Researchers Identify Genetic Mutation Tied to Alzheimer’s Disease Protection

Boston, Mass. — A team of researchers has identified that a genetic mutation of the APOE gene, the major susceptibility gene for late-onset Alzheimer’s disease, may provide protection against the devastating neurological illness. The findings from this study, a collaboration of multiple institutions, including Massachusetts Eye and Ear, Mass General Hospital, the University of Antioquia, and Banner Alzheimer’s Institute, were published November 4 in Nature Medicine and may provide scientists with a new target for research and therapeutic treatment for Alzheimer’s and other neurodegenerative diseases.

Studying people with Alzheimer’s disease-causing mutations, who do not show signs of the disease until older ages, could help in the discovery of risk-reducing genes. This case report describes one such patient, a woman who was part of study of 1,200 people in Colombia who were found to be at highest genetic risk to develop early-onset Alzheimer’s disease due to a E280A mutation in a gene called presenilin 1 (PSEN1). This woman, however, did not develop mild cognitive impairment until her late 70s, which was about 30 years later than other genetic carriers in the study.

Imaging tests showed she had unusually high levels of amyloid plaque deposits in the brain, which are telltale markers of Alzheimer’s disease, despite not showing symptoms. When the researchers performed whole exome sequencing, they found that in addition to the PSEN1 E280A mutation, the woman had two copies of a rare variant of the APOE3 gene, called Christchurch (APOEch).

Having two copies of the APOEch mutation may have provided resistance to the neurodegenerative effects brought on by the PSEN1 E280A mutation. According to the authors, this may have protected her against developing Alzheimer’s disease, despite her high familial risk and the presence of amyloid plaque deposits in her brain.

“This finding suggests that artificially modulating the binding of APOE could have potential benefits for the treatment of Alzheimer’s disease, even in the context of high levels of amyloid pathology,” said co-first author Joseph F. Arboleda-Velasquez, MD, PhD, Assistant Scientist at Schepens Eye Research Institute of Mass. Eye and Ear and Assistant Professor of Ophthalmology at Harvard Medical School. “While additional research is necessary, the results from this case study identifying protection from the development of Alzheimer’s disease through the APOEch gene mutation could be used to develop interventions to slow Alzheimer’s disease progression.”

“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 study senior author Yakeel T. Quiroz, PhD, a clinical neuropsychologist and neuroimaging researcher at Mass General Hospital.

“This study underscores the importance of APOE in the development, treatment and prevention of Alzheimer’s, not to mention the profound impact that even one research volunteer can have in the fight against this terrible disease,” added Eric M. Reiman, MD, executive director of Banner Alzheimer’s Institute and co-senior author of the study. “We hope that our findings galvanize and inform the discovery of APOE-related drug and gene therapies, such that we can put them to the test in treatment and prevention studies as soon as possible.”

This multi-institutional collaboration began for Dr. Arboleda-Velasquez and his Mass. Eye and Ear colleagues about two years ago when the Department of Ophthalmology at Mass. Eye and Ear tasked vision researchers with seeking research projects outside of ophthalmology. Dr. Arboleda-Velasquez and colleagues became interested in studying potential factors involved in neuroprotection, as age-related macular degeneration (AMD) is a neurodegenerative condition of the eye and a leading cause of blindness in people over 50. Some subjects whose genomes were sequenced in the paper were examined at Mass. Eye and Ear by John B. Miller, MD, and Leo A. Kim, MD, PhD, members of the Retina Service.

"We encourage our vision scientists to collaborate across medical disciplines in order to explore new approaches to understanding and treating blinding eye diseases," said Joan W. Miller, MD, Chief of Ophthalmology at Massachusetts Eye and Ear and Massachusetts General Hospital and Chair of Ophthalmology and David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School. "This exciting research is an important result of such a collaboration. Further research may lead to new treatment targets for neurodegenerative eye diseases like age-related macular degeneration."

The study was funded by the U.S. National Institutes of Health (NIH), Massachusetts General Hospital Executive Committee on Research, Alzheimer’s Association, Grimshaw-Gudewicz Charitable Foundation, Banner Alzheimer’s Foundation, Nomis Foundation, State of Arizona, and Anonymous Foundation.

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

Authors of the study in addition to Drs. Arboleda-Velasquez, Quiroz, and Reiman, include: Francisco Lopera, Michael O’Hare, Santiago Delgado-Tirado, Claudia Marino, Natalia Chmielewska, Kahira L. Saez-Torres, Dhanesh Amarnani, Aaron P. Schultz, Reisa A. Sperling, David Leyton-Cifuentes, Kewei Chen, Ana Baena, David Aguillon, Silvia Rios-Romenets, Margarita Giraldo, Edmarie Guzmán-Vélez, Daniel J. Norton, Enmanuelle Pardilla-Delgado, Arabiye Artola, Justin S. Sanchez, Juliana Acosta-Uribe, Matthew Lalli, Kenneth S. Kosik, Matthew J. Huentelman, Henrik Zetterberg, Kaj Blennow, Rebecca A. Reiman, Ji Luo, Yinghua Chen, Pradeep Thiyyagura, Yi Su, Gyungah R. Jun, Marcus Naymik, Xiaowu Gai, Moiz Bootwalla, Jianling Ji , Lishuang Shen, John B. Miller, Leo A. Kim, Pierre N. Tariot, Keith A Johnson. Drs. Arboleda-Velasquez, Lopera, and O’Hare contributed equally to this article. Drs. Quiroz and Reiman are co-senior authors

About Massachusetts Eye and Ear

Massachusetts Eye and Ear, founded in 1824, is an international center for treatment and research and a teaching hospital of Harvard Medical School. A member of Partners HealthCare, Mass. Eye and Ear specializes in ophthalmology (eye care) and otolaryngology–head and neck surgery (ear, nose and throat care). Mass. Eye and Ear clinicians provide care ranging from the routine to the very complex. Also home to the world's largest community of hearing and vision researchers, Mass. Eye and Ear scientists are driven by a mission to discover the basic biology underlying conditions affecting the eyes, ears, nose, throat, head and neck and to develop new treatments and cures. In the 2019–2020 “Best Hospitals Survey,” U.S. News & World Report ranked Mass. Eye and Ear #4 in the nation for eye care and #2 for ear, nose and throat care. For more information about life-changing care and research at Mass. Eye and Ear, visit our blog, Focus, and follow us on Instagram, Twitter and Facebook.

About Harvard Medical School Department of Ophthalmology

The Harvard Medical School Department of Ophthalmology (eye.hms.harvard.edu) is one of the leading and largest academic departments of ophthalmology in the nation. More than 400 full-time faculty and trainees work at eight Harvard Ophthalmology affiliate institutions, including Massachusetts Eye and Ear [home to Schepens Eye Research Institute], Massachusetts General Hospital, Brigham and Women’s Hospital, Boston Children’s Hospital, Beth Israel Deaconess Medical Center, Joslin Diabetes Center/Beetham Eye Institute, Veterans Affairs Boston Healthcare System, and Cambridge Health Alliance. Formally established in 1871, the department has been built upon a strong and rich foundation in medical education, research, and clinical care. Through the years, faculty and alumni have profoundly influenced ophthalmic science, medicine, and literature—helping to transform the field of ophthalmology from a branch of surgery into an independent medical specialty at the forefront of science.