Cedars-Sinai Investigators Find Clues in the Eye That Point to Earliest-Stage Disease

Blood vessel abnormalities in the eye are a major factor in the progression of Alzheimer’s disease, according to research from Cedars-Sinai investigators published in the peer-reviewed journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association. These changes correspond to changes in the brain, offering a new possibility for early diagnosis.

“This study provides a new understanding of the vascular changes associated with Alzheimer's disease,

 especially in the retina, the layer of nerve tissue at the back of the eye,” said Maya Koronyo-Hamaoui, PhD, professor of Neurology, Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “It also points to the damage Alzheimer’s disease causes to the blood vessels in the retina, enabling a new, noninvasive pathway to early diagnosis and monitoring of disease progression.”

Investigators compared blood vessels in retinas collected from 24 human donors with Alzheimer’s disease, 10 donors with mild cognitive impairment and 27 with normal cognition.

In patients with Alzheimer’s disease and mild cognitive impairment, they found one of the earliest signs of Alzheimer’s disease to date: disruption of the blood-retinal barrier, where tightly joined cells prevent harmful substances from entering the retinal tissue.

“In patients with Alzheimer’s disease, we found that there was a deficit of as much as 70% in that barrier, meaning harmful substances can pass through and enter the retinal tissue,” said Haoshen Shi, MD, PhD, project scientist and first author of the study. “We see that this occurs very early on, in patients with only mild functional impairment.”

Damage to the blood-retinal barrier was strongly associated with a condition called cerebral amyloid angiopathy (CAA)—the accumulation of amyloid proteins in small blood vessels—and other vascular disease in the brain.

“Currently, the only way to detect CAA in patients is in post-mortem brain tissue samples,” said Koronyo-Hamaoui. “With additional research and the development of advanced retinal imaging, vascular and blood-retinal barrier damage could give us the first opportunity to detect CAA in living patients.”

The study also found that deposits of a protein called amyloid beta 40 accumulated in the retinal arteries of Alzheimer’s disease patients, making the arteries stiff, disrupting blood flow and preventing the arteries from clearing harmful substances from the retina. Further studies are necessary to determine whether the deposits accumulate because of blood vessel damage, or actually cause the damage, Koronyo-Hamaoui said.

“Retinal and brain tissues are rich in blood vessels, and high blood supply is fundamental for their function,” Koronyo-Hamaoui said. “Restriction of blood supply, which may occur due to the damage we show happening here, means that these cells do not get the oxygen and the nutrients that they need.”

Advanced retinal imaging, which would look at the blood vessels and protein accumulation noninvasively in living patients, is in development but is not yet approved by the Food and Drug Administration, Koronyo-Hamaoui said.

“As an anatomical extension of the brain, the retina has been extensively examined as a window to central nervous system disorders,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “This work adds to recent progress in advanced retinal imaging and identification of other retinal biomarkers to advance the science of Alzheimer’s disease early detection.”

Meanwhile, Koronyo-Hamaoui advises people to do what they can to keep their circulatory system, including the blood vessels in the retina and the brain, healthy to help prevent CAA and dementia.

“Controlling hypertension, eating a healthy diet low in sugar, reducing alcohol consumption and avoiding smoking helps prevent chronic inflammation and damage to blood vessels,” Koronyo-Hamaoui said. “Our study shows that blood vessel damage is a major element in the progression of Alzheimer’s disease.”

Funding: This study was supported by Alzheimer's Association Research Fellowship to Promote Diversity grant number AARFD-21-851509; National Institute on Aging of the National Institutes of Health grant numbers R01 AG055865, R01 AG056478, and R01 AG075998; The Thomas J. Gordon and The Saban Family Foundations; The Ray Charles Foundation; and National Eye Institute of the National Institutes of Health grant numbers R01 EY013431 and P30 AG 066530.

Learn more on the Cedars-Sinai Blog: Q&A: Dementia Expert Dr. Zaldy Tan