Summary of Research Project Results under JSPS FY2004
"Research for the Future Program"

1. Research Institution   Osaka University
2. Research Area Life Sciences
3. Research Field Genome Research
4. Term of Project FY 2000 - FY 2004
5. Project Number 00L01413
6. Title of Project Analysis of Alzheimer Disease-Related Genes

7. Project Leader

Name Institution, Department Title of Position
Masatoshi, Takeda Osaka University, Graduate School of Medicine Professor

8. Core Members

Names Institution, Department Title of Position
Kouzin, Kamino Osaka University, Graduate School of Medicine Assistant Professor
Tetsuro, Miki Ehime University, School of Medicine Professor
Hideshi, Kawakami Hiroshima University Hospital, Department of Neurology Lecturer

9. Summary of Research Results

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.

10. Key Words

( 1 ) Alzheimer disease ( 2 ) Genome scan ( 3 ) Genetic factors
( 4 ) Apolipoproteins ( 5 ) Fatty acid ( 6 ) Chromosome 9
( 7 ) Chromosome 21 ( 8 ) Chromosome 12 ( 9 )POU2F1