Rare genetic resilience to Alzheimer’s identified in second patient

A rare genetic resilience to Alzheimer’s disease has been identified in a second patient, a new study suggests.

Researchers found a patient with a genetic predisposition for developing early-onset Alzheimer’s who remained cognitively intact until his late 60s.

According to the study a new genetic variant (differences in DNA between people) that provides protection from the disease.

The variant occurs in a different gene than in a case from the same family reported in 2019, but points to a common disease pathway, the study suggests.

The findings also identify a region of the brain that may provide an ideal treatment target in the future, according to an international team led by investigators from two Mass General Brigham hospitals in America – Massachusetts General Hospital (MGH) and Mass Eye and Ear.

The researchers suggest the findings could open a door for the prevention and treatment of incurable diseases.

Co-senior author Joseph Arboleda-Velasquez, an associate scientist at Mass Eye and Ear, said: “The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms.

“These are the kinds of insights we cannot gain without patients.”

The case that caught the investigators’ attention involved a family member of the world’s largest-known family and relations with a genetic variant called the “Paisa” mutation.

Carriers of this variant usually develop mild cognitive impairment at an average age of 44, dementia at 49, and die from complications of the conditions in their 60s.

Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellin, Colombia, a co-first author of the Nature Medicine paper, is the neurologist who discovered this family and has been following them for the last 30 years.

The researchers had previously studied a woman from the family who remained unimpaired until her 70s and whose case was reported in 2019.

In the new study, they describe a case of a male carrier of the mutation who remained cognitively intact until age 67.

He progressed to mild dementia at age 72 and died at 74 – decades after most people with the Paisa mutation typically do, researchers say.

Co-senior author Yakeel Quiroz, is a clinical neuropsychologist and neuroimaging researcher, director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital.

She said: “Extraordinary cases like this one illustrate how individuals and extended families with Alzheimer’s disease can help advance our understanding of the disease and open new avenues for discovery.

“The insights we are gaining from this second case may guide us on where in the brain we need to look to delay and stop disease progression and will help us form new hypotheses about the series of steps that may actually lead to Alzheimer’s dementia.”

Dr Lopera said: “What we have done with the study of these two protected cases is to read mother nature.

“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.”

Dr Lopera added: “A great door has been opened for the prevention and treatment of incurable diseases.”

The male patient was enrolled in the Mass General Colombia-Boston biomarker study, which brings members of an extended family group of 6,000 people with the known Paisa mutation to Boston for advanced neuroimaging, biomarker and genetic examinations.

The same study previously detected a case in which a female patient carried two copies of a rare Christchurch genetic variant, which affects APOE3 — a protein that is heavily implicated in Alzheimer’s disease.

However, the researchers ruled out the presence of the APOE Christchurch genetic variant in the male patient.

Instead, the most promising candidate was a new and rare variant, never before reported in the Reelin gene. The team named it Reelin-COLBOS.

As investigators look for treatment that may in the future deliver treatments that can modify or manipulate gene expression, understanding what region of the brain to focus on for delivery will become increasingly important.

Many treatments for Alzheimer’s target reducing amyloid plaque build-up.

However the researchers say the new findings point to potential new avenues for treatment because the two patients with protection had extremely high levels of amyloid in their brains, and yet they were protected.

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