This study provides new insights into the genetic etiology of Alzheimer's disease (AD) and related dementias (ADD) through a two-stage genome-wide association study (GWAS) involving 111,326 clinically diagnosed AD cases and 677,663 controls. The analysis identified 75 risk loci, 42 of which were novel at the time of the study. Pathway enrichment analyses highlighted the involvement of amyloid/tau pathways and microglial implications. Gene prioritization identified 31 genes associated with new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex (LUBAC). A genetic risk score (GRS) based on these variants was developed and showed significant association with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia, with a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to the effects of age and the APOE ε4 allele. The study also explored the genetic overlap with other neurodegenerative diseases and performed pathway and single-cell expression enrichment analyses, providing a comprehensive understanding of the genetic landscape and potential biological mechanisms underlying AD and related dementias.This study provides new insights into the genetic etiology of Alzheimer's disease (AD) and related dementias (ADD) through a two-stage genome-wide association study (GWAS) involving 111,326 clinically diagnosed AD cases and 677,663 controls. The analysis identified 75 risk loci, 42 of which were novel at the time of the study. Pathway enrichment analyses highlighted the involvement of amyloid/tau pathways and microglial implications. Gene prioritization identified 31 genes associated with new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex (LUBAC). A genetic risk score (GRS) based on these variants was developed and showed significant association with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia, with a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to the effects of age and the APOE ε4 allele. The study also explored the genetic overlap with other neurodegenerative diseases and performed pathway and single-cell expression enrichment analyses, providing a comprehensive understanding of the genetic landscape and potential biological mechanisms underlying AD and related dementias.