Conference Coverage

Retinal Changes May Reflect Brain Changes in Preclinical Alzheimer’s Disease

Retinal nerve fiber layer volume loss may occur in patients with brain amyloid plaques, which suggests that retinal scans could become a noninvasive and inexpensive way to identify people at risk of Alzheimer’s disease.


BOSTON—Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.

Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta-amyloid brain plaques well before cognitive problems arise. The changes can be measured with equipment present already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.

Peter J. Snyder, PhD

The findings suggest that retinal scans might eventually be an easy, noninvasive, and inexpensive way to identify people who may be at elevated risk for Alzheimer’s disease, Dr. Snyder said.

“If we are lucky enough to live past age 45, then it is a given that we are all going to develop some presbyopia,” he said. “So, we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical Alzheimer’s disease profile to specialty care for more comprehensive diagnostic evaluations.”

A Potential Window to the Brain

The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense, then, that early neuronal changes in Alzheimer’s disease could occur in the retina as well, said Dr. Snyder, Professor of Neurology and Surgery (Ophthalmology) at Rhode Island Hospital and Brown University in Providence.

“The retina is really a protrusion of the brain, and it is part and parcel of the CNS,” Dr. Snyder said. “In terms of the neuronal structure, the retina develops in layers with specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That is why it is, potentially, literally a window that could let us see what is happening in the brain in early Alzheimer’s disease.”

Prior studies have examined the retina as a predictive marker for Alzheimer’s disease. At the 2016 Alzheimer’s Association International Conference, Fang Sarah Ko, MD, an ophthalmologist in Tallahassee, Florida, presented three-year data associating retinal nerve fiber layer thinning to cognitive decline in the UK Biobank, an ongoing prospective health outcomes study.

Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.

Patients Had Subjective Memory Complaints

For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.

Dr. Snyder imaged each subject’s retinas at baseline and at 27 months, when everyone underwent a second amyloid PET scan. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina that typically is used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma, and multiple sclerosis.

Dr. Snyder examined the optic nerve head and macula at both time points and assessed volumetric changes in the peripapillary retinal nerve fiber layer, the macular retinal nerve fiber layer, the ganglion cell layer, the inner plexiform layer, the outer nuclear layer, the outer plexiform layer, and the inner nuclear layer. He also computed changes in total retinal volume.

Between-Group Differences

At baseline assessment, Dr. Snyder found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but … it suggests that there may be inflammatory processes going on in this early stage and that we are catching that inflammation.” An independent research group has replicated this finding with a larger sample of participants and plans to report its results later this year, Dr. Snyder noted.

At 27 months, the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical Alzheimer’s disease group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.

In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.

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