The FAS gene, brain volume, and disease progression in Alzheimer's disease.
OBJECTIVE
We sought to identify single-nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) progression and brain volume.


METHODS
Ninety-seven SNPs were genotyped in 243 subjects from a longitudinal study of healthy aging. Subjects who received a diagnosis of cognitive impairment (CI) at any study visit (before their most recent visit) and had DNA in the study's DNA bank were included. Progression of AD was defined as the duration from onset of CI to diagnosis of AD. Association of each of the 97 SNPs with AD progression was tested via Cox model. Those SNPs meeting a criterion of nominal significance (P < 0.05) for association with AD progression were reassessed to account for multiple testing by repeating the marker selection process in 10,000 random permutations. Next, the association between the one SNP that survived the multiple-testing adjustment and brain volume was determined by multiple regression analysis in a subgroup of subjects for whom magnetic-resonance imaging (MRI)-derived brain-volume data were available. Brain volumes were adjusted for age at MRI, gender, and time from MRI to onset of CI.


RESULTS
The minor allele of rs1468063 in the FAS gene, which is member 6 of the tumor necrosis factor receptor superfamily, was significantly associated with faster AD progression after adjustment for multiple testing (P(permutation) = 0.049). The same allele in rs1468063 was associated with smaller brain volumes and larger ventricular volumes (P = 0.02 and 0.04, respectively).


CONCLUSIONS
The FAS gene, which plays a role in apoptosis, may be associated with AD by modulating the apoptosis and neuronal loss secondary to AD neuropathology.
Erten-Lyons
Deniz
D
Veterans Affairs Medical Center, Portland, OR, USA. ertenlyo@ohsu.edu
Jacobson
Anne
A
Kramer
Patricia
P
Grupe
Andrew
A
Kaye
Jeffrey
J
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D019014:fas Receptor / Q000235:genetics*
C491901:FAS protein, human; D019014:fas Receptor