APOE4 Carrier Status Modifies Alzheimer’s Disease Plasma Biomarker Concentrations in Healthy Adults Over 85 Years Old

Abstract Background Many blood‐based biomarkers have been thoroughly investigated in the context of Alzheimer’s disease (AD) and other dementias. However, few studies have examined these biomarkers in healthy seniors in the absence of dementia or other age associated morbidities. Investigating biomarkers in a healthy geriatric population allows for the identification of novel biological associations that might otherwise be masked by presence of disease. This study will investigate the effect of APOE genotype on plasma biomarkers of AD to determine whether carrying the APOE4 allele, which increases risk of AD, modifies biomarker concentrations in healthy seniors. Plasma biomarkers analyzed include: amyloid beta 42/40 (Aβ42/40), phosphorylated tau‐181 (p‐tau‐181), neurofilament light (NF‐L), and glial fibrillary acidic protein (GFAP). Methods 370 plasma specimens from the Super Seniors study, which enrolled participants ≥85 years old who have never been diagnosed dementia, cancer, diabetes, cardiovascular or major pulmonary disease; were used. Biomarkers were analysed on the Quanterix Simoa HD‐X analyzer using commercial Neurology 4‐plex E and p‐tau‐181 assays. Group comparisons were performed using a Mann‐Whitney test for continuous variables and a Fisher’s exact test for categorical variables. The association between APOE genotype and biomarker concentration was analyzed using multivariable linear regression. Results 80 (22%) participants were APOE4 carriers (E3E4 N = 71, E4E4 N = 3, E2E4 N = 6) and 290 (73%) were non‐carriers (E2E2 N = 3, E2E3 N = 58, E3E3 N = 229). No significant differences were found between APOE4 carriers and non‐carriers in age (p = 0.3215), sex (p>0.9999), or mini mental state exam scores (p = 0.1327). In APOE4 carriers, Aβ42/40 is lower (0.0596 vs 0.0618 pg/ml, p = 0.0462), and p‐tau‐181 (3.24 vs 2.78 pg/ml, p = 0.0069) and GFAP (196 vs 172 pg/ml, p = 0.0474) are higher than in non‐ APOE4 carriers. NF‐L had no significant difference between carrier status (p = 0.1188). After adjusting for age and sex, p‐tau‐181 remains significantly associated with APOE4 carrier status (β = 0.066, p = 0.0112), while Aβ42/40 and GFAP no longer have significant associations. Conclusions p‐tau‐181 concentration is associated with APOE4 genotype in healthy seniors, making it an important variable to account for in future analysis.