Introduction: Late-onset Alzheimer disease (LOAD), as the leadingcause ofdementia worldwide, is associated with brain inflammatory processeswithsubstantial economicand public health implications. LOAD represents themain form of dementiacharacterized by progressive dementiatypicallymanifesting in the seventh to ninth decades.Neurodegenerativeimpairmentsprecede clinical symptomsby 10–20 years, resulting in clinicallyasymptomaticindividuals carrying neuropathologic features ofLOAD.Despitedifferent research efforts, current treatments have only marginal symptomaticbenefits and there is no effective clinical modifying or preventiveinterventions.Methods: Study design and sample selection were conductedto clarify ofphenotypic heterogeneity between different types of dementia and maximizestatistical power. The study design includes 2 primary phases: 1) assessingrecent whole-genome sequencing (WGS) and genome wide association studies(GWAS) for gene selection2) genotype analysis for case-control study3)confirmation by randomly sequencing. The main focus of this workwas ongenome-wide association studies that have successfully identified commongenetic variations at over 20 loci associated with LOAD outside of the APOElocus.Results: Screening for causative mutations revealed variants in CLU, TLR2,APOE, BIN1, CR1,
PICALM and ESR1 were nominally associated with LOAD risk.Conclusion:Our results suggest that these loci could be a promisingtherapeutic target for LOAD prevention. Competitive pathway analysis canrevealdeficiencies in the biological processes of neurogenesis and synapticregulation. In addition, our risk gene discovery approach can be expanded andadapted to other phenotypes and populations, thus serving as a model forfuture efforts to identify rare variants for LOAD and other complex humandiseases.