Plasma biomarkers for alzheimer’s disease and related neuropathology in relation to mci and dementia: the aric study

Abstract Blood-biomarkers for Alzheimer’s Disease and related neuropathological processes, including amyloidosis, tau deposition, and neurodegeneration, may revolutionize the monitoring of risk and progression of neurocognitive outcomes in older adults. At visit 5 (2011-13) of the ARIC study, a multi-center longitudinal cohort study, amyloid-beta (Aβ42:Aβ40), ptau-181, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) were measured in plasma using an ultrasensitive single-molecule array (Simoa; Quanterix N4PE + p-tau-181 single-plex) in a sample of 1,711 participants (Age=76±5 years, 60% Female, 28% Black). Neurocognitive outcomes included adjudicated dementia and mild cognitive impairment (MCI) through 2019 for a median follow-up of 5.6 years. Multinomial logistic regressions estimated Relative Risk Ratios (RRR) of the four-category outcome of MCI (n=543), dementia (n=371), and death (n=59) vs. cognitively unimpaired (n=736) for each base(2) log-transformed biomarker, adjusted for age, sex, education, site-race, hypertension, diabetes, BMI, APOE, and eGFR. When estimates appeared similar for MCI and dementia, an additional analysis modeled RRR of a three-category outcome of combined MCI/dementia, death, and cognitively unimpaired. Higher plasma Aβ42:Aβ40 ratio was associated with lower MCI/dementia risk (RRR=0.48, 95%CI: 0.32,0.73). Higher levels of all other biomarkers were associated with higher risk of MCI [p-tau181 (RRR=1.57, 95%CI: 1.23,2.00); GFAP (RRR=1.31, 95%CI: 1.03,1.67); NFL (RRR=1.64, 95%CI: 1.26,2.13)] and dementia [p-tau181 (RRR=3.16, 95%CI: 2.43,4.11); GFAP (RRR=2.40, 95%CI: 1.80,3.20); NFL (RRR=3.62, 95%CI: 2.58,5.09)]. These results indicate blood-biomarkers representative of multiple neuropathological processes were strongly associated with both MCI and all-cause dementia outcomes, emphasizing their potential role as tools in risk identification, early diagnosis, and possibly guiding interventions.