Study finds one copy of protective gene mutation helps prevent early-onset Alzheimer's disease

This study New England Journal of Medicine, “This is the first evidence that having one copy of the Christchurch mutation may confer some protection against autosomal dominant Alzheimer's disease, even if it is less effective than having two copies. This finding suggests the potential benefits of targeting this genetic pathway, with important implications for drug development.”

“As a clinician, I am very encouraged by the findings, which suggest the possibility of slowing cognitive decline and dementia in older adults. Now we must use this new knowledge to develop effective treatments to prevent dementia,” said co-first author Yakiel T. Quiroz, PhD, a clinical neuropsychologist, neuroimaging researcher, and director of the Familial Dementia Neuroimaging Laboratory in the Departments of Psychiatry and Neurology at Massachusetts General Hospital. “As a neuroscientist, I am excited by these findings because they highlight the complex relationship between APOE and Alzheimer's disease-defining mutations and may pave the way for innovative therapies for Alzheimer's disease, such as targeting APOE-related pathways.”

Quiroz and his team at MGH, and co-senior study author Joseph Arboleda Velásquez, MD, of Massachusetts Eye and Otolaryngology, are working with colleagues in Colombia as part of the MGH Colombia Boston (COLBOS) Biomarker Study to investigate family members of the world's largest known family of relatives who carry a genetic mutation called the “paisa” mutation (presenilin-1 E280A). The paisa mutation is an autosomal dominant mutation, meaning that inheriting one copy of the mutated gene from a parent is enough to cause the genetic disease. The family is made up of about 6,000 blood relatives, with about 1,200 carrying the mutation. Carriers of this paisa mutation are destined to develop Alzheimer's disease, most of whom will develop mild cognitive impairment in their 40s, dementia in their 50s, and die from dementia complications in their 60s. Francisco Lopera, MD, PhD, director of the Antioquia Neuroscience Group in Medellín, Colombia, NEJM The author of this paper is a neurologist who discovered this family and has followed them for the past 40 years.

Following a case report in 2019 of a family with two copies of the Christchurch variant, molecular studies added further biological evidence that this variant may play a protective role. In 2023, the research team identified another “resilience gene variant.” Leelin Corbos It appears to have the effect of delaying the onset of symptoms in other family members. NEJM We report a large group of people carrying a copy of the Christchurch variant within this family.

“Our initial work showed that prevention is possible, which was an important insight. But when you need two copies of a rare genetic mutation, it's a matter of luck,” said co-senior author Joseph F. Arboleda Velásquez, MD, associate scientist at Massachusetts Eye and Otolaryngology. “This new study is important because it gives us greater confidence that this target is not only preventative, but also druggable. We believe that prevented human-inspired therapies are likely to be more effective and safer.”

The research team studied 1,077 descendants of a Colombian family. They identified 27 family members who carried copies of both the Paisa and Christchurch mutations. On average, these family members began to show signs of cognitive impairment at age 52, while a matched group of family members without the mutations began to show signs at age 47. The family members also showed signs of dementia four years later than those without the mutations.

Two of the participants underwent functional brain imaging. The scans revealed that despite the presence of amyloid plaques, a protein that is a hallmark of Alzheimer's, they had low levels of tau and preserved metabolic activity in areas typically involved in Alzheimer's. The team also analyzed autopsy samples from four of the deceased individuals who showed less vascular pathology, a feature that may be important for the protective effect of APOE3 Christchurch.

The authors note that the study was limited to a relatively small number of people with both the Paisa and Christchurch genes and a single large family. Further studies in larger, more ethnically diverse samples of Alzheimer's disease could shed more light on the protective effect of the Christchurch gene and help determine whether findings from the Colombian families lead to treatment-relevant findings for sporadic Alzheimer's disease, the authors write.

“As a next step, we are now focused on improving our understanding of brain resilience in the remaining family members who carry one copy of the Christchurch variant. This involves conducting structural and functional MRI scans and cognitive assessments, as well as analysing blood samples to evaluate protein and biomarker profiles,” Quiroz said. “The unwavering commitment to research shown by Colombian patients with autosomal dominant Alzheimer's and their families has been essential in making this study possible and as we continue to work towards interventions for this devastating disease.”