In a big Colombian extended family that had long suffered the terrible genetic legacy of early onset Alzheimer’s disease, one woman at high risk remained dementia-free for decades beyond expectations.
Now, a team of researchers has identified a rare genetic mutation of the APOE gene, the major susceptibility gene for late-onset Alzheimer’s disease, that may have protected the woman against the devastating neurological illness. The findings from this study, a collaboration of multiple institutions in the U.S. and Colombia, were published in the journal Nature Medicine and may provide scientists with a new target for research and therapeutic treatment for Alzheimer’s and other neurodegenerative diseases.
“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,” said Eric M. Reiman, M.D., executive director of Banner Alzheimer’s Institute and co-senior author of the study.
Studying people with Alzheimer’s-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 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.
Researchers led by Colombian neurologist Francisco Lopera, M.D., have followed this family for years, collecting reams of data in the hope of finding a key to unlocking the secrets of the disease. Imaging tests in the U.S. showed the woman had unusually high levels of amyloid plaque deposits in the brain, which are telltale markers of Alzheimer’s disease – despite not showing symptoms.
The amyloid plaques are thought to lead to buildups of another deformed protein, called tau, along with inflammation and the ultimate destruction of neurons. But the woman didn’t have the characteristic tangles of tau. In addition, the regions of her brain that are most commonly affected by Alzheimer’s still seemed to be working just like they would in an otherwise healthy adult.
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 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, M.D., Ph.D., 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, Ph.D., a clinical neuropsychologist and neuroimaging researcher at Mass General Hospital.
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.