A genome-wide association study (GWAS) of Alzheimer’s disease (AD) involving over 16,000 individuals identified two new genetic loci associated with the disease: CLU and PICALM. The study, conducted in two stages, confirmed genome-wide significant associations with SNPs at these loci. The CLU gene, which encodes clusterin, was associated with a SNP (rs11136000) with an odds ratio of 0.840, while the PICALM gene was associated with a SNP (rs3851179) with an odds ratio of 0.849. These associations were replicated in an independent sample of 2,023 cases and 2,340 controls. The study also confirmed the established association with the APOE locus, with the most significant SNP (rs2076550) having a P-value of 1.8 × 10−157. Alzheimer’s disease is a highly heritable condition, with a heritability of up to 76%. It is characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles. While APOE has been the only confirmed susceptibility gene, this study identified two new loci associated with AD. The study involved a large collaborative effort across Europe and the United States, utilizing a combined sample of up to 19,000 individuals. After stringent quality control, the study tested 529,205 SNPs in up to 11,789 individuals. The genomic control inflation factor (λ) was 1.037, indicating minimal population stratification. The study also identified several other SNPs with genome-wide significance, including those at the APOE locus. The findings suggest that susceptibility genes are not randomly distributed but are involved in functional pathways related to AD. Clusterin, encoded by the CLU gene, is a multifunctional protein that interacts with β-amyloid and may influence its toxicity and aggregation. PICALM, which is involved in clathrin-mediated endocytosis, may also play a role in AD pathogenesis by affecting the trafficking of VAMP2 and the processing of amyloid precursor protein (APP). The study highlights the importance of large-scale GWAS in identifying new genetic loci associated with complex diseases. While the effect sizes of the identified SNPs are modest, the study's large sample size and rigorous quality control provide strong evidence for their association with AD. The findings may contribute to a better understanding of the genetic mechanisms underlying AD and could inform future therapeutic strategies. The study also emphasizes the need for further research to identify additional susceptibility genes and to elucidate the functional roles of the newly identified loci in AD pathogenesis.A genome-wide association study (GWAS) of Alzheimer’s disease (AD) involving over 16,000 individuals identified two new genetic loci associated with the disease: CLU and PICALM. The study, conducted in two stages, confirmed genome-wide significant associations with SNPs at these loci. The CLU gene, which encodes clusterin, was associated with a SNP (rs11136000) with an odds ratio of 0.840, while the PICALM gene was associated with a SNP (rs3851179) with an odds ratio of 0.849. These associations were replicated in an independent sample of 2,023 cases and 2,340 controls. The study also confirmed the established association with the APOE locus, with the most significant SNP (rs2076550) having a P-value of 1.8 × 10−157. Alzheimer’s disease is a highly heritable condition, with a heritability of up to 76%. It is characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles. While APOE has been the only confirmed susceptibility gene, this study identified two new loci associated with AD. The study involved a large collaborative effort across Europe and the United States, utilizing a combined sample of up to 19,000 individuals. After stringent quality control, the study tested 529,205 SNPs in up to 11,789 individuals. The genomic control inflation factor (λ) was 1.037, indicating minimal population stratification. The study also identified several other SNPs with genome-wide significance, including those at the APOE locus. The findings suggest that susceptibility genes are not randomly distributed but are involved in functional pathways related to AD. Clusterin, encoded by the CLU gene, is a multifunctional protein that interacts with β-amyloid and may influence its toxicity and aggregation. PICALM, which is involved in clathrin-mediated endocytosis, may also play a role in AD pathogenesis by affecting the trafficking of VAMP2 and the processing of amyloid precursor protein (APP). The study highlights the importance of large-scale GWAS in identifying new genetic loci associated with complex diseases. While the effect sizes of the identified SNPs are modest, the study's large sample size and rigorous quality control provide strong evidence for their association with AD. The findings may contribute to a better understanding of the genetic mechanisms underlying AD and could inform future therapeutic strategies. The study also emphasizes the need for further research to identify additional susceptibility genes and to elucidate the functional roles of the newly identified loci in AD pathogenesis.