# Leveraging genetic propensity to identify modifiable factors for the age at onset of Alzheimer's disease

## TL;DR

This study identifies modifiable factors like education and diabetes that influence when Alzheimer's disease starts, using genetic data to suggest ways to delay its onset.

## Contribution

The study introduces a novel approach using polygenic scores and Mendelian randomization to identify causal modifiable factors for Alzheimer's age at onset.

## Key findings

- Higher education and cognitive performance are linked to later onset of Alzheimer's disease.
- Type 2 diabetes and cardiovascular disease are causally associated with earlier Alzheimer's onset.
- Increased fat intake is associated with delayed Alzheimer's onset.

## Abstract

Knowledge of modifiable factors influencing age at onset (AAO) of Alzheimer's disease (AD) remains limited. This study utilizes genetic information to uncover such factors.

Using 43 exposure genome‐wide association studies (GWAS) summary statistics, we calculated corresponding polygenic scores (PGS) for 9219 AD cases and 10,345 controls from the Alzheimer's Disease Genetic Consortium (ADGC). Linear mixed model and survival analyses were performed to identify exposure‐PGS associated with AAO. Top exposures were cross‐evaluated using PGS from the PGS Catalog and Mendelian randomization (MR) for causal relationships.

Eight exposures showed significant exposure‐PGS associations with AAO of AD. Higher educational attainment, better cognitive performance, and greater relative fat intake were associated with later AAO; whereas the remaining were linked to earlier onset. MR analysis indicated a causal relationship between AAO and educational attainment, cardiovascular disease, and type 2 diabetes (T2D).

The eight modifiable factors, particularly educational attainment, cardiovascular disease, and T2D, may facilitate early intervention to delay the onset of AD.

We screened 43 modifiable factors for their association with the age at onset (AAO) of Alzheimer's disease (AD) using polygenic scores (PGS) as the proxy for the exposure.Higher educational attainment, better cognitive performance, and greater relative fat intake were linked to later AAO, suggesting an enhanced resilience against AD.Type 2 diabetes, cardiovascular disease, major coronary heart disease, and increased low‐density lipoprotein (LDL) ‐cholesterol and total cholesterol are associated with earlier AAO.Mendelian randomization analysis revealed causal effects of educational attainment, type 2 diabetes, and cardiovascular disease on AAO of AD.

We screened 43 modifiable factors for their association with the age at onset (AAO) of Alzheimer's disease (AD) using polygenic scores (PGS) as the proxy for the exposure.

Higher educational attainment, better cognitive performance, and greater relative fat intake were linked to later AAO, suggesting an enhanced resilience against AD.

Type 2 diabetes, cardiovascular disease, major coronary heart disease, and increased low‐density lipoprotein (LDL) ‐cholesterol and total cholesterol are associated with earlier AAO.

Mendelian randomization analysis revealed causal effects of educational attainment, type 2 diabetes, and cardiovascular disease on AAO of AD.