Plasma biomarkers associations with cognitive change in preclinical Alzheimer’s disease

Abstract

AbstractBackgroundBlood biomarkers to detect Alzheimer’s disease pathology are needed as screening tools and to predict the onset of cognitive decline. Although there is increasing data on their potential usefulness across AD continuum, comprehensive comparisons of their ability to predict cognitive decline in cognitively unimpaired (CU) populations are still lacking.MethodWe studied 214 CU individuals from the ALFA+ cohort (Table 1), which had baseline measurements of plasma p‐tau181, p‐tau217, p‐tau231, t‐tau, GFAP, NfL and Ab42/40. All biomarkers were measured with Simoa, except for plasma p‐tau217 and t‐tau that were MSD‐based assay measures (Eli Lilly and Company ). Longitudinal measures of cognition (Preclinical Alzheimer Cognitive Composite [PACC]) at 3 years’ follow‐up were available. All participants remained CU at follow‐up.We tested the associations of baseline plasma biomarkers with PACC scores change (delta score computed as V2‐V1) using linear regression models adjusted by age, sex, education and time between neuropsychological visits. We further stratified by CSF Aβ‐status (Aβ+ if CSF Aβ42/40 <0.071) and interaction terms between each biomarker and Aβ‐status were evaluated. Finally, we studied the associations between baseline plasma biomarkers and cognitive change specifically in participants that displayed the steepest (<1SD) cognitive decline (“decliners”).ResultIn the whole sample, higher baseline plasma p‐tau181 (P=0.003) and t‐tau (P=0.007) were significantly associated with lower PACC scores at follow‐up. In CSF Aβ‐positive individuals, plasma p‐tau181, p‐tau231, t‐tau and NfL at baseline were significantly associated with cognitive decline while no significant associations were found in the Aβ‐negative group. The interaction with CSF Aβ status was significant only for plasma p‐tau231 (P=0.028) (Figure 1). In individuals that displayed a steeper decline (n = 33 [16% of the sample], Table 2), plasma p‐tau181, p‐tau217 and t‐tau were significantly associated with longitudinal change in PACC scores (Figure 2).ConclusionIn preclinical AD, baseline plasma levels of p‐tau181, tau231, t‐tau and NfL are associated with cognitive decline at follow‐up. In the group of decliners, higher p‐tau181, p‐tau217 and t‐tau at baseline associate with cognitive change. These results have important implications for the consideration of plasma biomarkers for clinical trials targeting asymptomatic individuals or individuals with subtle cognitive decline.