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Discovery of Genetic Mutation Linked to Alzheimer’s Protection May Spur Research for Treatments of Retinal and Blinding Eye Diseases

A research team, which includes scientists from the Schepens Eye Research Institute of Massachusetts Eye and Ear, identified a genetic mutation that may protect against Alzheimer’s disease. Their work could pave the way for learning more about the disease and finding future treatments for Alzheimer’s, and, one day, neurodegenerative diseases that affect vision.

In the study published in November in Nature Medicine, the scientists reported that they found a mutation of the APOE gene – the gene linked to increased Alzheimer’s disease risk in those who possess certain variants. This mutation may have helped prevent a Colombian woman with a strong family history and high risk of early-onset Alzheimer’s from developing the disease.

“While more research is needed, the results from this case study could one day be used to develop interventions to slow Alzheimer’s disease progression,” co-first author Joseph Arboleda-Velasquez, MD, PhD, assistant scientist at Schepens Eye Research Institute, told Focus. “We hope to use this insight to learn how these genetic resistance pathways could also target neurodegenerative diseases that affect vision.”

Joseph Arboleda-Velasquez, MD, PhD, at his office in the Schepens Research Institute of Mass. Eye and Ear in Boston. Credit: Tony Luong/The New York Times

Alzheimer’s mutation: an unexpected discovery

It may not seem typical for vision researchers to be part of a major Alzheimer’s discovery, but this collaboration was borne out of a call from Joan W. Miller, MD, chief of Ophthalmology at Mass. Eye and Ear.

“We encouraged our vision scientists to collaborate across medical disciplines in order to explore new approaches to understanding and treating blinding eye diseases,” said Dr. Miller, who is also the chair of Ophthalmology at Harvard Medical School. “This exciting research is an important result of such collaboration.”

During his training, Dr. Arboleda-Velasquez was a member of Dr. Francisco Lopera’s lab at the University of Antioquia in Colombia. There, they had been carefully studying members of a 6,000-person family who were found to have the highest genetic risk of developing early-onset Alzheimer’s disease by the age of 50. This risk was linked to having the E280A mutation in a gene called presenilin 1 (PSEN1).

Yakeel Quiroz, PhD, who had also been in Dr. Lopera’s lab, and is now the Director of the Familial Dementia Neuroimaging Lab at Massachusetts General Hospital (MGH), has been regularly flying subjects in this family from Colombia to MGH for brain imaging examinations as part of a longitudinal biomarker study. With that infrastructure in place, Dr. Arboleda-Velasquez joined the project and coordinated vision exams for the participants with doctors from the Retina Service at Mass. Eye and Ear, including Leo Kim, MD, PhD and John Miller, MD. It was one of these patients whose imaging revealed she had high levels of amyloid protein in the brain, indicative of Alzheimer’s disease. However, this woman was in her 70s and did not have dementia.

Genome sequencing revealed a genetic mutation: in addition to the PSEN1 E280A mutation, the woman had two copies of a rare variant of the APOE3 gene, called Christchurch (APOEch). This may have provided resistance to the neurodegenerative effects brought on by the PSEN1 E280A mutation this family possessed. The mutation may also explain why this woman was protected against Alzheimer’s, despite her significant familial risk and the high levels of amyloid plaques in her brain, the authors said.

What’s next? Discovery may fuel vision research

Future studies will look at how to advance these genetic findings toward a better understanding of the biology behind Alzheimer’s. Notably, no new Alzheimer’s medications have been released in decades, and several high-profile trials that excited the scientific community have failed in later testing phases.

“This single case opens a new door for treatments of Alzheimer’s disease, based more on the resistance to Alzheimer’s pathology rather than on the cause of the disease. In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology,” said Dr. Quiroz, senior author of the new study.

Dr. Arboleda-Velasquez aims to see how scientists can apply the findings to protection against degenerative diseases that rob people of their vision, such as age-related macular degeneration (AMD).

He points out that AMD and Alzheimer’s disease have many things in common like both impacting elderly individuals. Intriguingly,  he added, amyloid, a molecule critical to Alzheimer’s disease pathology, is also found in drusen, a deposit found in the eyes of patients with AMD.

“True innovation occurs when you bring together people across multiple fields to look at the same problem from different perspectives,” said Dr. Arboleda-Velasquez. “This single case finding has the potential to impact many medical conditions, and in the case of our work at Mass. Eye and Ear, we will utilize it to learn ways to protect against diseases that destroy vision, such as macular degeneration and diabetic retinopathy.”

Dr. Arboleda-Velasquez, Dr. John Miller, and Dr. Leo Kim’s work was funded by the Grimshaw-Gudewicz Charitable Foundation via the grant program coordinated by the Center of Excellence in Age-Related Macular Degeneration at Mass. Eye and Ear.

Read more about the study in:

The New York Times: Why Didn’t She Get Alzheimer’s? The Answer Could Hold a Key to Fighting the Disease

WBUR: How A Woman In Her 70s Might Be The Key To A New Alzheimer’s Treatment

Science Magazine: Rare case offers clues to staving off Alzheimer’s


2 thoughts on “Discovery of Genetic Mutation Linked to Alzheimer’s Protection May Spur Research for Treatments of Retinal and Blinding Eye Diseases”

  1. I am very interested in this knowledge & how it may impact my eyesight ( being Rx’d @ Mass Eye & Ear) & family hx of Alzheimer’s disease with myself now approaching 69 .

    1. Thank you for your comment and for reading Margaret. Dr. Arboleda-Velasquez and his team are hard at work at follow-up studies looking at this gene and more genes that may be associated with Alzheimer’s. We’ll be sure to provide an update here on Focus when more research comes out.

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