Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk

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

doi:10.1016/j.neurobiolaging.2019.09.001

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk

Neurobiol Aging. 2019 Nov:83:114-121. doi: 10.1016/j.neurobiolaging.2019.09.001. Epub 2019 Sep 9.

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; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA. Electronic address: wkremen@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 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; Psychology Service, VA San Diego Healthcare System, La Jolla, CA, USA.
⁴ 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.
⁵ 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.
⁶ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁷ National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry and Biomedical Genetics Section, Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁸ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
⁹ Department of Psychology, University of California, Riverside, Riverside, CA, USA.

PMID: 31585363
PMCID: PMC6931134
DOI: 10.1016/j.neurobiolaging.2019.09.001

Abstract

Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer's disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillary responses in middle-aged CN adults. Pupillary responses during digit span tasks were heritable (h² = 0.30-0.36) in 1119 men aged 56-66 years. In a CN subset-all with comparable span capacities (n = 539)-higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit) cognitive load condition (Cohen's d = 0.36 for upper vs. lower quartile of AD-PRS distribution). Results held up after controlling for APOE genotype. Results support pupillary response-and by inference, LC dysfunction-as a genetically mediated biomarker of early mild cognitive impairment/AD risk. In combination with other biomarkers, task-evoked pupillary responses may provide additional information for early screening of genetically at-risk individuals even before cognitive declines.

Keywords: Biomarker; Early identification; Locus coeruleus; Mild cognitive impairment; Polygenic risk score; Risk indicator.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Alzheimer Disease / genetics
Alzheimer Disease / psychology*
Amyloid beta-Peptides / genetics
Biomarkers / analysis*
Cognition / physiology*
Cognition Disorders / complications
Cognition Disorders / genetics
Cognitive Dysfunction / psychology*
Female
Humans
Male
Middle Aged
Risk Factors
tau Proteins / genetics

Substances

Amyloid beta-Peptides
Biomarkers
tau Proteins

Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk

Authors

Affiliations

Abstract

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MeSH terms

Substances

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