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APOE Mutation May Protect Against Alzheimer's

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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, 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. “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.

“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 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."


Arboleda-Velasquez et al. (2019) Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine. DOI: https://doi.org/10.1038/s41591-019-0611-3

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