According to study data published in the Neurobiology of Aging, pupillary dilation during cognitive tasks was associated with Alzheimer disease polygenic risk scores (AD-PRSs). These results support the use of pupillary response as a genetically mediated biomarker for the detection of early mild cognitive impairment (MCI) and Alzheimer disease (AD). 

Investigators used data from wave 2 of the Vietnam Era Twin Study of Aging, a longitudinal genetic study of cognition and brain aging in men. Pupillary responses were recorded during digit span tasks, in which participants were asked to recall a set of aurally provided digits. Digit tasks were presented in blocks of 3-, 6-, and 9-digit trials, representing low, moderate, and high cognitive load conditions, respectively. Genome-wide genotyping was then performed on individual twins. AD-PRSs were computed as weighted averages of sample additive imputed single nucleotide polymorphism (SNP) dosage. The weights for each SNP were calculated using summary data from a prior genome-wide association study. Apolipoprotein E (APOE)-ε2 and APOE-ε4 were also genotyped directly. A Cholesky decomposition was fitted to the data to examine the relative contribution of genetic and environmental factors to pupil response.

Pupillary responses were collected from 1119 men aged 56 to 66 years. According to the Cholesky decomposition, all 3 pupillary response measures were significantly heritable (h2 =.30-.36). The remaining model variance was accounted for by environmental factors. Genetic correlations were high between pupillary response measures (r =.73-.99), suggesting that a single common factor drives genetic influences on pupil dilation. Phenotypic correlations, representing overall shared variance, were moderate (r =.42-.60). In a subsample of cognitively normal men with comparable span capacities (n=539), AD-PRSs were significantly correlated with pupil dilation response during the 9-digit recall task (r =.10; P <.03). The upper quartile of AD-PRSs had greater pupillary dilation during digit recall compared with the lower quartile (Cohen d =.36; P =.005). The association between AD-PRS and pupillary response remained significant after controlling for both APOE alleles (P <.02). No differences in pupillary response were observed between the left and right eye during the 6-digit (P =.12) or the 9-digit (P =.46) tasks, but significantly greater dilation was observed in the right eye at the 3-digit task (P =.008).

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These data suggest that pupillary response may be a genetically-mediated biomarker of early MCI and AD risk. Locus coeruleus (LC) dysfunction is recognized as an early identification measure for AD. Through targeting pupillary response measures, and — by proxy — LC function, high MCI/AD risk could be identified before cognitive decline begins in patients.

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures


Kremen WS, Panizzon MS, Elman JA, et al. Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: association with Alzheimer’s disease polygenic risk. Neurobiol Aging. 2019;83:114-121.