Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

Abstract

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 (h 2 =.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.

Neural and Retinal Characteristics in Relation to Working Memory in Older Adults with Mild Cognitive Impairment

“…In addition, their WM performance was poorer than those without MCI. These findings, alongside similar results in other studies [40,41],…”

Aging impairs reactive attentional control but not proactive distractor inhibition.

“…In Alzheimer's disease (AD) research, the eye has been investigated as a potential biomarker (Lim et al, 2016) and pupillary responses has shown to predict AD risk (Granholm et al, 2017;Kremen et al, 2019). In addition, eye movements have shown to be sensitive in distinguishing between neurodegenerative diseases (Garbutt et al, 2008;Lage et al, 2021;Liu et al, 2021) and also between patients with AD and prodromal stages such as mild cognitive impairment (MCI) using the antisaccade task (Chehrehnegar et al, 2019(Chehrehnegar et al, , 2022Opwonya et al, 2022;Peltsch et al, 2014;Wilcockson et al, 2019).…”

The impact of age and Alzheimer’s disease on locus coeruleus mediated neuromodulation of neural circuits and goal-directed behavior

“…Of particular interest in relation to the discussion in above (Section 3), this LFBV effect was found in regions of the ventral attention network, including the anterior cingulate cortex. Further support for this hypothesis came from a subsequent study in which a polygenic risk score for AD (AD-PRS) was shown to covary with pupil responses during a cognitive load task [Kremen et al, 2019].…”