Genetic and Modifiable Factors for Age at Onset of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia. Its genetic heritability is estimated to be ~58-79% for AD risk and ~42% for age at onset (AAO). Although numerous genetic variants and genes contributing to AD susceptibility have been identified, the variants that specifically influence AAO-either independently or together with AD risk-are less well understood. In addition, several modifiable risk factors, such as educational attainment, psychosocial factors, comorbidities, and lifestyle factors, have been associated with AD, but their impact on AAO remains unclear. To investigate this, we conducted a genome-wide association study (GWAS) involving 9,219 AD cases and 10,345 controls, employing two statistical approaches to identify variants related to AAO. We detected 11 genome-wide significant loci, including six previously reported AD risk genes and five novel loci-UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25-associated with AAO. Sex-stratified analyses identified CD300LG and MLX/TUBG2 as female-specific loci and MIR4445 as male-specific. Using the same dataset, we further examined modifiable factors affecting AAO through polygenic score and Mendelian randomization (MR) approaches. Higher educational attainment, better cognitive performance, and greater relative fat intake were linked to a later AAO, whereas cardiovascular disease and type 2 diabetes were associated with an earlier onset. MR analyses supported causal effects of educational attainment, cardiovascular disease, and type 2 diabetes on the AAO of AD.