An international team of researchers, led by Massachusetts General Hospital and Harvard Medical School, has conducted a meta-analysis revealing that women with high β-amyloid (Aβ) exhibit significantly faster tau accumulation in key brain regions compared to men. Findings suggest that sex differences in Alzheimer's disease (AD) pathology may influence treatment efficacy, prompting a need for sex-specific therapeutic strategies.

The paper is published in the journal JAMA Neurology.

Alzheimer's disease is nearly twice as prevalent in women compared to men, yet the biological mechanisms driving this disparity remain unclear. While both sexes show similar levels of Aβ burden, studies indicate that women may be more susceptible to tau pathology, a protein linked to neurodegeneration and cognitive decline.

Previous research has shown higher tau deposition in women through cross-sectional studies, but longitudinal evidence confirming whether women experience faster tau accumulation has been limited.

In the study, titled "Sex Differences in Longitudinal Tau-PET in Preclinical Alzheimer Disease: A Meta-Analysis," researchers performed a meta-analysis of longitudinal data from six major aging and Alzheimer's disease cohorts. The objective was to determine whether the female sex is associated with faster tau accumulation in the presence of high Aβ levels and to examine whether sex modifies the relationship between APOEε4 carrier status and tau accumulation.

Data was sourced from 1,376 participants across the Alzheimer's Disease Neuroimaging Initiative (ADNI), Berkeley Aging Cohort Study (BACS), BioFINDER 1 (BF-1), Harvard Aging Brain Study (HABS), Mayo Clinic Study of Aging (MCSA), and the Wisconsin Registry for Alzheimer Prevention (WRAP).

Participants had a mean age of 71.9 years, with 55% identifying as female. At baseline, 401 participants (29%) exhibited high Aβ levels, and 412 participants (30%) carried the APOEε4 allele. Longitudinal tau accumulation was measured using positron emission tomography.

Primary analyses focused on mixed-effects modeling to assess the relationship between sex, Aβ status, and tau accumulation over an average follow-up period of 2.8 years. Secondary analyses examined whether sex modified the association between APOEε4 carrier status and tau accumulation.

Among individuals with high Aβ, women showed significantly faster tau accumulation in specific brain regions compared to men. These accelerated accumulations were detected in the inferior temporal cortex, temporal fusiform gyrus, and lateral occipital cortex.

Women who carried the APOEε4 allele also experienced faster tau accumulation in the inferior temporal region. No significant differences were observed in other brain regions.

Findings indicate that sex differences in tau accumulation rates may contribute to the increased prevalence of Alzheimer's disease in women.

Elevated tau in women with high Aβ may accelerate disease progression, warranting sex-specific considerations in future therapeutic interventions. Further research is needed to explore the underlying biological mechanisms, including the role of hormones and genetic factors, in sex-specific AD pathology.

More information: Gillian T. Coughlan et al, Sex Differences in Longitudinal Tau-PET in Preclinical Alzheimer Disease, JAMA Neurology (2025). DOI: 10.1001/jamaneurol.2025.0013

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