Abstract
Background: Alzheimer’s disease (AD) is the leading cause of dementia, defined by amyloid plaques and neurofibrillary tangles. Yet, variability in disease onset and progression cannot be explained solely by pathology. Neuroplasticity, the brain’s ability to reorganize and adapt, is increasingly recognized as central to resilience in AD, with compelling evidence that it differs between sexes.
Objective: This paper evaluates sex differences in neuroplasticity in AD, focusing on neuropathology, hormonal regulation, and genetic interactions, while highlighting translational and societal implications.
Content summary: Evidence demonstrates that women, especially carriers of the APOE ε4 allele, experience greater hippocampal atrophy, impaired synaptic connectivity, and accelerated decline relative to men. Estrogen promotes synaptic plasticity and neurogenesis; its decline during menopause coincides with increased vulnerability, compounded by rises in follicle-stimulating and luteinizing hormones. Genetic factors, including sex-specific APOE ε4 effects, estrogen receptor interactions, and epigenetic regulation, further amplify risk in women. Despite robust molecular and imaging evidence, inconsistencies persist due to small samples, limited diversity, and reliance on insensitive cognitive measures.
Conclusions: Neuroplasticity in AD is profoundly shaped by sex. Women bear a disproportionate burden due to hormonal decline and genetic vulnerabilities, yet plasticity also represents a reservoir for resilience. Recognizing sex as a biological variable is essential for refining diagnostics, tailoring therapies, and advancing equitable health policy. Future studies must adopt longitudinal, sex-aware designs and integrative approaches to drive precision medicine in AD.
Keywords
Alzheimer’s disease, Neuroplasticity, Sex differences, Estrogen, APOE ε4, Hippocampal atrophy