APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

作者：Ramanan V K; Risacher S L; Nho K; Kim S; Swaminathan S; Shen L; Foroud T M; Hakonarson H; Huentelman M J; Aisen P S; Petersen R C; Green R C; Jack C R; Koeppe R A; Jagust W J; Weiner M W; Saykin A J^*

来源：Molecular Psychiatry, 2014, 19(3): 351-357.

DOI：10.1038/mp.2013.19

• Alzheimer's disease (AD)
• amyloid
• apolipoprotein E (APOE)
• butyrylcholinesterase (BCHE)
• florbetapir (AV-45)
• genome-wide association study (GWAS)

Deposition of amyloid-beta (A beta) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical A beta load until now. We employed florbetapir (F-18) positron emission tomography (PET) imaging to assess brain A beta levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical A beta load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P = 5.5 x 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P = 2.7 x 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical A beta levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with A beta deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with A beta burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

• 出版日期2014-3