Longevity Briefs: Preventing Alzheimer’s By Swapping A Single Gene Variant?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

APOE4 is a gene variant that affects how the brain handles lipids (fats), inflammation and protein clearance. It is infamous for its role in Alzheimer’s disease: compared to having two copies of the most common variant (APOE3), carrying one copy each of APOE3 and APOE4 is associated with double to triple the risk of Alzheimer’s disease, depending on other factors like ethnicity. By contrast, having two copies of APOE2 is highly protective against cognitive decline and Alzheimer’s disease.

How exactly the APOE variants have such a large effect on Alzheimer’s risk is still not entirely understood, but it raises an intriguing question: can swapping an individual’s APOE from a ‘risky’ form to a protective form reverse Alzheimer‑related changes or improve cognitive function? That is the question researchers set out to answer in this study, with some promising results.

The discovery:

Researchers discovered that genetically switching mice from expressing human APOE4 to APOE2 was associated with significant reductions in Alzheimer’s-like pathology and improved cognitive function.

The authors started by building a genetically engineered mouse model that expressed human APOE4 by default, but would stop expressing APOE4 and instead express APOE2 after being given the drug tamoxifen. In brief, this was done by producing a genetic construct that contained both APOE2 and APOE4 in which only APOE4 was expressed. Tamoxifen activates an enzyme called Cre recombinase, which removes APOE4 from the sequence and brings APOE2 into the part of the sequence that gets expressed. This happens in both chromosomes, meaning that mice essentially go from expressing two copies of the high-risk APOE4 to expressing two copies of the low-risk APOE2.

They then compared mice that underwent the E4→E2 switch at two months of age to control mice who were not given tamoxifen. They found that this switch produced a metabolic and lipid profile resembling that of humans carrying two copies of APOE2, and caused widespread changes in gene expression in the brain, most notably in astrocytes. These are star‑shaped cells that play multiple important roles in the brain, such as controlling the supply of nutrients to neurons and modulating synaptic connections.

They then repeated this test in 6 month-old mice produced by crossing their genetically engineered mice with another mouse model prone to Alzheimer’s-like pathology. However this time, the genetic switch was restricted to astrocytes. Converting just astrocytes from APOE4 to APOE2 expression was associated with improved cognitive performance, reduced amyloid plaque burden and reduced inflammation compared with control mice. Sample sizes in the cognitive tests ranged from 8 to 16 in each group (control and experimental).

The implications:

This study suggests that targeted APOE variant replacement – especially in astrocytes – suppresses changes in the brain relevant to Alzheimer’s disease and may preserve cognitive function during ageing. Unfortunately, while translating this to humans carrying the APOE4 variant is theoretically possible, it will not be an easy task. Astrocytes have a very low turnover rate, so replacing them with new astrocytes engineered to express other APOE variants may not be an option, and would also require invasive procedures. Gene therapy is capable of suppressing APOE4 expression while introducing other variants, or even permanently replacing APOE4. However, this comes with many risks and challenges, including the fact that expression of APOE2 outside of the brain is associated with other health conditions related to lipid metabolism.

While we are not about to see everyone become low-risk APOE2 carriers via gene therapy, there are more immediate implications for this research. It reinforces the idea that lipid metabolism and astrocytes play a fundamental role in Alzheimer’s risk and that therapies targeting astrocytes and APOE expression are worth pursuing.