Retinal Scans Tie Blood Vessel Deterioration to Genetic Marker for Alzheimer’s Disease
By
Vicky Stein, University of California San Francisco
May
13, 2021 -- While it has been said that the eyes are a window to the soul, a
new study shows they could be a means for understanding diseases of the brain.
According to new research by scientists at the UCSF Weill Institute for Neurosciences,
retinal scans can detect key changes in blood vessels that may provide an early
sign of Alzheimer’s disease, while offering important 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,” said lead author Fanny Elahi, MD, PhD. “We
still don’t fully understand how this variant increases 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.”
Studies
in mice have explored the effect of APOE4 on capillaries in the brain. Elahi,
an assistant professor of neurology and member of the UCSF Memory and Aging Center (MAC),
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 colleagues turned to the eye. In the new study,
which publishes May 15, 2021, in the journal Alzheimer’s
and Dementia: Diagnosis, Assessment & Disease Monitoring, Elahi and
her team have shown that APOE4-associated capillary changes can 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
team – which includes Ari
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 – 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.
The
team leveraged the well-characterized cohorts of people enrolled in ongoing
studies of brain aging and neurodegenerative disease at the 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.”
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,” said Elahi.
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 said. "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,"
https://www.ucsf.edu/news/2021/05/420526/eyes-offer-window-alzheimers-disease
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