Neuroimaging Alzheimer’s Disease Through a Sex-Specific Lens: Implications for Women’s Brain Health

Background/Objectives: Alzheimer’s disease (AD) disproportionately affects women, who account for nearly two-thirds of affected individuals worldwide. This sex imbalance cannot be explained by longevity alone and likely reflects complex interactions among biological sex, endocrine aging, genetic susceptibility, and brain-specific mechanisms of vulnerability. Neuroimaging has played a pivotal role in characterizing these sex-related differences in vivo, enabling the assessment of amyloid-β deposition, tau propagation, neurodegeneration, cerebral glucose metabolism, and network reorganization. This invited review examines AD through a rigorously sex-specific neuroimaging perspective, with particular emphasis on implications for women’s brain health. Methods: We integrated evidence from structural MRI, FDG-PET, amyloid-PET, tau-PET, estrogen receptor PET, diffusion MRI, and fluid biomarkers, together with epidemiological, molecular, genetic, and endocrine studies. The review focuses on female-specific trajectories of AD initiation and progression, highlighting the contribution of neuroendocrine aging, menopause, metabolic dysfunction, and sex-modulated genetic risk factors. Results: Available evidence indicates that women exhibit distinct biological and neuroimaging signatures across the AD continuum. Menopause emerges as a critical neuroendocrine transition associated with metabolic decline, altered brain connectivity, increased amyloid and tau vulnerability, and progressive neurodegeneration. Female-specific patterns of tau propagation and sex-dependent interactions with genetic risk factors further contribute to differential disease trajectories. Advanced multimodal neuroimaging approaches have substantially improved the characterization of these mechanisms and their relationship with cognitive decline and clinical progression. Conclusions: A sex-specific neuroimaging framework is essential to improve understanding of AD pathophysiology and to advance precision medicine approaches tailored to women’s brain health. Recognition of endocrine aging and female-specific biological vulnerability may inform earlier identification of at-risk individuals and the development of targeted prevention and treatment strategies. Future research should prioritize sex-aware longitudinal studies and multimodal biomarker integration to optimize personalized interventions in AD.