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Within the next few years, doctors may be able to spot signs of Alzheimer’s disease and other dementias using routine eye exams well before symptoms appear, a new study suggests.

The research, recently published in Alzheimer’s & Dementia, links abnormal changes in the tiny blood vessels of the retinas of mice with a common genetic mutation known to increase Alzheimer’s disease risk. The findings build on previous work from the same group at The Jackson Laboratory (JAX), which found similar vascular changes in mice’s brains and linked abnormalities in specific retinal cells to early dementia risk, strengthening the case that the retina is a powerful biomarker for Alzheimer’s disease and other dementias.

“If you’re at an optometrist or ophthalmologist appointment, and they can see odd vascular changes in your retina, that could potentially represent something that is also happening in your brain, which could be very informative for early diagnostics,” said Alaina Reagan, a neuroscientist at The Jackson Laboratory (JAX) who led the work with Gareth Howell, professor and Diana Davis Spencer Foundation Chair for Glaucoma Research at JAX who spearheaded the previous study.

Because the retina is part of the central nervous system, scientists often see it as an extension of the brain that shares essentially the same tissue. That’s why changes in retinal blood vessels can offer early clues about brain health and diseases like Alzheimer’s, Reagan said.

Your retina is essentially your brain, but it’s much more accessible because your pupil is just a hole, and we can see tons of stuff. All the cells are very similar, all the neurons are quite similar, all the immune cells are quite similar, and they behave similarly under pressure if you’ve got a disease.”

Alaina Reagan, neuroscientist, The Jackson Laboratory

The team studied mice with a mutation called MTHFR^677C>T, which is found in up to 40% of people. They found that the mice’s retinas had twisted vessels, narrowed and swollen arteries, and less vessel branching as early as six months of age. This reflects similar changes in the brain linked to poor blood flow and increased risk of cognitive decline. Vessels that appear more twisted and looped than normal can signal problems with hypertension, as the narrowing tissue limits nutrient and oxygen transport, Reagan said.

“We can see these wavy vessels in the retinas, which can occur in people with dementia,” Reagan said. “That speaks to a more systemic problem, not just a brain- or retina-specific problem. It could be a blood pressure problem affecting everything.”

In 2022, a study by the same group revealed similar vascular changes in the brains of mice with the same MTHFR^677C>T mutation, highlighting the link between vascular health in the retina that resembles human disease.

“These mice have fewer vessels in their cortex and reduced blood flow to their brains,” Reagan said. “These changes are subtle, but they are there.”

The team also discovered changes in protein patterns in both the brain and retina. They found disruptions in how cells produce energy, remove damaged proteins, and maintain the structure and support of blood vessels, offering important clues about how the MTHFR^677C>T mutation affects the eye. The results also support a growing theory that blood vessel health plays a central role in neurodegenerative diseases, Reagan said.

“A lot of these molecular changes are happening in conjunction, which suggests these systems in brain and retinal tissue are working in tandem,” she said.

Even though more studies are needed to gain a deeper understanding of how vascular health in the retina affects the risk of dementia, the new insights have important implications for people with this genetic factor, Reagan said.

For example, the study also captured the influence of sex and age, with female mice showing worse outcomes. By 12 months, they showed reduced vessel density and branching, highlighting progressive vascular changes. Similarly, women develop dementia more often than men, according to the World Health Organization.

To see if the link between the mutation and vascular changes occurs in humans, as well as whether the new insight could be used in eye exams, the team is partnering with clinicians and dementia care specialists at Northern Light Acadia Hospital in Bangor, Maine.

The idea is to study not just one cause or solution for Alzheimer’s and other dementias, as these conditions depend on many different genetic and environmental factors, but to learn more about how eye health adds to overall risk for these diseases. If the clinicians know which signs to look for, they could communicate those risk factors to patients and recommend further tests.

“Most people over 50 have some kind of vision impairment and get checked annually for prescription changes,” Reagan said. “Are they more at risk if they have these vascular changes, and is that a point when doctors could start mitigating brain changes? That could be 20 years before cognitive damage becomes noticeable to patients and their families.”

Other authors are Michael MacLean, Travis L. Cossette, and Gareth R. Howell from The Jackson Laboratory.

Messenger RNA, or mRNA, vaccines entered the public consciousness when they were introduced during the COVID-19 pandemic, and both Pfizer-BioNTech and Moderna used the technology in developing their highly effective vaccines to fight the virus. 

Since then, scientists have been fine-tuning this vaccine delivery system to make it more effective. A Yale research team has now developed a technology that improves both the power of mRNA vaccines and their effectiveness against a host of diseases.

The new technology offers the promise of expanding the reach of these vaccines, including for the prevention of other diseases, including cancer and autoimmune diseases.

The results of their study are published in Nature Biomedical Engineering.

Unlike traditional vaccines, which typically deliver an inactivated or weakened version of a virus to stimulate a person’s immune response, mRNA vaccines deliver genetic instructions that create a bit of a virus inside the individual’s cells. The cells then make the protein needed to create an immune response.

Everyone is very familiar with mRNA vaccines from the pandemic. But we wondered why the vaccine was working so well in COVID, but not so much in many other diseases that it was being tested on.”

Sidi Chen, associate professor of genetics and neurosurgery at the Yale School of Medicine, study’s senior author

The answer, it turns out, lies in the body’s response to antigens. Antigens are the substances that the immune system recognizes as foreign or possibly harmful, which then triggers an immune response.

But if the body doesn’t recognize an antigen, it can’t mount a good immune response. To be recognized by the body, antigens must attach to the surface of cells, where they are more easily detected. The problem, Chen explained, is that some antigens created by mRNA vaccine are unable to make it to surface. They get stuck deep within cells, evading the body’s immune response system.

To solve this challenge, they developed what they called a molecular vaccine platform (or MVP), which attaches a sort of “cell-GPS” module to the proteins that mRNA vaccines deliver to cells. This, in turn, guides the proteins to the cell surface where they stimulate greater antigen expression and can be seen by the immune system.

Researchers created these “GPS” modules from natural membrane proteins, such as signal peptides and transmembrane anchors that help antigens travel to the cell surface. (Signal peptides are short amino acid sequences that direct a protein to its correct location in a cell, and transmembrane anchors are segments within amino acids that secure proteins to cells, allowing them to move and to communicate.) 

In a series of laboratory experiments, researchers tested the new platform on mpox (formerly known as monkeypox,) human papillomavirus (HPV, which is inked to cervical cancer,) and varicella-zoster virus (shingles.) In all cases, the platform produced stronger immune responses with dramatic improvements in antigen expression, antibody production, and T cell activation, Chen said. 

The new platform could make future mRNA vaccines more reliable and effective against a host of different viruses, as well as other diseases.

“We’re taking an important step forward to allow us to broaden what the vaccines can be used for,” Chen said. “We’re trying to expand this type of technology to other diseases, such as cancer, HIV, and autoimmune conditions.”

Chen is also a member of the Systems Biology Institute at Yale’s West Campus and an affiliate of Yale Cancer Center, Yale Stem Cell Center, and Yale Center for Biomedical Data Science.

The study included 11 Yale-affiliated authors, with postdoctoral fellow Zhenhao Fang and Ph.D. candidate Valter Monteiro serving as first authors. In addition to Chen, senior authors were Carolina Lucas, assistant professor of immunobiology, and Daniel DiMaio, the Waldemar Von Zedtwitz Professor of Genetics, professor of molecular biophysics and biochemistry, and professor of therapeutic radiology.