This study conducted a large genome-wide association study (GWAS) to identify genetic loci associated with Alzheimer's disease (AD) risk. The study included 71,880 clinically diagnosed AD cases and 383,378 controls, with an additional AD-by-proxy phenotype based on parental diagnoses. The meta-analysis identified 29 risk loci, implicating 215 potential causative genes. These genes are strongly expressed in immune-related tissues and cell types, such as spleen, liver, and microglia. Gene-set analyses revealed biological mechanisms involving lipid-related processes and amyloid precursor protein degradation. The study also showed strong genetic correlations with multiple health-related outcomes and suggested a protective effect of cognitive ability on AD risk. These findings contribute to the understanding of AD etiology and provide novel insights into the neurobiology of the disease.This study conducted a large genome-wide association study (GWAS) to identify genetic loci associated with Alzheimer's disease (AD) risk. The study included 71,880 clinically diagnosed AD cases and 383,378 controls, with an additional AD-by-proxy phenotype based on parental diagnoses. The meta-analysis identified 29 risk loci, implicating 215 potential causative genes. These genes are strongly expressed in immune-related tissues and cell types, such as spleen, liver, and microglia. Gene-set analyses revealed biological mechanisms involving lipid-related processes and amyloid precursor protein degradation. The study also showed strong genetic correlations with multiple health-related outcomes and suggested a protective effect of cognitive ability on AD risk. These findings contribute to the understanding of AD etiology and provide novel insights into the neurobiology of the disease.