期刊
NEUROBIOLOGY OF AGING
卷 101, 期 -, 页码 123-129出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2021.01.008
关键词
Alzheimer's disease; Amyloid; Pre-clinical; PET; APOE4; KLOTHO; Heterozygosity
资金
- Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging
- NIH [AG060747, AG047366, AG066206]
- Alzheimer's Association [AARF-20-683984]
- Medical Research Council (MRC) eMedLab Medical Bioinformatics Career Development Fellowship [MR/L016311/1]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Genentech, Inc.
- Fujirebio
- GE HealtControlsare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co. Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- National Institutes of Health National Institute on Aging
- Accelerating Medicines Partnership
- GHR Foundation
- Commonwealth Scientific Industrial and research Organization (CSIRO)
- Edith Cowan University (ECU)
- Mental Health Research institute (MHRI)
- National Aging Research Institute (NARI)
- Austin Health
- CogState Ltd.
- National Health and Medical Research Council (NHMRC)
- Dementia Collaborative Research Centres program (DCRC2)
- Science and Industry Endowment Fund (SIEF)
- Cooperative Research Centre (CRC) for Mental Health through the CRC Program, an Australian Government Initiative [20100104]
- Alzheimer's Research UK [ARUK-PG2014-1946, ARUK-PG2017-1946]
- Medical Research Council Dementias Platform UK [CSUB19166]
- Wolfson Foundation [PR/ylr/18575]
- Medical Research Council [MC_UU_12019/1, MC_UU_12019/3]
- Wellcome Trust [200,109/Z/15/Z]
- Brain Research Trust [UCC14191]
KL*VSHET+ reduces the risk of amyloid positivity in APOE*4 carriers but not in APOE*4 non-carriers. The combination of APOE*4 and KL*VS genotypes might enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD.
KLOTHO*VS heterozygosity (KL*VSHET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE*4 carriers. Additional studies suggest that KL*VSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KL*VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE*4 status. KL*VSHET+ reduced the risk of amyloid positivity in APOE*4 carriers (odds ratio = 0.67 [0.52-0.88]; p = 3.5 x 10(-3)), but not in APOE*4 non-carriers (odds ratio = 0.94 [0.73-1.21]; p = 0.63). The combination of APOE*4 and KL*VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE*4 and AD are warranted. (C) 2021 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据