APOE4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD.

Abstract

Apolipoprotein-ε4 (APOE-ε4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE-ε4 has been associated with younger onset of AD symptoms in multiple studies. Some have hypothesized that APOE-ε4 effect shows a peak between ages 65-75 years [1, 2] suggesting that in the early-onset AD variant (EOAD), APOE-ε4 might be counterintuitively associated with later disease onset. Here we explored the association of APOE-ε4 genotype with age of symptom onset in a large sample of late-onset AD (LOAD) and EOAD subjects from the National Alzheimer's Coordinating Center's (NACC) database. We analyzed the data of 988 EOAD and 2503 LOAD NACC participants (age at symptom onset < or ≥ 65). T-tests and Fisher's exact tests were used to compare the age of onset in APOE-ε4 carrier and non-carrier in the EOAD and LOAD subjects separately. Diagnosis of AD was established by clinical consensus at all NACC participating sites. EOAD and LOAD were defined by age at symptom onset < or ≥ 65 years, respectively. Table shows the demographic characteristics of the EOAD and LOAD groups. In LOAD mean symptom onset was 73.0 (+/-5.4) vs. 76.2 years (+/-6.1) APOE-ε4 carriers vs. noncarriers, respectively (p-value<0.0001). In EOAD mean symptom onset was 57.9 (+/-5.0) vs. 56.7 years (+/-5.3) for APOE-ε4 carriers vs. noncarriers, respectively (p-value=0.0006). The age at symptom onset distributions can be seen in Figure. The top portion of the figure shows APOE-ε4 carriers and noncarriers by disease subtype and the bottom potion shows the overlay within disease subtypes. Despite the fact that the dataset used for our analyses is primarily focused on LOAD and thus recruitment of EOAD participants might have been limited, we found that in EOAD APOE-ε4 is associated with later disease onset as hypothesized. Prospective multi-site studies such as the Longitudinal Early-Onset AD study (LEADS) focused exclusively on EOAD will further characterize the genetic influences of APOE-ε4 and other genetic risk factors on disease onset and progression in this disease variant.