Investigators at the University of California San Francisco (UCSF) Weill Institute for Neurosciences may have found the window into understanding and potentially diagnosing Alzheimer’s disease early. New findings from the researchers—published recently in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring through an article entitled “Retinal imaging demonstrates reduced capillary density in clinically unimpaired APOE ε4 gene carriers”—showed that retinal scans could detect key changes in blood vessels that may provide an early sign of Alzheimer’s while offering essential insights into how one of the most common Alzheimer’s risk genes contributes to the disease.

“The most prevalent genetic risk for Alzheimer’s disease is a variant of the APOE gene, known as APOE4,” explained lead study investigator Fanny Elahi, MD, PhD, an assistant professor at UCSF’s Weill Institute for Neurosciences .“We still don’t fully understand how this variant increases the risk of brain degeneration, we just know that it does and that this risk is modified by sex, race, and lifestyle. Our research provides new insights into how APOE4 impacts blood vessels and may provide a path forward for early detection of neurodegenerative disease.”

Previous studies in mice have explored the effect of APOE4 on capillaries in the brain. Elahi has long suspected these tiny blood vessels may play a significant role in Alzheimer’s disease since they deliver nutrients and oxygen, carry away waste, and police immune system responses through the protective shield known as the blood-brain barrier. Damage to these blood vessels could cause a host of problems, she says, including the protein buildup and cognitive decline seen in individuals affected by Alzheimer’s disease.

Because the technology does not exist to visualize individual capillaries in living people’s brains, Elahi and her colleagues turned to the eye. In the current study, the researchers observed that APOE4-associated capillary changes could be detected in humans through an easy, comfortable eye scan. As a light-penetrating tissue that shares biology with the brain, the retina, researchers believe, may help determine what APOE4 variants may be doing to similar capillaries inside the brain, even in those without dementia.

The research team used an advanced retinal imaging technique known as optical coherence tomography angiography (OCTA) to peer into the eyes of aging people with and without APOE4 mutations to evaluate the smallest blood vessels at the back of the eye.

“We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations,” the authors wrote.

Additionally, the scientists leveraged the well-characterized cohorts of people enrolled in ongoing studies of brain aging and neurodegenerative disease at the Memory and Aging Center (MAC) at UCSF. 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.”

Analyzing the retinal scans, the researchers found reduced capillary density in APOE4 carriers, an effect that increased with participant age. To test whether those scans accurately reflected what was happening in the brain, the team then compared the abnormalities seen in OCTA scans of retinal capillaries to measurements of brain perfusion, or the flow of blood through the brain, as measured via MRI. They found that people with higher retinal capillary density also had greater blood flow in the brain.

Finally, the team looked to participants with prior PET scans of beta-amyloid, the protein associated with Alzheimer’s disease, to see how their retinal capillary measurements related to the burden of amyloid plaques in the brain, which is the major focus of Alzheimer’s disease diagnosis, research, and treatment to date. They found that capillary density did not differ between groups with and without amyloid plaques, nor did it vary along with amyloid burden. According to Elahi, that independence suggests that capillary abnormalities are unlikely to be driven by amyloid pathology or that their relation may at most be indirect.

“This is the first time that we have demonstrated in living, asymptomatic humans that the smallest blood vessels are affected in APOE4 gene carriers,” Elahi noted.

That’s important, she added, because it suggests that the increased risk of brain degeneration and Alzheimer’s disease in APOE4 carriers may be through its effect on blood vessels.

Elahi and her colleagues 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.

“This is just the beginning,” Elahi concluded. “But the implications for early detection and possible intervention can be significant in combatting Alzheimer’s disease and other neurodegenerative disorders. It’s much harder to regenerate neurons than to stop their degeneration from happening in the first place. Similar to cancer, early detection can save lives.”

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