Background: The pupillary dilation response during cognitive tasks is a validated index of cognitive effort. Given the same score, requiring greater effort suggests being closer to the point when compensatory capacity will be exceeded. We previously showed that adults with single-domain amnestic MCI showed greater pupil dilation during digit span tasks than cognitively normal (CN) individuals despite equivalent task performance (Granholm EL, Panizzon MS, Elman JA, Jak AJ, Hauger RL, Bondi MW, Lyons MJ, Franz CE, Kremen WS [2017] Pupillary responses as a biomarker of early risk for Alzheimer's disease. J Alzheimers Dis 56(4):1419-1428). We have also shown that higher Alzheimer’s disease polygenic risk scores (AD-PRSs) were associated with significantly increased odds of having MCI in adults who were only in their 50s (Logue MW, Panizzon MS, Elman JA, Gillespie NA, Hatton SN, Gustavson DE, Andreassen OA, Dale AM, Franz CE, Lyons MJ, Neale MC, Reynolds CA., Tu XM, Kremen WS [2018] Use of an Alzheimer’s disease polygenic risk score to identify mild cognitive impairment in adults in their 50s. Mol Psychiatry Epub ahead of print). To validate pupillary responses as a psychophysiological biomarker of early risk for AD, here we tested whether the AD-PRS was associated with pupil dilation during digit span tasks in rigorously-defined CN individuals.
Methods: Participants were in wave 2 of the Vietnam Era Twin Study of Aging (VETSA). With a neuropsychological test battery comprising 18 tests covering 6 cognitive domains, CN was defined as having no domains below the impairment threshold. We tested 576 CN participants on digit spans at low (3-digit), moderate (6-digit), and high (9-digit) cognitive loads while pupillary changes were recorded. Mean age=62 years; range=56-66. The AD-PRS was developed from the International Genomics of Alzheimer’s Project (IGAP) database. We used the single nucleotide polymorphism (SNP) p-value threshold that best differentiated CN versus MCI in our study and CN versus AD in prior studies. We controlled for the first 3 principal components (to account for ethnic stratification), age, anticholingeric medications, and clustered twin data.
Results: Higher AD-PRSs were not associated with digit span performance, but they were associated with significantly greater pupil dilation at the high cognitive load. Results held up after excluding APOE-related SNPs from the AD-PRS.
Conclusions: Increased pupil dilation at high cognitive loads indicates increased compensatory effort in late middle-aged adults with normal neuropsychological function. The significant association with genetic risk based on the AD-PRS supports task-related pupillary response as a psychophysiological biomarker of early risk for AD. Further support stems from the fact that this pupillary response is largely driven by the locus coeruleus, the earliest sites of tau deposition in the brain. Both the AD-PRS and pupillary responses are non-invasive indicators that may augment prediction of increased risk for AD while people are still relatively young. Importantly, this analysis included only CN individuals. Thus, these are non-invasive indicators that may aid in identifying people at increased risk even before neuropsychological performance becomes impaired.
Aging , Cognition: Education, Intelligence, Memory, Attention , Neuropsychology (e.g. Dyslexia, Handedness, Language)
