A new genetic target for Alzheimer’s treatments

The Neuro will be the only site in Quebec with a trial that hopes to switch off APOE4, a gene variant that sharply increases Alzheimer’s risk

January 26, 2026  |  by Sophie Lorenzo

“For the past decade, research has focussed on reducing tau and amyloid beta to slow the progression of Alzheimer’s Disease, with interesting, but insufficient results. We now have the technology to look at new treatment approaches and target the biggest genetic risk factor for common Alzheimer’s Disease — the APOE4 gene variant. It’s very exciting,” explains Simon Ducharme, MD, a neuropsychiatrist at The Neuro (Montreal Neurological Institute-Hospital).

Starting this spring, the Clinical Research Unit at The Neuro (Neuro CRU) will be the only site in Quebec with a clinical trial studying an RNA interference therapy that hopes to block the APOE gene. It will be among the first handful of trial sites worldwide studying this new approach to slow the progression of Alzheimer’s Disease.

Genes that Change the Odds

For each gene in our genetic code, we inherit two alleles — one from each parent — which determine distinct traits, like eye colour, blood type and the risk for certain diseases.

Alleles can also carry disease risk variations. So, some people will inherit variants like APOE2 that can be protective against Alzheimer’s, or APOE4 that may increase their chances of developing the disease.

“If you have one APOE4 allele, you double your risk of developing Alzheimer’s. If you carry two, then your risk is more than 10 times greater than average. Around 15-20% of people carry at least one APOE4 allele,” notes Ducharme.

The Alzheimer’s Society of Canada stresses that Alzheimer’s is caused by a complex combination of genetics, environment and lifestyle factors. Like most of the 70 genes that have been found to influence Alzheimer’s risk, APOE variants do not directly cause the disease, though they can make us more inclined to develop it.

Shutting It Down

The APOE gene provides instructions for making a protein called apolipoprotein E. The issue is that the APOE4 variant of the gene produces a protein that is thought to interfere with neuronal metabolism and is associated with greater accumulation of amyloid in the brain, leading to Alzheimer’s. It also increases inflammation in the brain and interferes with the repair of neurons — cells responsible for carrying signals in the brain.

While the APOE gene provides the code for our body to create apolipoprotein E, it needs to go through an intermediary, using our body’s messenger RNA (mRNA) to carry out the instructions.

The potential treatment being studied will target the mRNA using an antisense oligonucleotide (ASO), a small molecule designed to bind to the mRNA associated with APOE and block it from producing the protein.

“It’s like having architectural plans to build a house, but stopping the contractor from starting work on it,” he explains.

Early Intervention, New Combinations

If this phase one trial shows promising results, the potential new treatment could eventually be given in the earliest stages of the disease to reduce the production of apolipoprotein E, thereby slowing or even halting the pathological progression of Alzheimer’s.

“We now have a treatment that helps to reduce amyloid plaque, which has been shown to slow the progression of Alzheimer’s by about 30%. There is still a lot of room for improvement and it is very promising that we can finally target a new component of the disease. This could lead us to combine therapies to address different elements that are causing the pathological changes of Alzheimer’s Disease,’’ concludes Ducharme.

For more information, contact Neurocognitive Trials Team at The Neuro:
neurocog-cru.neuro@mcgill.ca; (514) 398-5500; cru.mcgill.ca/ad_en.