The latest study discovered that having one copy of a protective genetic variant, APOE3 Christchurch, helped to delay the onset of Alzheimer’s disease for 27 members of a family in Colombia. This family has about 6,000 people and they are at a high risk of developing early-onset Alzheimer’s in their 40s due to carrying the ‘Paisa’ (Presenilin-1 E280A) mutation. This research is an extension of a case report from 2019, which involved a woman from this same family who had two copies of the Christchurch variant and delayed the onset of Alzheimer’s until her 70s. These new findings are significant because they demonstrate that having just one copy of the variant provides some level of protection. This discovery has also increased the confidence of researchers that this genetic pathway could be targeted for therapeutic interventions.
The journey began with the discovery of a remarkable patient and has now led to important scientific developments. In 2019, a team of researchers from Mass Eye and Ear and Massachusetts General Hospital (MGH) reported on a patient who did not show signs of cognitive impairment until her late 70s, despite being at high genetic risk for early-onset Alzheimer’s disease. This patient had the genetic variant for Alzheimer’s disease and also had two copies of a rare AP variant.The research team has discovered an additional 27 family members who carry only one copy of the APOE3Ch gene variant, known as Christchurch. These individuals experienced a delayed onset of the disease. The study, published in The New England Journal of Medicine, is the first evidence that having one copy of the Christchurch variant may provide some level of protection against autosomal dominant Alzheimer’s disease, although the protection is less pronounced than when two copies are present. These findings are significant for drug development, as they suggest the potential impact of targeting this genetic variant.pathway.
“Our findings are very encouraging for clinicians, as they indicate the potential to delay cognitive decline and dementia in older individuals. This new knowledge can be used to develop effective treatments for dementia prevention,” said co-first author Yakeel T. Quiroz, PhD, a clinical neuropsychologist and neuroimaging researcher who is also the director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital.” As a neuroscientist, I am excited about our findings because they highlight the complex relationship between APOE and a deterministic mutation for dementia.Alzheimer’s disease could potentially be treated in new ways by targeting APOE-related pathways, according to researchers at MGH and Mass Eye and Ear. Quiroz and her team have been collaborating with colleagues in Colombia to study family members with the “Paisa” mutation, which is the largest-known kindred with a genetic variant called Presenilin-1 E280A. This mutation is autosomal dominant, meaning that inheriting just one copy of the mutated gene from a parent is enough to cause the condition.of the Paisa variant who developed Alzheimer’s at age 51, the researchers have observed a 73-year-old woman from the family who remains cognitively healthy despite having two copies of the variant. The researchers speculate that protective factors may be at play in this case. They are currently conducting further studies to better understand these protective factors and potentially develop treatments to delay or prevent the onset of Alzheimer’s in carriers of the variant. This discovery highlights the importance of studying rare genetic variants in understanding the underlying causes of complex diseases like Alzheimer’s.Molecular studies have provided additional biological evidence that the Christchurch variant could be serving a protective function. In 2023, a research team identified another “resiliency gene variant” known as Reelin-COLBOS that seemed to delay the onset of symptoms in other family members. A new study in NEJM now focuses on a larger group of individuals from this family who possess a copy of the Christchurch variant. “Our initial study showed us that protection was possible, which was a significant revelation. However, if a person requires two copies of a rare genetic variant, it ultimately comes down to luck,” stated co-senior.The study conducted by Joseph F. Arboleda-Velasquez, MD, PhD, an associate scientist at Mass Eye and Ear, is important because it strengthens our confidence in the potential of this target for protection and drug development. Therapies based on protected humans are more likely to be effective and safe.
The research team examined 1,077 descendants of a Colombian family and found 27 family members who carried both the Paisa mutation and one copy of the Christchurch variant. These individuals, on average, began showing signs of cognitive impairment at age 52, in contrast to a matched group of family members who did not have these mutations.The study involved a family with a genetic variant linked to Alzheimer’s disease. The variant caused symptoms to appear later in life, with family members showing signs of dementia four years later than those without the variant. Two individuals in the family underwent brain imaging, which revealed lower levels of tau and preserved metabolic activity in areas affected by Alzheimer’s disease, despite the presence of amyloid plaques. Autopsy samples from four deceased individuals also showed less pathology in blood vessels, which is believed to be important for the protective effects of the APOE3 Christchurch variant.The study conducted by the authors was limited to a small number of individuals who had both the Paisa and Christchurch variants, and to a single, extended family. They suggest that additional research involving larger and more diverse samples of people with Alzheimer’s disease may provide further insights into the protective effects of the Christchurch variant. This could also help determine whether the findings from the Colombian family could be applied to treating other forms of Alzheimer’s disease. The authors are now working on better understanding the resilience of the brain in the other family members.Researchers are studying individuals who have the Christchurch variant by using MRI scans, cognitive evaluations, and analyzing blood samples to understand more about the disease. According to Quiroz, the commitment of Colombian patients and their families with autosomal dominant Alzheimer’s has been crucial in making this study possible. Their dedication has allowed researchers to continue working towards finding interventions for this devastating disease.
