Genetic risk for coronary heart disease alters the influence of Alzheimer's genetic risk on mild cognitive impairment

Jeremy A Elman; Matthew S Panizzon; Mark W Logue; Nathan A Gillespie; Michael C Neale; Chandra A Reynolds; Daniel E Gustavson; Brinda K Rana; Ole A Andreassen; Anders M Dale; Carol E Franz; Michael J Lyons; William S Kremen

doi:10.1016/j.neurobiolaging.2019.06.001

Genetic risk for coronary heart disease alters the influence of Alzheimer's genetic risk on mild cognitive impairment

Neurobiol Aging. 2019 Dec:84:237.e5-237.e12. doi: 10.1016/j.neurobiolaging.2019.06.001. Epub 2019 Jun 8.

Authors

Affiliations

¹ Department of Psychiatry University of California, San Diego, La Jolla, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA. Electronic address: jaelman@ucsd.edu.
² Department of Psychiatry University of California, San Diego, La Jolla, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA.
³ National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry and the Biomedical Genetics Section, Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston MA, USA.
⁴ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁵ Department of Psychology, University of California, Riverside, CA, USA.
⁶ NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷ Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA; Department of Radiology, University of California, San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁸ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
⁹ Department of Psychiatry University of California, San Diego, La Jolla, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA.

PMID: 31272697
PMCID: PMC6899214
DOI: 10.1016/j.neurobiolaging.2019.06.001

Abstract

Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of genetic risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how genetic risk for one disease can modify the impact of genetic risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for genetic risk prediction.

Keywords: Alzheimer's disease; Cognitive impairment; Coronary artery disease; Incidence-prevalence bias; Neyman bias; Polygenic risk scores.

Genetic risk for coronary heart disease alters the influence of Alzheimer's genetic risk on mild cognitive impairment

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