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Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study
Author(s) -
Ahmad Shahzad,
Bannister Christian,
Lee Sven J.,
Vojinovic Dina,
Adams Hieab H.H.,
Ramirez Alfredo,
EscottPrice Valentina,
Sims Rebecca,
Baker Emily,
Williams Julie,
Holmans Peter,
Vernooij Meike W.,
Ikram M. Arfan,
Amin Najaf,
Duijn Cornelia M.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.01.005
Subject(s) - clathrin , apolipoprotein e , disease , white matter , neuroscience , bioinformatics , medicine , biology , magnetic resonance imaging , endocytosis , receptor , radiology
Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. Methods We constructed weighted Genetic risk scores, first based on 20 genome‐wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume. Results The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment ( P = 1.44 × 10 −4 ). Immune response ( P = .016) and clathrin/AP2 adaptor complex pathway ( P = 3.55 × 10 −3 ) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction ( P = 9.09 × 10 −4 ). Discussion Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E ( APOE ).