Summary: Adults with mild cognitive impairment (MCI), a precursor to Alzheimer’s disease, have greater pupil dilation when taking cognitive tests than their cognitively normal peers. Task-evoked pupillary response may be a cost-effective, and low invasive screening test for those at genetic risk for Alzheimer’s before the symptoms of the disease take hold.
Alzheimer’s disease (AD) begins to alter and damage the brain years — even decades — before symptoms appear, making early identification of AD risk paramount to slowing its progression.
In a new study published online in the September 9, 2019 issue of the Neurobiology of Aging, scientists at University of California San Diego School of Medicine say that, with further developments, measuring how quickly a person’s pupil dilates while they are taking cognitive tests may be a low-cost, low-invasive method to aid in screening individuals at increased genetic risk for AD before cognitive decline begins.
In recent years, researchers investigating the pathology of AD have primarily directed their attention at two causative or contributory factors: the accumulation of protein plaques in the brain called amyloid-beta and tangles of a protein called tau. Both have been linked to damaging and killing neurons, resulting in progressive cognitive dysfunction.
The new study focuses on pupillary responses which are driven by the locus coeruleus (LC), a cluster of neurons in the brainstem involved in regulating arousal and also modulating cognitive function. Tau is the earliest occurring known biomarker for AD; it first appears in the LC; and it is more strongly associated with cognition than amyloid-beta. The study was led by first author William S. Kremen, PhD, and senior author Carol E. Franz, PhD, both professors of psychiatry and co-directors of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine.
The LC drives pupillary response — the changing diameter of the eyes’ pupils — during cognitive tasks. (Pupils get bigger the more difficult the brain task.) In previously published work, the researchers had reported that adults with mild cognitive impairment, often a precursor to AD, displayed greater pupil dilation and cognitive effort than cognitively normal individuals, even if both groups produced equivalent results. Critically, in the latest paper, the scientists link pupillary dilation responses with identified AD risk genes.
“Given the evidence linking pupillary responses, LC and tau and the association between pupillary response and AD polygenic risk scores (an aggregate accounting of factors to determine an individual’s inherited AD risk), these results are proof-of-concept that measuring pupillary response during cognitive tasks could be another screening tool to detect Alzheimer’s before symptom appear,” said Kremen.
Co-authors include: Matthew S. Panizzon, Jeremy A. Elman, Anders M. Dale, Daniel E. Gustavson and Nathan Whitsel, UC San Diego; Eric L. Granholm, UC San Diego and Veterans Affairs San Diego Healthcare System; Ole A. Andreassen, Oslo University Hospital; Nathan A. Gillespie and Michael C. Neale, Virginia Commonwealth University; Mark W. Logue, VA Boston Healthcare System and Boston University; Michael J. Lyons, Boston University; and Chandra A. Reynolds, UC Riverside.
Disclosure: Anders Dale is founder and holds equity in CorTech Labs, Inc. and serves on its scientific advisory board. He also has equity interest in and is a member of the scientific advisory board of Human Longevity, Inc., and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc.
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Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk
Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer’s disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment (MCI) have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillary responses in middle-aged CN adults. Pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. In a CN subset—all with comparable span capacities (n=539)—higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit) cognitive load condition (Cohen’s d=.36 for upper versus lower quartile of AD-PRS distribution). Results held up after controlling for APOE genotype. Results support pupillary response—and by inference, LC dysfunction—as a genetically-mediated biomarker of early MCI/AD risk. In combination with other biomarkers, task-evoked pupillary responses may provide additional information for early screening of genetically at-risk individuals even before cognitive declines.
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