Plasma biomarker trajectories: Impact of AD genetic risk and clinical progression.

Background: We examined long-term plasma biomarker trajectories among participants who were cognitively unimpaired and primarily middle aged at baseline and whether trajectories differed by Alzheimer's disease (AD) genetic risk and among those who developed cognitive impairment.

Methods: Plasma amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells, and chitinase 3-like protein 1 were measured longitudinally in 177 BIOCARD participants (M baseline age = 57.7 years; M follow-up = 15.8 years), including 57 who developed cognitive impairment. Measures of AD genetic risk included apolipoprotein E (APOE) ε4 and an AD polygenic risk score (AD-PRS).

Results: Compared to non-carriers, APOE ε4 carriers had lower Aβ42/Aβ40 and greater longitudinal increases in p-tau181 and GFAP; in contrast, the AD-PRS (excluding the APOE region) was associated with greater declines in Aβ42/Aβ40 among APOE ε4 non-carriers. Rates of increase in p-tau181, NfL, and GFAP were greater among those who later developed cognitive impairment.

Conclusions: Monitoring changes in plasma p-tau181, NfL, and GFAP may be particularly informative during preclinical AD. We examined plasma biomarker changes in cognitively normal individuals over 15.8 years.Apolipoprotein E (APOE) ε4 was related to lower amyloid beta (Aβ)42/Aβ40 and greater increases in phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP).In APOE ε4 non-carriers, higher Alzheimer's disease (AD) polygenic risk score was related to greater Aβ42/Aβ40 declines.P-tau181, NfL, and GFAP increases were greater among those who progressed to mild cognitive impairment.Results highlight the predictive value of plasma biomarkers during preclinical AD.