Influence of sex on tau distribution across Braak stages in the Alzheimer's disease spectrum

Sex differences in Alzheimer's disease (AD) phenotypes have been consistently documented across epidemiological, clinical, and neuropathological studies. Females account for about two-thirds of AD cases worldwide, a disparity not fully explained by life expectancy. Emerging evidence suggests that biological sex influences disease onset, progression, and neuropathological burden, including amyloid-beta deposition, tau pathology, and neurodegeneration. ¹

Tau protein aggregation and neurofibrillary tangle formation are central to AD pathogenesis, correlating strongly with cognitive decline. ² Braak staging provides a framework for mapping tau pathology progression, beginning in the transentorhinal region and advancing through limbic and neocortical areas. While amyloid-β accumulation often precedes tau pathology, tau burden is more closely linked to clinical symptoms and functional impairment. Recent advances in tau-PET imaging have enabled in vivo quantification of tau deposition, offering unprecedented insights into underlying disease processes. ³

It has been shown that females with mild cognitive impairment (MCI) exhibit the highest brain inter-region network density and highest closeness centrality compared to other clinical groups. This can be interpreted as a network characteristic that favors accelerated brain-wide tau spread. This accelerated spread could consequently lead to the observed higher neocortical tau standardized uptake value ratios in females, particularly at the MCI stage. ⁴

In this relevant study, Wang et al. leveraged a tau-PET imaging dataset within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to examine sex-specific patterns of tau propagation across Braak stages ⁵ (Figure 1). Their analysis incorporated cognitive performance and amyloid status, providing a multidimensional view of disease progression. The findings revealed that females exhibit faster tau spread and accelerated clinical decline during advanced Braak stages compared to males. This observation aligns with recent reports suggesting that females may experience more rapid cognitive deterioration once symptomatic, despite having an even lower amyloid burden. ⁶

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Figure 1.

Simplified schematics of the original clinical design from the study “Sex-specific patterns in tau spreading throughout the Braak stages in the Alzheimer's Disease Spectrum” by Wang et al., 2026. ⁵

Several mechanisms may account for these sex-related disparities: hormonal factors, particularly estrogen depletion during menopause, have been implicated in heightened vulnerability to tau pathology.^7,8 While estrogen may exert neuroprotective effects through antioxidant properties, modulation of synaptic plasticity, and regulation of tau phosphorylation, the loss of these protective influences may accelerate tau aggregation in females during their postmenopausal age. ⁹ Furthermore, 17β-estradiol has been shown to increase total tau and induce dephosphorylation at the proline-directed site of the molecule in vitro models. ¹⁰ Moreover, estradiol prevented okadaic acid-induced tau hyperphosphorylation, an effect that was sexually dimorphic in rodents’ cortical neurons. ¹⁰

Additionally, genetic factors such as apolipoprotein (APOE) ε4 allele status interact with sex to influence disease risk and progression. Females carrying APOE ε4 exhibit disproportionately higher risk and faster cognitive decline compared to male carriers, suggesting a synergistic effect between sex and genotype. Furthermore, studies have indicated that the interaction effect between APOE ε4 and amyloid-β, rather than their independent effects, is related to increased tau load in AD-vulnerable regions. ¹¹ In addition, other important factors, including neurodevelopmental organizational differences and the female verbal memory advantage, need to be also considered. ¹²

Although this study offers valuable insights into the role of sex in AD progression, it also warrants cautious interpretation. Neuroimaging-pathology discordance remains a challenge; tau-PET signal may not perfectly reflect histopathological burden, particularly in early stages where the tau levels are low, similar to frontotemporal degeneration (FTLD) cases with atypical tau pathology. ¹³ As an example, histopathological studies have shown overlaps between Tau-PET signals and specific FTLD tau markers. ¹⁴ Moreover, coexisting neurodegenerative co-pathologies may also confound imaging and clinical outcomes.^15,16 However, tau PET in FTLD remains relatively nascent, and histopathological studies examining sex differences in tau pathology are still lacking.

Another limitation concerns the demographic composition of the ADNI cohort, which lacks substantial racial and ethnic diversity. This restricts the generalizability of findings across populations and may obscure interactions between sex, genetics, and sociocultural factors. Socioeconomic status, education, and lifestyle behaviors also intersect with sex to shape disease trajectories, underscoring the importance of inclusive research designs. ¹⁷ Without addressing these gaps, precision medicine initiatives risk perpetuating health disparities rather than mitigating them.

Despite these limitations, the findings underscore the importance of incorporating sex as a biological variable in AD research and clinical practice. Accelerated tau propagation in females suggests that sex-specific risk stratification may enhance early detection and intervention strategies. Precision medicine approaches, integrating genetic, hormonal, and imaging biomarkers, could enable timely, individualized therapies aimed at slowing disease progression.

Future research should prioritize longitudinal, multi-ethnic cohorts to validate sex-specific patterns of tau propagation and clinical decline. Advanced imaging techniques, combined with fluid biomarkers such as phosphorylated tau and neurofilament light chain, may further refine our understanding of neuroimaging-pathology relationships. Investigating interactions between sex hormones, genetic risk factors, and environmental exposures will illuminate mechanistic pathways driving differential disease trajectories. Furthermore, computational modeling of tau spread, informed by sex-specific biological parameters, could improve predictive accuracy and guide therapeutic development. ¹⁸

Consistent with the findings of Wang et al., which suggest that females may experience faster tau spreading and disease progression at more advanced stages, future studies should adapt their clinical designs accordingly when incorporating tau-PET. These designs should account for the influence of sex on disease evolution, as this has important implications for both diagnosis and treatment. As such, evidence from recent preclinical tau-PET longitudinal studies suggests that sex differences are increasingly recognized. ¹⁹ Ultimately, translating these insights into clinical practice requires robust evidence to inform personalized diagnostic criteria, therapeutic targets, and care models. By embracing sex as a critical determinant of AD pathophysiology, researchers and clinicians can move toward a more nuanced understanding of disease heterogeneity, paving the way for interventions that are not only effective but equitable. Therefore, a comprehensive understanding of sex-related variations in disease phenotypes will play a critical role in shaping precision medicine for AD. ²⁰ Integrating individualized, multimodal, biomarker-driven, and sex-conscious approaches to prevention, detection, therapeutic development, and clinical care will expand future research.