摘要
Background:The combinatorial efect of multiple genetic factors calculated as a polygenic risk score(PRS)has been studied to predict disease progression to Alzheimer’s disease(AD)from mild cognitive impairment(MCI).Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene.These studies may have missed the APOE genotype-specifc predictability of PRS for disease progression to AD.Methods:We analyzed 732 MCI from the Alzheimer’s Disease Neuroimaging Initiative cohort,including those who progressed to AD within 5 years post-baseline(n=270)and remained stable as MCI(n=462).The predictability of PRS including and excluding the APOE region(PRS_(+APOE) and PRS_(−APOE))on the conversion to AD and its interaction with the APOEε4 carrier status were assessed using Cox regression analyses.Results:PRS_(+APOE)(hazard ratio[HR]1.468,95%CI 1.335-1.615)and PRS_(−APOE)(HR 1.293,95%CI 1.157-1.445)were both associated with a signifcantly increased risk of MCI progression to dementia.The interaction between PRS_(+APOE) and APOEε4 carrier status was signifcant with a P-value of 0.0378.The association of PRSs with the progression risk was stronger in APOEε4 non-carriers(PRS_(+APOE):HR 1.710,95%CI 1.244-2.351;PRS_(−APOE):HR 1.429,95%CI 1.182-1.728)than in APOEε4 carriers(PRS_(+APOE):HR 1.167,95%CI 1.005-1.355;PRS_(−APOE):HR 1.172,95%CI 1.020-1.346).Conclusions:PRS could predict the conversion of MCI to dementia with a stronger association in APOEε4 noncarriers than APOEε4 carriers.This indicates PRS as a potential genetic predictor particularly for MCI with no APOEε4 alleles.
基金
Alzheimer’s Disease Neuroimaging Initiative(National Institutes of Health Grant U01 AG024904)and DOD ADNI(Department of Defense award number W81XWH-12–2-0012).ADNI is funded by the National Institute on Aging
the National Institute of Biomedical Imaging and Bioengineering,and through generous contributions from the following: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.Hofmann-La Roche Ltd and its afliated company Genentech,Inc.
Fujirebio
GE Healthcare
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
Pfzer Inc.
Piramal Imaging
Servier
Takeda Pharmaceutical Company
and Transition Therapeutics.The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada.Private sector contributions are facilitated by the Foundation for the National Institutes of Health(www.fnih.org).The grantee organization is the Northern California Institute for Research and Education,and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California.ADNI data are dis‑seminated by the Laboratory for Neuro Imaging at the University of Southern California.
