences in disease progression are subtle, studying them could help improve accuracy in detection and the management of Alzheimer’s in populations with genetic predisposition.
Del Hoyo Soriano L, Wagemann O, Bejanin A, Levin J, Fortea J. Sex-related differences in genetically determined Alzheimer’s disease. Front Aging Neurosci 2025;17. https://doi.org/10.3389/fnagi.2025.1522434.
