APOE and AβPP Gene Variation in Cortical and Cerebrovascular Amyloid-β Pathology and Alzheimer's Disease: A Population-Based Analysis

Article type: Research Article

Authors: Peuralinna, Terhi^{a; b} | Tanskanen, Maarit^c | Mäkelä, Mira^c | Polvikoski, Tuomo^d | Paetau, Anders^c | Kalimo, Hannu^c | Sulkava, Raimo^e | Hardy, John^f | Lai, Shiao-Lin^g | Arepalli, Sampath^h | Hernandez, Dena^h | Traynor, Bryan J.^g | Singleton, Andrew^h | Tienari, Pentti J.^{a; i} | Myllykangas, Liisa^{b; c; *}

Affiliations: [a] University of Helsinki, Research Program of Molecular Neurology, Biomedicum-Helsinki, Helsinki, Finland | [b] Folkhälsan Institute of Genetics, Helsinki, Finland | [c] Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland | [d] Institute for Aging and Health, Newcastle University, Newcastle upon Tyne, UK | [e] Department of Public Health and General Practice Division of Geriatrics, University of Kuopio and Kuopio University Central Hospital, Kuopio, Finland | [f] Department of Molecular Neuroscience, Institute of Neurology, London, UK | [g] Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA | [h] Molecular Genetics Unit, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA | [i] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

Correspondence: [*] Correspondence to: Dr. Liisa Myllykangas, Department of Pathology, University of Helsinki, Haartman Institute and HUSLAB, POB 21, FIN-00014, Finland. Tel.: +358 50 4286667; Fax: +358 9 19126700; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β deposition, AβPP, APOE, cerebral amyloid angiopathy, neuropathology

DOI: 10.3233/JAD-2011-102049

Journal: Journal of Alzheimer's Disease, vol. 26, no. 2, pp. 377-385, 2011