Higher Tau Levels Linked to Faster Cognitive Decline in Women Than Men: Meta-Analysis
USA: A large meta-analysis published in Alzheimer’s & Dementia has found that elevated tau accumulation in the temporal lobes predicts more rapid cognitive decline in women than in men, highlighting important sex-based differences in Alzheimer’s disease progression. The study was led by Annie Li, MD, from the Department of Neurology at Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues.
Tau protein, which forms neurofibrillary tangles in the brain, is a hallmark of Alzheimer’s disease alongside beta-amyloid plaques. Previous research has shown that women are disproportionately affected by Alzheimer’s disease and often exhibit greater regional tau deposition on imaging and postmortem examination. However, whether tau burden translates differently into cognitive decline between sexes—particularly before symptoms emerge—has remained uncertain.
To address this gap, the researchers conducted a longitudinal meta-analysis combining data from three well-characterized cohorts. The analysis included 1,007 cognitively unimpaired adults aged 46 to 93 years, of whom 648 (64%) were women. Approximately 39% carried the apolipoprotein E (APOE) ε4 allele, a known genetic risk factor for Alzheimer’s disease. Participants underwent tau PET imaging and amyloid beta PET scans using F-18 flortaucipir or F-18 MK-6240 tracers. Cognitive performance was tracked over an average of 8.6 years.
Using linear mixed-effects models incorporating sex-by-tau-by-time interactions, followed by random-effects meta-analysis, the investigators examined how tau levels influenced cognitive trajectories.
The following were the key findings:
- Higher tau standardized uptake value ratios (SUVRs) in medial and lateral temporal regions were associated with significantly faster cognitive decline in women compared with men.
- Women exhibited greater tau accumulation than men in four key regions involved in early and later stages of tau spread: the parahippocampal gyrus (β = −0.1), fusiform gyrus (β = −0.08), inferior temporal gyrus (β = −0.09), and middle temporal gyrus (β = −0.06).
- Across all three cohorts, higher temporal tau burden consistently translated into a greater cognitive impact in women than in men.
- At lower tau levels, women initially outperformed men on cognitive assessments.
- As tau accumulation increased, the early cognitive advantage observed in women diminished and eventually reversed, leading to a more pronounced decline.
- The observed sex differences remained significant even after adjusting for amyloid burden, indicating that tau pathology independently exerts a stronger cognitive effect in women.
The authors noted that only one smaller prior study has explored sex-based differences in tau-related cognitive decline during the preclinical stage of Alzheimer’s disease. The present study’s strengths include its large sample size, multicohort design, and long-term follow-up.
The findings have important implications for precision medicine. According to the researchers, incorporating sex-specific patterns of tau accumulation into risk assessment and therapeutic planning may help refine the timing and targeting of disease-modifying treatments. They concluded that further research is needed to clarify the biological mechanisms underlying women’s heightened vulnerability to tau-associated cognitive deterioration and to determine whether similar sex differences emerge as tau continues to accumulate.
Reference:Li A, Klinger HM, Seto M, Birkenbihl C, Properzi MJ, Farrell M, Thibault E, Schultz AP, Townsend DL, Cuppels M, Brown JA, Papp KV, Amariglio RE, Yang HS, Donohue MC, Rissman RA, Betthauser TJ, Langhough RE, Jonaitis EM, Cody K, Johnson SC, Rentz DM, Johnson KA, Sperling RA, Buckley RF, Coughlan GT; A4 Study Team. Elevated temporal tau PET predicts faster cognitive decline in women than men: A meta-analysis. Alzheimers Dement. 2026 Feb;22(2):e71031. doi: 10.1002/alz.71031. PMID: 41705602; PMCID: PMC12914651.
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