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,
Carol E. Franz
Posted 02 May 2019
bioRxiv DOI: 10.1101/624767 (published DOI: 10.1016/j.neurobiolaging.2019.09.001)
Posted 02 May 2019
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.
- Downloaded 525 times
- Download rankings, all-time:
- Site-wide: 33,798 out of 100,737
- In genetics: 1,952 out of 5,016
- Year to date:
- Site-wide: 23,559 out of 100,737
- Since beginning of last month:
- Site-wide: 33,228 out of 100,737
Downloads over time
Distribution of downloads per paper, site-wide
- 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!