Pupillary responses as a biomarker of early risk for Alzheimer’s disease: Association with tau not beta‐amyloid

Abstract

AbstractBackgroundWe examined pupillary responses as a novel biomarker of early risk for Alzheimer’s disease (AD). Pupil dilation recorded during cognitive tasks provides a biomarker of the extent of cognitive effort required to achieve a given test score. Greater dilation indicates greater effort. Test scores decline when capacity to compensate is exceeded, so individuals allocating more effort are likely closer to maximum compensatory capacity and at higher risk for decline. We previously found greater pupil dilation in individuals with mild cognitive impairment (MCI) relative to cognitively‐normal (CN) controls. Pupillary responses reflect neuromodulatory activity in the locus coeruleus (LC), and studies implicate the LC as an early site of AD degenerative changes, especially tauopathy. The present study, therefore, examined whether greater pupil dilation (compensatory cognitive effort) on the digit span task was associated with greater tau biomarker levels.MethodPupillary responses were recorded using a Tobii pupillometer during the digit span task and CSF biomarkers of AD (Aβ40; Aβ42 and p‐tau181) were collected in CN (N=37) and MCI (N=17) participants. Three trials at each span length (3‐9 digits) were administered until reaching max span (highest span with at least one correct trial).ResultIn the total sample, greater p‐tau was significantly associated with greater pupil dilation during the digit span task. However, pupil dilation was not significantly associated with beta‐amyloid. Importantly, performance (max span or total accuracy of digit recall) was not significantly correlated with pupil dilation or any of these biomarkers, so pupil dilation, but not performance, was associated with p‐tau biomarker risk.ConclusionGreater tau deposition, but not beta‐amyloid, was associated with greater compensatory cognitive effort during the digit span task. This simple 5‐min pupil dilation task holds promise as a novel marker of early AD risk specifically linked to tauopathy and impaired functionality of the LC years prior to cognitive decline and diagnosis.