A two-stage genome-wide association study (GWAS) involving 111,326 clinically diagnosed Alzheimer's disease (AD) cases and 677,663 controls identified 75 risk loci, of which 42 were new. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglial implication. Gene prioritization identified 31 genes associated with new biological processes, including the tumor necrosis factor alpha pathway. A genetic risk score (GRS) was developed, showing a 1.6- to 1.9-fold increase in AD risk from the lowest to highest decile. The study also found genetic overlap with other neurodegenerative diseases, with some loci showing colocalization with Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Pathway analyses revealed significant associations with immune-related processes, including microglial activation. The study also identified new loci and genes associated with AD, including SHARPIN, RBCK1, and OTULIN. The GRS was associated with increased risk of AD conversion in population-based cohorts and patients with mild cognitive impairment (MCI). The study highlights the importance of genetic factors in AD and provides insights into potential therapeutic targets and biomarkers. The results emphasize the role of microglial endocytosis in AD and the potential for personalized medicine based on genetic risk scores. The study also discusses the limitations of current genetic findings and the need for further research to fully characterize the genetic basis of AD.A two-stage genome-wide association study (GWAS) involving 111,326 clinically diagnosed Alzheimer's disease (AD) cases and 677,663 controls identified 75 risk loci, of which 42 were new. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglial implication. Gene prioritization identified 31 genes associated with new biological processes, including the tumor necrosis factor alpha pathway. A genetic risk score (GRS) was developed, showing a 1.6- to 1.9-fold increase in AD risk from the lowest to highest decile. The study also found genetic overlap with other neurodegenerative diseases, with some loci showing colocalization with Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Pathway analyses revealed significant associations with immune-related processes, including microglial activation. The study also identified new loci and genes associated with AD, including SHARPIN, RBCK1, and OTULIN. The GRS was associated with increased risk of AD conversion in population-based cohorts and patients with mild cognitive impairment (MCI). The study highlights the importance of genetic factors in AD and provides insights into potential therapeutic targets and biomarkers. The results emphasize the role of microglial endocytosis in AD and the potential for personalized medicine based on genetic risk scores. The study also discusses the limitations of current genetic findings and the need for further research to fully characterize the genetic basis of AD.