Alzheimer’s risk gene points to new drug target
The biggest genetic risk factor for Alzheimer’s disease sits in a single gene: APOE4.
The protein APOE4 affects how fat is transported in the brain and how well brain cells clear harmful protein aggregates. For APOE to function properly, it needs to be loaded with fat molecules. That process is driven by a protein called ABCA1. Both proteins are regulated by a receptor inside the cell nucleus known as LXR (liver X receptor).
LXR activators raise ABCA1 levels and thereby improve APOE function. In animal models of Alzheimer’s disease and atherosclerosis, they work well. But in clinical trials, they cause a significant side effect: the liver begins overproducing fat (hepatic lipogenesis). That has blocked their use in humans.
Finding the right molecular signature
The researchers, publishing in eLife, developed an assay that reveals which co-proteins an LXR activator attracts or repels inside the cell nucleus. This method, called coregulator TR-FRET, allows them to identify molecules that activate ABCA1 without switching on the liver’s fat-production programme. Testing a range of structurally related molecules, they found wide variation: some behaved as full activators, others as partial activators, and some blocked the receptor entirely.
Towards a more selective therapy
The findings suggest it may be possible to design LXR activators that increase ABCA1 in brain cells while leaving hepatic fat production untouched. Whether such a selective molecule would be safe and effective in humans remains to be shown. From a longevity perspective, this line of research is relevant: APOE4 does not only raise Alzheimer’s risk, it also influences vascular ageing and fat metabolism in later life.