Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis

Apolipoprotein E (APOE) is a confirmed risk factor for Alzheimer disease. APOE is also involved in several other neurodegenerative disorders, including Parkinson disease and multiple sclerosis. Previous studies of amyotrophic lateral sclerosis (Lou Gehrig disease, ALS) have investigated the effect of APOE on the risk of developing ALS, age at onset, site of onset, and duration of the disease. The results have been inconsistent, possibly due to small sample sizes and complete reliance on case-control data. No family-based association studies were performed. To address these limitations, we investigated the relationship between APOE functional polymorphisms and age at onset of ALS in a large set of 508 families. We treated age at onset as a quantitative trait and performed family-based association analysis using the TDTQ5 method. APOE-2 is protective against earlier onset (P =0.001) with an average age at onset of APOE-2 carriers approximately 3 years later than that of non-APOE-2 carriers. Similar to our previous report, we did not find APOE associated with ALS risk. Our findings suggest that APOE may express its strongest effect through age at onset rather than on risk.