title: APOE and AβPP gene variation in cortical and cerebrovascular amyloid-β pathology and Alzheimer's disease: a population-based analysis.
abstract: Cortical and cerebrovascular amyloid-β (Aβ) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) ε4 is a major genetic modulator of Aβ deposition and AD risk. Variants of the amyloid-β protein precursor (AβPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AβPP variants in cortical and cerebrovascular Aβ deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥ 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the ε4 allele with cortical (p = 4.91 × 10-17) and cerebrovascular (p = 9.87 × 10-11) Aβ deposition as well as with NIA-RI AD (p = 1.62 × 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AβPP locus. In single SNP or haplotype analyses there were no statistically significant AβPP locus associations with cortical or cerebrovascular Aβ deposition or with NIA-RI AD. We sequenced the promoter of the AβPP gene in 40 subjects with very high Aβ deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Aβ depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE ε4 variant. Promoter mutations or common allelic variation in the AβPP gene do not have a major contribution to cortical or cerebrovascular Aβ deposition, or very late-onset AD in this Finnish population based study.
authors.affiliation: University of Helsinki, Research Program of Molecular Neurology, Biomedicum-Helsinki, Helsinki, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Peuralinna
authors.forename: Maarit
authors.initials: M
authors.lastname: Tanskanen
authors.forename: Mira
authors.initials: M
authors.lastname: Mäkelä
authors.forename: Tuomo
authors.initials: T
authors.lastname: Polvikoski
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Raimo
authors.initials: R
authors.lastname: Sulkava
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Shiao-Lin
authors.initials: SL
authors.lastname: Lai
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.forename: Liisa
authors.initials: L
authors.lastname: Myllykangas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005387:Finland; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E