Scientists have made significant strides in Alzheimer’s disease research, with recent findings suggesting that a rare genetic variant could potentially delay its onset. In 2019, a global team of researchers, including specialists from Mass Eye and Ear and Massachusetts General Hospital (MGH), unraveled the peculiar case of a woman who only began showing signs of cognitive impairment in her late 70s. This was unusual given her family’s high genetic predisposition to early-onset Alzheimer’s disease.
The woman had a unique genetic makeup. Apart from the genetic variant triggering autosomal dominant Alzheimer’s disease, she also had two copies of a rare variant of the APOE3 gene, named Christchurch (APOE3Ch). The investigators have since discovered 27 other family members carrying only one copy of the variant, who also showed delayed disease onset.
The research, published in The New England Journal of Medicine, offers the first evidence that even a single copy of the Christchurch variant could offer some protection against autosomal dominant Alzheimer’s disease. This discovery has profound implications for the development of new drugs, suggesting the possibility of targeting this genetic pathway.
Yakeel T. Quiroz, PhD, clinical neuropsychologist and neuroimaging researcher at MGH, said the findings were encouraging. They could potentially pave the way for the development of treatments to delay cognitive decline and dementia in older individuals and inspire innovative treatment approaches for Alzheimer’s disease. Quiroz and her team, along with Joseph Arboleda-Velasquez, MD, PhD, from Mass Eye and Ear, have been studying a large Colombian family known to carry a genetic variant called the “Paisa” mutation (Presenilin-1 E280A), an autosomal dominant variant that inevitably leads to Alzheimer’s disease.
The family boasts about 6,000 blood relatives, with roughly 1,200 carrying the variant. Carriers usually begin experiencing mild cognitive impairment in their 40s, full-blown dementia in their 50s, and often die from complications of dementia in their 60s.
The research team evaluated over 1,000 descendants of the Colombian family and found 27 who carried both the Paisa mutation and one copy of the Christchurch variant. Compared to family members without the variant, these individuals started showing signs of cognitive impairment five years later, on average.
Brain imaging of two such individuals revealed lower levels of tau and preserved metabolic activity in areas typically affected by Alzheimer’s disease, despite the presence of amyloid plaques, a distinguishing feature of the disease. Autopsy samples from four deceased individuals also showed less pathology in blood vessels, a trait seemingly crucial for the protective effects of APOE3 Christchurch.
The study, however, was confined to a relatively small group of people carrying both the Paisa and Christchurch variants, and to a single, large family. Further research involving larger, more diverse groups may offer more insight into the Christchurch variant’s protective effect and whether these findings could lead to treatments for more common forms of Alzheimer’s disease.
Quiroz mentioned that their next focus is on enhancing their comprehension of brain resilience among family members carrying one copy of the Christchurch variant. This will involve conducting MRI scans, cognitive evaluations, and blood sample analyses to assess protein and biomarker profiles. She expressed gratitude to their Colombian patients and their families for their unwavering commitment to research, which has been critical in advancing their study and ongoing efforts to find interventions for this debilitating disease.
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