Grant: Catalyst Grant: Analysis of CLSA Data - INMHA Mandate

By 2050, 1.7 million Canadians will be living with dementia, making prevention strategies critically important. We know that three factors strongly predict Alzheimer's disease risk: older age, being female, and carrying a specific genetic variant called APOE e4. Women with this genetic variant face 2-4 times higher dementia risk than men with the same gene, but we don't understand why. Cholesterol and other blood fats (collectively called lipids) may hold the key to this puzzle. The APOE gene controls how our bodies process these lipids, and high cholesterol in midlife contributes to 7% of dementia cases worldwide. However, no one has definitively shown whether the APOE gene increases dementia risk through its effects on lipids, or through completely separate pathways. This distinction matters enormously: if lipids are the main pathway, then cholesterol-lowering treatments could reduce genetic risk, transforming an "unchangeable" genetic fate into something we can actually prevent. We will combine data from 26,000 individuals in the Canadian Longitudinal Study on Aging with data from 11,000 individuals in the US-based Alzheimer's Disease Sequencing Project, allowing us to look at how lipid levels and cognitive abilities change over time in males and females with different APOE variants. By tracking these patterns alongside cognitive changes, we can identify when and how lipids contribute to dementia risk differently in each sex. This research will reveal whether cholesterol-lowering strategies can mitigate genetic dementia risk, particularly in females. More importantly, it will identify the life stages when such interventions might be most effective, enabling doctors to provide personalized prevention advice based on a person's sex, age, and genetic profile. The research will also create a valuable database connecting Canadian aging research with international studies, accelerating future dementia prevention research.