Scientists are investigating a novel therapeutic strategy for Alzheimer's disease that focuses on enhancing the liver's capacity to clear amyloid, a toxic protein implicated in the disease's progression, from the bloodstream. This research suggests that boosting the liver's efficiency in removing amyloid could reduce its buildup in the brain and potentially reverse memory impairment.
The findings, detailed in a study published in the journal Neuron, indicate that the liver plays a more significant role in Alzheimer's than previously recognized. Current treatments for Alzheimer's can slow cognitive decline but cannot halt or reverse the disease, and often come with side effects like nausea, dizziness, and, in some cases, brain swelling or bleeding.
Amyloid, a byproduct of normal brain cell function, can accumulate and form plaques between brain cells, disrupting neural communication. While the brain typically clears amyloid efficiently, a substantial portion, up to 60%, enters the bloodstream, where the liver is responsible for its breakdown. The APOE gene plays a role in this clearance process in both the brain and the liver.
However, a significant portion of the population carries a less efficient variant of the APOE gene, known as APOE4. Carrying one copy of APOE4 increases the risk of developing Alzheimer's by two to threefold, while carrying two copies raises the risk up to 15-fold. This inefficiency allows amyloid to accumulate in the brain, leading to plaque formation and subsequent damage to brain cells.
The new therapeutic concept centers on a rare variant of the APOE gene, APOE3 Christchurch, which has demonstrated a superior ability to help the body clear amyloid. This variant gained attention following the case of a woman in Colombia who, despite carrying genetic mutations typically associated with early-onset Alzheimer's, remained cognitively healthy due to possessing two copies of APOE3 Christchurch.
In the recent study, researchers utilized an adeno-associated virus, a common gene therapy vector, to deliver the APOE3 Christchurch gene to mice engineered to have Alzheimer's-like changes. These mice carried the APOE4 gene. The results indicated that the treatment nearly halved the amyloid plaque levels in the mice's brains, as liver cells showed increased efficacy in absorbing amyloid from the blood. The study also observed reduced inflammation, less nerve cell damage, and improved memory in the treated mice.
Dr. Richard Oakley of the Alzheimer's Society commented that these findings support the concept of exploring external factors, such as the liver's function, for reducing amyloid in the early stages of Alzheimer's. However, he emphasized that the research is in its nascent stages and has only been tested in mice. Further investigation is needed to understand the impact of tau tangles, another key feature of Alzheimer's disease not present in the mouse model used.
The research team plans to conduct further studies in larger animals, such as primates, before potentially moving to human trials. Gene therapies typically require at least five years to advance from animal studies to initial human testing, suggesting that any approved treatment could be a decade or more away.