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Two views on Alzheimer's biomarkers: Eyeing changes in vision or pupils

Findings in two separate NIA-funded papers focus on different ways to develop noninvasive, less expensive ways to detect very early-stage Alzheimer’s disease in cognitively healthy people. The studies suggest that changes in vision and pupil responses may be effective biomarkers for Alzheimer’s in those at greater risk for dementia.

In one study, published in Brain Communications, a reduced ability in adults age 50 and older to see differences in flickering light was associated with accumulation in the brain of amyloid and tau, two hallmark proteins of Alzheimer’s. In the other study, published in Neurobiology of Aging, greater dilation of middle-aged adults’ pupils during cognitive testing was linked to higher genetic risk scores for the disease.

P E T scans; see text for explanation
Image courtesy of Shannon L. Risacher, Ph.D., Indiana School of Medicine

In the first study, researchers from the Indiana Alzheimer Disease Center, Indianapolis, assessed visual contrast sensitivity — the ability to distinguish objects from their background — in 74 older adults, including 31 cognitively healthy individuals and others at various stages of cognitive impairment. Participants also had brain scans, including magnetic resonance imaging to measure brain volume, positron emission tomography (PET) to measure amyloid accumulation, and, in 46 participants, PET to measure tau accumulation — all of which can show the earliest brain changes of Alzheimer’s, before memory loss and other symptoms are evident.

Many people with Alzheimer’s disease have visual problems, such as changes in color vision, and past studies have shown retinal and other changes in their eyes. The researchers wanted to know if a test for impaired visual contrast sensitivity could detect Alzheimer’s when amyloid and tau abnormalities are just beginning to occur in the brain. They measured visual contrast sensitivity in participants, none of whom had serious eye diseases, using frequency doubling technology. People with poorer contrast sensitivity took longer to complete the exam than those with normal contrast sensitivity.

In all participants, poorer visual contrast sensitivity was significantly associated with amyloid and tau deposits in certain parts of the brain, as well as a lower temporal lobe volume. Based on these findings, the authors suggest that visual contrast sensitivity may detect very early-stage Alzheimer’s more easily, less invasively and less expensively than current imaging and spinal-tap methods. Larger studies are needed to further test visual contrast sensitivity as a potential biomarker for Alzheimer’s and to probe the underlying biological causes of eye changes in people with the disease.

In the second study, researchers from the University of California, San Diego, investigated another noninvasive method — pupil dilation during cognitive test taking — in more than 1,000 men age 56 to 66 who were enrolled in the Vietnam Era Twin Study of Aging. A prior study by the research team showed that pupils of people with mild cognitive impairment (MCI), who are at higher risk for Alzheimer’s, became bigger than those of cognitively normal individuals when taking a test of verbal short-term memory, indicating greater cognitive effort. The new study related the degree of pupil dilation during testing, or pupillary response, to genetic risk for Alzheimer’s.

The researchers found that participants who exerted more effort during the most demanding cognitive test (as shown by bigger pupils) had a higher genetic risk for Alzheimer’s than those whose pupils were less dilated.

Pupillary response might be a new, noninvasive method that, combined with other biomarkers, identifies cognitively normal people who are at risk for Alzheimer’s early in the disease process, the authors concluded. It was also noted that since this study involved white, middle-aged men of European ancestry, future studies that include more diverse populations are needed to assess the generalizability of the findings.

The research published in Brain Communications was funded in part by NIA grants K01AG049050, R01AG061788, R01AG19771 and P30AG10133. The research published in Neurobiology of Aging was funded in part by NIA grants R01AG050595, R01AG022381, P01AG055367, R01AG059329, K08AG047903 and AG054509.

These activities relate to NIA’s AD+ADRD Research Implementation Milestone 9.F. “Initiate studies to develop minimally invasive biomarkers for detection of cerebral amyloidosis, AD and AD-related dementias pathophysiology.”

References: Risacher SL, et al. Visual contrast sensitivity is associated with the presence of cerebral amyloid and tau deposition. Brain Communications. Published online Feb. 26, 2020. https://doi.org/10.1093/braincomms/fcaa019.

Kremen WS, et al. Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s disease: Association with Alzheimer’s disease polygenic risk. Neurobiology of Aging. 2019;83:114-121.