Sex Differences in Alzheimer's Disease — mechanisms and therapeutic implications

SUMMARY

# Sex Differences in Alzheimer's Disease — mechanisms and therapeutic implications ## Background and Rationale Women comprise approximately two-thirds of Alzheimer's disease patients worldwide, representing one of the most profound epidemiological mysteries in modern medicine. This striking sex disparity cannot be fully explained by differences in lifespan, as women experience greater cognitive decline even after adjusting for survival advantage. Recent evidence suggests fundamental biological d

METHODOLOGY NOTES

Phase 1: Participant recruitment and baseline assessment (Months 1-12). Enroll 800 participants aged 65-85 years (400 women, 400 men) across cognitive spectrum: cognitively normal (n=400), mild cognitive impairment (n=300), mild dementia (n=100). Inclusion criteria: MMSE ≥20, stable medications, informed consent. Exclusion: major psychiatric disorders, substance abuse, contraindications to MRI/PET. Phase 2: Comprehensive baseline evaluation (Months 6-18). Conduct neuropsychological testing (ADAS-Cog, CDR, TMT-A/B), MRI structural imaging, amyloid PET (18F-florbetapir), tau PET (18F-MK-6240), lumbar puncture for CSF collection, blood draw for plasma biomarkers and genomic DNA. Phase 3: Longitudinal follow-up (Months 18-60). Repeat assessments every 12 months including cognitive batteries, plasma biomarkers (Aβ42/40, p-tau217, GFAP, NfL via Simoa), and annual MRI. Repeat PET imaging at 24 months. Phase 4: Sex-stratified analysis (Months 54-66). Perform genome-wide association studies foc