Genetic variations have the potential to influence the likelihood of developing Alzheimer’s disease (AD) and other forms of dementia, with certain gene variants having been identified as key indicators. Among these, variations in the APOE gene are some of the most well understood. The APOE gene is crucial for the transportation of cholesterol and lipids in the brain and body. Notably, the APOE4 variant stands out for increasing the risk of AD dementia, while the APOE2 variant appears to confer a degree of resistance against the onset of dementia.
In groundbreaking research conducted in 2019, a particular gene variant known as APOE3 Christchurch (APOE3Ch) was suggested to potentially offer a defense against dementia. This discovery emerged from the study of a woman who, although carrying a familial PSEN1 gene variation associated with early-onset AD, remarkably showed no cognitive decline well into her seventies, a contrast to other family members who exhibited symptoms by middle age. This difference was attributed to her possession of two copies of the APOE3Ch variant.
However, the question remained whether possessing just a single copy of the APOE3Ch variant could also guard against cognitive deterioration in individuals with AD-inducing PSEN1 mutations. To probe this further, a recent study engaged with the extensive familial network of the woman in Colombia, which included 1,077 individuals. Spanning from 1995 to 2022, the study meticulously tracked the cognitive health of these participants, revealing new insights into the protective potentials of the APOE3Ch variant.
Under the guidance of Dr. Yakeel Quiroz from Massachusetts General Hospital, together with Dr. Francisco Lopera of the Grupo de Neurociencias de Antioquia in Medellín, Colombia, and Dr. Joseph Arboleda-Velasquez from Mass Eye and Ear, a skilled research team embarked on a comparative analysis of the onset of cognitive impairment and dementia between family members carrying one copy of the APOE3Ch gene variant and those who do not possess this potential safeguard. Findings from this insightful NIH-backed investigation have been documented in a publication released on June 20, 2024, by the prestigious New England Journal of Medicine.
Within the studied genealogy of 1,077 individuals, 27 were carriers of a solitary copy of APOE3Ch. Upon adjusting for various other contributory factors to dementia such as gender, educational attainment, and differing APOE mutations, individuals harboring a single copy of the APOE3Ch gene revealed a relative deterrent against dementia. It was observed that these carriers encountered mild cognitive impairment—a forerunner to dementia—on average five years subsequent to their non-carrying kin, at the age of 52 versus 47. Moreover, they satisfied criteria for dementia approximately four years beyond the anticipated age of onset, 54 in contrast with 50.
The investigative team also performed brain imaging on a duo of these subjects. The resulting scans disclosed a reduced accumulation of tau protein tangles, which are believed to play a part in the demise of neural cells in Alzheimer’s disease, and maintained metabolic activity in brain territories typically implicated in AD. Intriguing as it may seem, akin to observations in the initial woman examined, the brains bore elevated amyloid-β plaque levels, another distinguishing feature of Alzheimer’s disease.
The research extended to analyzing brain tissue samples collected post-mortem from four individuals possessing a single copy of APOE3Ch. These samples revealed a lesser extent of vascular damage compared to those from individuals that did not carry the APOE3Ch variant—damage that traditionally correlates with cognitive decline and dementia.
Dr. Quiroz expressed optimism about the results, “I find our findings very promising—they hint at the possibility of postponing the onset of cognitive decline and dementia in the elderly. This new understanding lays the groundwork for devising effective interventions for dementia prevention.”
The researchers are now delving deeper into the protective mechanisms employed by APOE3Ch in the brain. Drawing on insights from the study of this gene variant, they are already crafting a therapeutic strategy that has demonstrated efficacy in rodent models. Further research is imperative to ascertain if APOE3Ch can also postpone the progression of dementia in individuals lacking the PSEN1 mutation.