PT  - JOURNAL ARTICLE
AU  - William S. Kremen
AU  - Matthew S. Panizzon
AU  - Jeremy A. Elman
AU  - Eric L. Granholm
AU  - Ole A. Andreassen
AU  - Anders M. Dale
AU  - Nathan A. Gillespie
AU  - Daniel E. Gustavson
AU  - Mark W. Logue
AU  - Michael J. Lyons
AU  - Michael C. Neale
AU  - Chandra A. Reynolds
AU  - Nathan Whitsel
AU  - Carol E. Franz
TI  - Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk
AID  - 10.1101/624767
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 624767
4099  - http://biorxiv.org/content/early/2019/05/02/624767.short
4100  - http://biorxiv.org/content/early/2019/05/02/624767.full
AB  - Pathological changes in Alzheimer’s disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to one’s compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohen’s d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response—and by inference, locus coeruleus dysfunction—as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.