To elucidate the mechanism of the development of Alzheimer disease (AD), we systemically searched for loci and genes related to sporadic AD in Japanese population. 1. FUNCTIONAL APPROACH: (1) We detected significant associations with AD in 3 out of 67 genes reportedly associated with AD, and 10 out of 163 genes reportedly associated with atherosclerosis. (2) A promoter polymorphism of PS1 showed risk effects on AD. While one novel PS1 mutation was found in a familial case, no mutations were found in any sporadic early-onset AD. (3) Among genes related to lipid metabolism, APOA2 and APOC2 affected on age-at-onset of late-onset AD, and LRP, ALB, APOBEC1 showed risk effects on late-onset AD. (4) MTHFR showed a risk effect in non-APOE4 carriers. 2. PATHOLOGICAL APPROACH: (1) APOE4 was a risk for dementia with Lewy bodies, but TAFI was not a risk for cerebral infarction. (2) FGF1 was a novel risk for AD, but BDNF was not. (3) Among 35 genes showing altered expressions in AD cortex, 8 genes showed significant associations with AD, and POU2F1 was the most notable. 3. THE WHOLE GENOME SCAN: Using microsatellite-based scan of pooled DNA of patients with AD and controls, about 70% of the whole genome was scanned. 4. CANDIDATE REGION APPROACH: (1) The microsatellite-based scan of the whole chromosome 9 detected 14 candidate risk regions. (2) By dense genotyping around IDE region (chromosome 10), IDE was confirmed as a risk gene for LOAD. (3) SNP-based scan with 100kb-interval of the short arm of chromosome 12 identified 9 novel risk genes for LOAD. (4) SNP-based scan of chromosome 21 identified 5 novel risk genes for LOAD. These findings provide experimental targets to elucidate the etiology of AD, potentially leading to preventive and therapeutic clues for AD.