TY - JOUR
T1 - Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study
AU - Ahmad, Shahzad
AU - Bannister, Christian
AU - van der Lee, Sven J.
AU - Vojinovic, Dina
AU - Adams, Hieab H.H.
AU - Ramirez, Alfredo
AU - Escott-Price, Valentina
AU - Sims, Rebecca
AU - Baker, Emily
AU - Williams, Julie
AU - Holmans, Peter
AU - Vernooij, Meike W.
AU - Ikram, M. Arfan
AU - Amin, Najaf
AU - van Duijn, Cornelia M.
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/7
Y1 - 2018/7
N2 - Introduction: 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).
AB - Introduction: 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).
KW - Alzheimer's disease
KW - Endocytosis
KW - Genetic risk score
KW - Immune response
KW - Mild cognitive impairment
KW - White matter lesions
UR - http://www.scopus.com/inward/record.url?scp=85044253651&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2018.01.005
DO - 10.1016/j.jalz.2018.01.005
M3 - Article
C2 - 29494809
AN - SCOPUS:85044253651
SN - 1552-5260
VL - 14
SP - 848
EP - 857
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 7
ER -
