The researchers from Mass General Brigham have discovered a genetic variant that may help protect people predisposed to developing early-onset Alzheimer’s disease, potentially leading to new therapeutic targets. Early-onset Alzheimer’s disease affects about 32 million people globally, with symptoms appearing before the age of 65. Most cases are believed to be caused by genetic factors, including the rare variants amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The recent study focused on the Paisa mutation (Presenilin-1 E280A) and the APOE3 gene variant Christchurch (APOE3Ch) to explore potential protective mechanisms against cognitive decline.
The APOE gene, which contains directions for making apolipoprotein E, has different types that contribute to Alzheimer’s disease development. A study in 2019 by Mass General Brigham researchers showed a person with an extremely high genetic risk for Alzheimer’s and two copies of the Christchurch variant did not develop cognitive impairment until her late 70s. Another study in 2024 found the Christchurch mutation may protect the brain against clumps formed by excessive protein tau, a hallmark of Alzheimer’s disease.
Analyzing genetic data from 1,077 descendants of a Colombian family with the Paisa mutation, researchers identified 27 family members carrying both the Paisa mutation and the Christchurch variant. These individuals did not show signs of cognitive impairment until age 52, compared to family members without the variant who showed symptoms at age 47. The Christchurch variant carriers displayed signs of dementia four years later than those without the variant, suggesting a potential delay in cognitive decline.
Dr. Yakeel T. Quiroz, a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital, expressed optimism about the findings, indicating potential for delaying cognitive decline and dementia in older individuals. The discovery of protective mechanisms in early-onset Alzheimer’s may pave the way for innovative treatment approaches, including targeting APOE-related pathways. Additional research is focused on understanding brain resilience among family members with the Christchurch variant through MRI scans and biomarker evaluations.
Karen D. Sullivan, a board-certified neuropsychologist, highlighted the importance of the study in uncovering protective mechanisms in early-onset Alzheimer’s. She emphasized the need to expand research to larger participant groups and other subtypes of Alzheimer’s to investigate the potential protective effects of the Christchurch variant. Dr. Manisha Parulekar, director of the Division of Geriatrics at Hackensack University Medical Center, emphasized the benefits of understanding genetic variants in implementing comprehensive care plans for individuals with Alzheimer’s.
In conclusion, the discovery of a genetic variant that may protect against early-onset Alzheimer’s disease represents a significant advancement in the field of dementia research. By identifying potential therapeutic targets and mechanisms for delaying cognitive decline, this study offers hope for individuals at high genetic risk for Alzheimer’s. Further research is needed to explore the protective effects of the Christchurch variant in other subtypes of Alzheimer’s and to enhance understanding of brain resilience in affected individuals. Increased access to genetic information and education on Alzheimer’s variants can aid in developing comprehensive care plans for patients and their families facing this devastating disease.
