Sex Differences in Alzheimer’s Disease: Life-Course Modifiers of Biomarker Coupling, Vulnerability, and Therapeutic Response

Alzheimer's disease (AD) is increasingly recognized as a heterogeneous disorder in which biological sex may modify not only disease risk, but also the clinical meaning of pathology across the disease continuum.Although women bear a greater AD burden, sex differences are not explained by longevity alone and should not be interpreted as uniform differences in susceptibility.Here, we propose a life-course coupling framework in which biological sex is viewed not as a uniform risk factor.Within this framework, sex may shape how amyloid, tau, glial activation, metabolic dysfunction, neurodegeneration, and cognition become linked across the AD continuum.Evidence from epidemiology, fluid and imaging biomarkers, genetics, transcriptomics, neuroinflammation, metabolism, and therapeutic trials supports this context-dependent interpretation.Accordingly, disease stage, genotype, hormonal history, biomarker profile, and cellular context should be considered together when interpreting sex-related differences.This framework may help explain inconsistent findings across studies and support more precise approaches to biomarker interpretation, trial design, and AD care.