Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease

TY - JOUR

T1 - Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease

AU - Nordestgaard, Liv Tybjærg

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Børge G

AU - Frikke-Schmidt, Ruth

N1 - Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - INTRODUCTION: The adenosine triphosphate-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways.METHODS: We tested whether a loss-of-function mutation in ABCA1, N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals.RESULTS: N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE (P = 1 × 10(-11)). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32-12.9) for AD, 2.46 (1.10-5.50) for cerebrovascular disease, and 8.28 (2.03-33.7) for the hemorrhagic stroke subtype.DISCUSSION: A loss-of-function mutation in ABCA1, present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population.

AB - INTRODUCTION: The adenosine triphosphate-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways.METHODS: We tested whether a loss-of-function mutation in ABCA1, N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals.RESULTS: N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE (P = 1 × 10(-11)). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32-12.9) for AD, 2.46 (1.10-5.50) for cerebrovascular disease, and 8.28 (2.03-33.7) for the hemorrhagic stroke subtype.DISCUSSION: A loss-of-function mutation in ABCA1, present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population.

U2 - 10.1016/j.jalz.2015.04.006

DO - 10.1016/j.jalz.2015.04.006

M3 - Journal article

C2 - 26079414

SN - 1552-5260

VL - 11

SP - 1430

EP - 1438

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 12

ER -