Earlier Insight into Alzheimer’s Disease

Published in Wilmer - Fall 2021

When ophthalmologists look into the eye, they can see more than the health of our eyes. They can see if our blood pressure might be elevated and whether or not we have diabetes and even catch a glimpse of our brain in the form of our retina. And one day soon they could be able to spot the beginning of Alzheimer’s disease before someone has even experienced any symptoms.

Researchers have known for a long time that Alzheimer’s disease is characterized by the abnormal function and accumulation of at least two kinds of proteins: amyloid beta and tau. But the changes in those proteins happen over the course of decades — long before memory loss occurs. “The causation is incompletely understood but part of the picture may be that amyloid in some way impairs capillary function,” says Amir Kashani, M.D., Ph.D., a retina specialist and Wilmer’s Boone Pickens Professor of Ophthalmology.

Kashani and his team are using high-resolution imaging equipment called optical coherence tomography angiography (OCTA) to look in the eye to almost micron level — about 1,000th of a millimeter — to identify cellular-level changes in the body. They are tracking the action of capillaries inside the eye to discover if, and in what ways, capillary function could be affected in people with Alzheimer’s disease.

Kashani’s path to studying Alzheimer’s disease began when John Ringman, M.D., a neurologist at the University of Southern California, approached him to collaborate. “I became aware that Amir was using OCTA and developing cutting-edge measures of blood vessels in the eye — how to directly quantify perfusion [blood flow] in the eye and blood vessel density,” he says.

“I thought that would be potentially a good biomarker for what’s going on in the brain,” says Ringman. The retina can be a good model for the brain because it is neural tissue and has a blood-retina barrier similar to the blood-brain barrier.

A central challenge of research into Alzheimer’s disease, however, is the age of most people who have it. “It’s very hard to disentangle the problems that are caused by late-onset Alzheimer’s [LOAD] and everything else that accumulates with time and age,” Kashani says.

For the past two decades, however, Ringman has been working with a population of people with specific genetic mutations that predispose them to develop a highly genetic, very rare kind of Alzheimer’s disease called autosomal dominant Alzheimer’s disease (ADAD). “They’re very enthusiastic about research participation,” says Ringman, who has engaged with this population on multiple research projects. Ringman and Kashani as a team began to study them in 2018.

“Being relatively young, they tend to have little else wrong with them. They don’t have high blood pressure. They don’t have diabetes. They are generally not overweight or underweight. They’re just young, healthy people who happen to have this mutation,” says Kashani.

When someone has inherited the mutation for ADAD, the age of onset for symptoms can be predicted based on when their family members developed symptoms. This relative predictability allowed Kashani’s team to image the retinas of people with ADAD to correlate changes with the age at which a person might be predicted to develop symptoms of the disease.

“It gave us an opportunity to look at these people’s retinas and say, do they have changes in their retina five years before they develop clinical symptoms of Alzheimer’s? Two years before? At the time of? And see if we can detect changes in their capillaries before they actually develop disease,” says Kashani.

What they found was unexpected. “It turns out that people with ADAD-causing mutations that we looked at had abnormally increased levels of capillary blood flow long before they were expected to develop symptoms. Not only that, they also have different patterns of blood flow from those without the mutation,” says Kashani. “It suggests there’s something wrong with the way capillaries are regulating blood flow even before there are any signs of neurological or retinal problems.”

Because the study subjects were healthy other than the genetic mutation, the researchers could conclude that there was likely a direct link between the abnormal blood flow at the capillary level and the mutations that cause ADAD. In fact, the study, which made the cover of Alzheimer’s & Dementia in 2021, showed the first such link between abnormal retinal capillary blood flow and genetic mutations known to cause ADAD in living human subjects.

Kashani’s team has also made strides in identifying a similar association between capillary behavior and the much more common late-onset form of Alzheimer’s disease. In a study published in Alzheimer’s & Dementia (2021), Kashani and colleague Fanny Elahi, M.D., Ph.D., from University of California, San Francisco, showed significant abnormalities in capillary density in the eyes of people with the APOEε4 mutation (the most prevalent genetic risk factor for developing late-onset Alzheimer’s) but without any other signs of cognitive impairment.

“These pair of studies demonstrate that we can detect subclinical capillary-level changes that are associated with Alzheimer’s pathology in human subjects at high risk for disease but without any symptoms,” says Kashani. He adds, “In medicine, typically, before you can cure or treat anything, you have to measure it safely and reliably.” Changes in capillary blood flow offer such an objective measurement.

Kashani and his team hope future studies measuring retinal blood flow in patients will help neurologists more easily identify patients at high risk for developing Alzheimer’s disease — patients who could, ideally, benefit from treatments developed in the future. Perhaps retinal blood flow itself could even become the target for such a future treatment, he says.