A genome-wide meta-analysis identified 29 risk loci and 215 potential causative genes associated with Alzheimer’s disease (AD) risk. These loci are strongly expressed in immune-related tissues and cell types, including the spleen, liver, and microglia. Gene-set analyses suggest biological mechanisms involving lipid-related processes and amyloid precursor protein degradation. The study found strong genetic correlations between AD and multiple health outcomes, with Mendelian randomization indicating a protective effect of cognitive ability on AD risk. The study included 455,258 individuals of European ancestry, with 71,880 cases and 383,378 controls. The analysis identified 2,357 genome-wide significant variants, located in 29 distinct loci, including 15 of the 18 loci from the first phase and 13 novel loci. The study also identified 9 novel loci not previously reported. Functional annotation of these variants showed they are mostly located in non-coding regions, with some exonic non-synonymous SNPs likely to have deleterious effects. The study also identified several genes implicated in AD, including CLU/PTK2B, HLA-DRB1, and KAT8. Gene-set analysis revealed associations with lipid-related processes and amyloid precursor protein degradation. The study also found that genetic factors influencing AD overlap with other diseases and traits, including cognitive ability and educational attainment. The results suggest that AD pathogenesis involves an interplay between inflammation and lipids, with lipid changes potentially harming immune responses of microglia and astrocytes. The study also found that genetic factors influencing AD may affect cognitive reserve, rather than being directly involved in AD pathology. The study highlights the importance of considering epigenetic influences in addition to physical location when identifying causal genes. The results provide new insights into the neurobiology of AD and could serve as a valuable resource for future functional studies and drug development. The study used a combination of genome-wide association studies, functional mapping, and gene-set analysis to identify these associations. The findings suggest that AD risk is influenced by a complex interplay of genetic and environmental factors, with a strong genetic component. The study also found that the genetic overlap between AD and other diseases and traits may be due to shared biological mechanisms. The results emphasize the importance of considering both genetic and environmental factors in understanding AD risk and pathogenesis. The study provides a comprehensive understanding of the genetic factors contributing to AD risk and highlights the need for further research into the biological mechanisms underlying AD. The study also found that the genetic factors influencing AD may have indirect effects on AD pathogenesis through cognitive reserve. The study's findings have important implications for the development of new therapies and interventions for AD. The study used a large sample size and multiple analytical approaches to ensure the robustness of the findings. The results suggest that AD is a complex disease with a strongA genome-wide meta-analysis identified 29 risk loci and 215 potential causative genes associated with Alzheimer’s disease (AD) risk. These loci are strongly expressed in immune-related tissues and cell types, including the spleen, liver, and microglia. Gene-set analyses suggest biological mechanisms involving lipid-related processes and amyloid precursor protein degradation. The study found strong genetic correlations between AD and multiple health outcomes, with Mendelian randomization indicating a protective effect of cognitive ability on AD risk. The study included 455,258 individuals of European ancestry, with 71,880 cases and 383,378 controls. The analysis identified 2,357 genome-wide significant variants, located in 29 distinct loci, including 15 of the 18 loci from the first phase and 13 novel loci. The study also identified 9 novel loci not previously reported. Functional annotation of these variants showed they are mostly located in non-coding regions, with some exonic non-synonymous SNPs likely to have deleterious effects. The study also identified several genes implicated in AD, including CLU/PTK2B, HLA-DRB1, and KAT8. Gene-set analysis revealed associations with lipid-related processes and amyloid precursor protein degradation. The study also found that genetic factors influencing AD overlap with other diseases and traits, including cognitive ability and educational attainment. The results suggest that AD pathogenesis involves an interplay between inflammation and lipids, with lipid changes potentially harming immune responses of microglia and astrocytes. The study also found that genetic factors influencing AD may affect cognitive reserve, rather than being directly involved in AD pathology. The study highlights the importance of considering epigenetic influences in addition to physical location when identifying causal genes. The results provide new insights into the neurobiology of AD and could serve as a valuable resource for future functional studies and drug development. The study used a combination of genome-wide association studies, functional mapping, and gene-set analysis to identify these associations. The findings suggest that AD risk is influenced by a complex interplay of genetic and environmental factors, with a strong genetic component. The study also found that the genetic overlap between AD and other diseases and traits may be due to shared biological mechanisms. The results emphasize the importance of considering both genetic and environmental factors in understanding AD risk and pathogenesis. The study provides a comprehensive understanding of the genetic factors contributing to AD risk and highlights the need for further research into the biological mechanisms underlying AD. The study also found that the genetic factors influencing AD may have indirect effects on AD pathogenesis through cognitive reserve. The study's findings have important implications for the development of new therapies and interventions for AD. The study used a large sample size and multiple analytical approaches to ensure the robustness of the findings. The results suggest that AD is a complex disease with a strong