3d illustration of the human brain with visible blood vessels illustrating Alzheimer's disease and dementia.
Credit: Lars Neumann/Getty Images

A simple retinal scan could predict risk of Alzheimer’s Disease in carriers of the APOE gene, according to new work from researchers at the University of California San Francisco (UCSF).

“This is the first time that we have demonstrated in living, asymptomatic humans that the smallest blood vessels are affected in APOE4 gene carriers,” said the study’s lead author, Fanny Elahi, MD, PhD. She added that their work suggests the increased risk of Alzheimer’s disease in APOE4 carriers may be through the variant’s effect on blood vessels.

An estimated 44 million people worldwide are affected by Alzheimer’s. There is a fevered search for biomarkers that predict this condition and its progression. APOE4 is the most prevalent genetic risk for Alzheimer’s.

While the most attention has been on the beta-amyloid brain plaques these patients form, mouse studies also suggest blood vessels in the brain may play a part in the cognitive decline it causes. As these researchers write in their paper, “It has become increasingly clear that Alzheimer’s disease (AD) is not strictly a disorder of neuronal dysfunction but that changes in vasculature could play an important role in disease pathogenesis.”

There is also considerable evidence that Alzheimer’s affects retinal health.

This team used an advanced retinal imaging technique known as optical coherence tomography angiography (OCTA) to evaluate the smallest blood vessels at the back of the eyes of aging people, with and without the APOE4 mutation.

The team leveraged patients in ongoing studies of brain aging and neurodegenerative disease at the UCSF Memory and Aging Center (MAC). By adding OCTA scans to existing MRI and PET scan data, they gain comparative insights without putting volunteer participants through additional discomfort.

“That’s the beauty of this technique,” Elahi said. “It’s very easy, noninvasive and participant-friendly.”

The researchers found reduced capillary density in APOE4 carriers, an effect that increased with participant age. They then compared the abnormalities seen in OCTA scans of retinal capillaries to measurements of brain perfusion as measured via MRI. Patients with higher retinal capillary density, they found, also had greater blood flow in the brain.

Finally, the team looked to participants with prior PET scans of beta-amyloid to see how their retinal capillary measurements related to the burden of these plaques in the brain. Capillary density did not differ between groups with and without amyloid plaques, nor did it vary along with amyloid burden, suggesting that capillary abnormalities are unlikely to be driven by amyloid pathology.

The team includes Ati Green, MD, a neuro-ophthalmologist, professor, and director of the UCSF Neurodiagnostic Center, and Amir Kashani, MD, PhD, associate professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute.

Elahi and her colleagues now plan to follow their study participants to better understand blood vessel dysfunction at a molecular level. That work could help detect the onset of Alzheimer’s disease before significant damage occurs to the brain and identify new vascular targets for early treatment.

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