Gene variant slows form of inherited Alzheimer’s disease

Brain PET images reveal tau levels, with blue the lowest and red the highest. Left panels are from a typical person with the PSEN1 variant who had mild cognitive impairment. Right panels are from a person with the PSEN1 variant who also had one copy of the APOE3Ch variant.Quiroz et al., NEJM

Variations in certain genes can modify the risk of developing Alzheimer’s disease (AD) and other types of dementia. Some of the best understood variants to date are in a gene called APOE. This gene plays a role in the transport of cholesterol and other fatty molecules in the brain and body. People with a variant of APOE called APOE4 have an increased risk of developing AD dementia. In contrast, people with a variant called APOE2 appear to have some protection against developing dementia.

In 2019, researchers found a hint that a gene variant called APOE3 Christchurch (APOE3Ch) may also provide protection against the development of dementia. They had been following a woman from a family with an inherited variant in another gene called PSEN1. All other family members with this PSEN1 variant developed early-onset AD by middle age. But this woman, who had the PSEN1 variant and two copies of the APOE3Ch gene variant, remained cognitively healthy into her 70s.

It wasn’t clear if having only one copy of APOE3Ch could also protect against cognitive decline in people with an AD-causing PSEN1 mutation. In a new study, the researchers returned to the woman’s extended family of 1,077 people in Colombia. All were tracked with cognitive testing between 1995 and 2022.

Led by Dr. Yakeel Quiroz from Massachusetts General Hospital, Dr. Francisco Lopera of the Grupo de Neurociencias de Antioquia in Medellín, Colombia, and Dr. Joseph Arboleda-Velasquez of Mass Eye and Ear, the research team compared the ages of cognitive impairment and dementia onset between family members with one copy of APOE3Ch and those without a copy of the potentially protective variant. Results from the new NIH-funded study were published on June 20, 2024, in the New England Journal of Medicine.

Out of the 1,077 family members, 27 had one copy of APOE3Ch. After accounting for other factors that influence dementia risk, including sex, education level, and other variations in APOE, the people with one copy of APOE3Ch had some protection against dementia. They developed mild cognitive impairment—the precursor to dementia—an average of five years later (age 52) than relatives without the variant (age 47). They also met the criteria for dementia about four years later than expected (age 54 vs 50).

The researchers conducted brain imaging on two of the participants. The scans revealed less buildup of tau protein tangles and preserved metabolic activity in brain regions associated with AD. Tau tangles are thought to contribute to the death of brain cells in AD. However, intriguingly, as seen in the first woman studied, the brains had high levels of amyloid-β plaque, another hallmark of AD.

The team also looked at brain tissue samples taken at autopsy from four of the people with one copy of APOE3Ch. The blood vessels in these samples showed less damage than in people without APOE3Ch. Such damage has been linked to cognitive decline and dementia.

“I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals. Now we must leverage this new knowledge to develop effective treatments for dementia prevention,” Quiroz says.

The team is now performing additional studies to understand the mechanisms through which APOE3Ch protects the brain. They are already taking advantage of the knowledge gained through study of this variant to design a therapy that shows promise in mouse models. Studies are also needed to measure whether APOE3Ch delays dementia in people who don’t carry a PSEN1 mutation.

—by Sharon Reynolds