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

Abstract

Deposition of amyloid-β (Aβ) 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 Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ 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 Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ 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 Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…Stein et al [50] conducted the first voxel-wise GWAS and suggested CSMD2 and CADPS2 as candidate genes for future investigation. Ramanan et al [51] used florbetapir ( 18 F) positron emission tomography (PET) to evaluate the cortical load of amyloid b, which revealed an association of APOE and BCHE with this load. Carrasquillo et al [52] revealed the association of IDE with amyloid b40 and total amyloid b levels in plasma.…”

No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population

“…Rs2075650 within APOE/TOMM40 has been studied for its associations with several age-related disorders and diseases in GWAS, such as cognitive decline 27,28 and Alzheimer's disease (AD), [29][30][31] as well as AMD. 12,13 Apolipoprotein E (ApoE), encoded by the APOE gene, was recognized for its crucial role in lipoprotein transport.…”

Complexity across scales: a walkthrough to linking neuro-imaging readouts to molecular processes

“…Increased expression of APOE also facilitates the molecular interaction between amyloid beta and Butyrylcholineesterase (BCHE) gene which results in the formation of a complex BCHE-Abeta-APOE (BaβA) complex [165][166][167]. This complex alters the structure of BCHE which accelerates the catalytic activity of the enzyme.…”