Alzheimer's disease does not affect men and women equally — women account for nearly two-thirds of all cases — yet most foundational research has treated sex as a footnote rather than a biological variable. An organized scientific effort to systematically address this disparity could reshape how the disease is understood, diagnosed, and treated across an aging global population.
Published in Nature Aging, this report introduces the Sex | Gender in Neurodegeneration (SIGN) Consortium, a coordinated research initiative designed to investigate how biological sex and sociocultural gender independently and jointly influence Alzheimer's disease risk, progression, and underlying neurobiology. The consortium framework integrates multi-omics approaches — including genomics, proteomics, and epigenomics — alongside neuroimaging and longitudinal clinical data to identify sex-differentiated molecular mechanisms. Key focus areas include hormonal contributions (particularly estrogen pathway dynamics across the menopause transition), X-linked gene expression, and immune system differences that may accelerate neuroinflammation differently in female versus male brains. Critically, SIGN distinguishes between biological sex and gender as separate analytical dimensions, an methodological refinement largely absent from prior Alzheimer's cohorts.
This initiative arrives at a moment when the field is recognizing that sex-stratified analyses are not merely an equity consideration but a scientific necessity. Several approved and investigational Alzheimer's therapeutics have shown differential efficacy or side-effect profiles by sex, yet trials have historically been underpowered to detect these differences. The SIGN Consortium's harmonized data-sharing model could address this by enabling adequately powered cross-cohort sex-stratified analyses for the first time. However, consortium reports of this nature are inherently aspirational — translating collaborative infrastructure into reproducible mechanistic findings takes years, and publication bias toward positive results remains a structural challenge. Still, the framing of sex and gender as primary — rather than secondary — research variables represents a meaningful and potentially paradigm-shaping shift in how neurodegeneration science will be conducted going forward.