Tau protein in Alzheimer's disease, illustration

An international team of investigators led by researchers from Mass General Hospital and Mass Eye and Ear have identified, in a single patient, a new genetic variant that is protective against the development of Alzheimer’s disease (AD).

The patient had previously been identified as having a predisposition for developing early-onset AD, but had remained cognitively healthy until his late 60s. A clinical assessment of the man uncovered a new genetic variant that is protective against the development of AD. The newly identified variant occurs in a different gene than the one found in a case from the same family four years ago, but suggests a common disease pathway. The findings are reported today in Nature Medicine.

“The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms,” said Joseph F. Arboleda-Velasquez, MD, PhD, an associate scientist at Mass Eye and Ear and co-senior author. “These are the kinds of insights we cannot gain without patients. They are showing us what’s important when it comes to protection and challenging many of the field’s assumptions about Alzheimer’s disease and its progression.”

The case is the second of a patient in the same family carrying a genetic variant called the “Paisa” mutation (Presenilin-1 E280A). People with this genetic variant typically develop mild cognitive impairment in their mid 40s, dementia at a median age of 49, dying of complications of AD in their 60s.

Co-first author Francisco Lopera, MD, director of the Neuroscience Group of Antioquia in Medellín, Colombia, discovered the family and has been following them for the past 30 years in his research. The first case, reported in 2019, was a woman in the family who remained cognitively healthy into her 70s. In the new study, the investigators report that a male carrier of the Paisa gene remained cognitively intact until he was 67, then progressed to mild dementia by 72 and died at 74, a disease progression that is decades later compared with most people possessing the Paisa mutation.

“What we have done with the study of these two protected cases is to read mother nature,” said Lopera. “The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it. Mother nature did an exceptional experiment with these two subjects: it endowed them both with a gene that causes Alzheimer’s and at the same time with another gene that protected them from the symptoms of the disease for more than two decades. Therefore, the solution is to imitate nature by developing therapies that mimic the mechanism of protection of these genetic variants in subjects at risk of suffering from the disease.”

To study the male subject, he was enrolled in the Mass General Colombia-Boston biomarker study (COLBOS), which has enrolled more than 6,000 people in the extended family group with the Paisa mutation. Subjects in the research are brought to Boston for advanced neuroimaging, biomarker and genetic examinations. The previous case reported in 2019 found the female carried two copies of a rare Christchurch genetic variant that affects the AD-implicated APOE3 gene.

But the new male subject didn’t have the Christchurch variant. Genetic and molecular analyses determined that a new variant in the Reelin gene was the most likely one protecting the man from the onset of AD. Dubbing the new variant Reelin-COLBOS, co-senior author Sepulveda-Falla, MD, of the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, and team verified the protective role of the Reelin-COLBOS variant in mouse models and neuropathological studies.

“Each of the protected cases, the APOE Christchurch and the Reelin-COLBOS case, shows a distinctive protective pattern in the postmortem analyses, one global and the other very localized,” said Sepulveda-Falla. “These outstanding cases are teaching us that Alzheimer’s protection can take different shapes, and that perhaps a therapy can be successful just by targeting key brain structures such as the entorhinal cortex. They are forcing us to revise our previous concepts about neurodegeneration and cognitive decline. These are exciting times for us, and hopefully for the Alzheimer’s research field as well.”

Reelin is a protein with a pivotal role in the regulation of brain cell development and function and the researcher describe it as a “cousin” of APOE. Previous research has linked Reelin to the development of other neurological diseases such as autism, schizophrenia, epilepsy, and bipolar disorder. But these disease-linked variants in Reelin result in loss of function, whereas Reelin-COLBOS increases the function of the protein.

The relationship between Reelin and APOE is one that sees them both compete to bind to similar cellular receptors. When Reelin binds to the receptors, it diminishes the phosphorylation of the tau protein, which is the protein responsible for the formation of the tangles that lead to AD.

“When we saw that one of our top candidates for the variant sat in Reelin, it was a bit shocking,” said Arboleda-Velasquez. “The fact that the first case showed us a variant affecting APOE and the second case affects Reelin tells us that this signaling pathway that controls the phosphorylation of tau, among other effects, may be key to understanding why these patients were protected. This is critical to guide therapies because it clearly tells us that more Reelin could potentially have beneficial effects.”

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