Genetic trait may help delay early onset disease

By Staff 8 Min Read

  • Some people are genetically predisposed to develop early-onset Alzheimer’s disease before the age of 65.
  • Researchers from Mass General Brigham have discovered a genetic variant that may help protect people with a variant of a different gene that predisposes them to developing early-onset Alzheimer’s disease.
  • This may offer potential for new therapeutic targets for early-onset Alzheimer’s disease.

About 32 million people around the world have Alzheimer’s disease — a type of dementia for which there is currently no cure.

Although most people do not develop Alzheimer’s disease before the age of 65, it can sometimes appear at an earlier age, even as early as a person’s 30s. Alzheimer’s disease before the age of 65 is called early-onset Alzheimer’s disease.

Researchers believe most early-onset Alzheimer’s cases are caused by genetic factors, including three rare genetic variants — amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).

Now, researchers from Mass General Brigham have discovered a genetic variant that seems to help protect people genetically predisposed to developing early-onset Alzheimer’s disease, potentially opening the door for new therapeutic targets.

The study was recently published in The New England Journal of Medicine.

For this study, researchers focused on two specific genetic mutations.

The first is called the Paisa mutation (Presenilin-1 E280A), which is known to be present in a large family in Colombia.

Previous research shows that people with the Paisa mutation are at a high risk of developing Alzheimer’s disease with symptoms beginning to show as early as their 40s.

The second genetic variant researchers examined in this study is on the APOE3 gene, called Christchurch (APOE3Ch).

The APOE gene contains directions needed to make a protein called apolipoprotein E. Different types of the APOE gene are known to contribute to the development of Alzheimer’s disease.

A study published in 2019 conducted by Mass General Brigham researchers showed a person with an extremely high genetic risk for Alzheimer’s disease and two copies of the Christchurch variant who did not develop cognitive impairment until her late 70s.

Another study in January 2024 found the Christchurch mutation may help protect the brain against clumps formed by excessive amounts of the protein tau, considered a hallmark of Alzheimer’s disease.

Scientists analyzed genetic data from 1,077 descendants of the Colombian family with the Paisa mutation.

They identified 27 family members who carried both the Paisa mutation and one copy of the Christchurch variant. On average, these family members did not start to show signs of cognitive impairment until age 52, compared to family members who did not have the Christchurch variant and showed symptoms at age 47.

Researchers also reported that family members carrying at least one copy of the Christchurch variant showed signs of dementia four years later than those not carrying the variant.

“As a clinician, I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals,” says Yakeel T. Quiroz, PhD, clinical neuropsychologist and neuroimaging researcher and director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital and co-first author of this study.

“Now, we must leverage this new knowledge to develop effective treatments for dementia prevention. As a neuroscientist, I’m thrilled by our findings because they underscore the complex relationship between APOE and a deterministic mutation for Alzheimer’s disease, potentially paving the way for innovative treatment approaches for Alzheimer’s disease, including targeting APOE-related pathways.”
— Yakeel T. Quiroz, PhD

“As a next step, we are currently focused on improving our understanding of the brain resilience among the remaining family members who carry one copy of the Christchurch variant,” Quiroz continues.

“This involves conducting structural and functional MRI scans and cognitive evaluations, as well as analyzing blood samples to assess their protein and biomarker profiles. The unwavering commitment to research shown by our Colombian patients with autosomal dominant Alzheimer’s and their families has been indispensable in making this study possible and allowing us to continue to work toward interventions for this devastating disease,” he explains.

After reviewing this study, Karen D. Sullivan, PhD, ABPP, a board-certified neuropsychologist, owner of I CARE FOR YOUR BRAIN, and Reid Healthcare Transformation Fellow at FirstHealth of the Carolinas in Pinehurst, NC told Medical News Today that this is an exciting study because it adds new evidence about protective mechanisms in early-onset Alzheimer’s disease.

“This illuminates a path forward for new drug targets in populations at the highest genetic risk for this devastating disease,” Sullivan explained. “It is a novel finding to see an APOE-related mechanism of increased protection rather than increased risk.

“We think about 60-80% of Alzheimer’s disease cases are related to genetic variants,” she continued. “There will be no cure for Alzheimer’s disease without cracking the genetic code.We need larger participant groups and people with other subtypes of Alzheimer’s disease including the much more common, older-onset variant to see if the protective effects of the Christchurch variant are at play there too.”

MNT also spoke with Manisha Parulekar, MD, FACP, AGSF, CMD, director of the Division of Geriatrics at Hackensack University Medical Center and co-director of the Center for Memory Loss and Brain Health at Hackensack University Medical Center in New Jersey, about this study.

“We are continuing to learn about pathophysiology and risk factors for Alzheimer’s and early-onset Alzheimer’s. Having a family member with early-onset disease is stressful for the individual. Having access to information about protective genetic markers will be beneficial to navigate these complex conversations.”
— Manisha Parulekar, MD

“Alzheimer’s impacts a large population across the globe,” she continued. “Learning details of various genetic variants is helpful in (the) implementation of care plans for the patients and their family members. Increasing access and education of the benefits of understanding genetic variants can allow us to help individuals and families with this disease with comprehensive care plans in a timely manner.”

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