CSF amyloid, tau, and neurodegeneration biomarkers are associated with longitudinal cognitive decline in preclinical AD

Abstract

AbstractBackgroundThis work examined heterogeneity in cognitive trajectories between amyloid(A) and tau(T) cerebrospinal fluid (CSF) stratified biomarker groups in late‐middle‐aged, initially cognitively unimpaired individuals. Additionally, candidate biomarkers of neurodegeneration were investigated for potential added value in predicting cognitive decline.MethodIndividuals (N=535) recruited from Wisconsin Alzheimer’s Disease Research Center (n=301) and Wisconsin Registry for Alzheimer’s Prevention (n=234) underwent a lumbar puncture and serial (1 to 9) cognitive assessments (Table 1). CSF biomarkers were measured using the exploratory Roche NeuroToolKit assays (Roche Diagnostics International Ltd). Four biomarker groups (A‐T‐, A‐T+, A+T‐ and A+T+) were established based on combinations of CSF Aβ42/40 and p‐tau biomarker positivity, where (A) and (T) positivity was determined as CSF Aβ42/40≤0.046 and CSF p‐tau≥24.8 pg/mL. Decline on a Preclinical Alzheimer’s Cognitive Composite (PACC‐3) was investigated using linear mixed effects models (including subject‐specific random intercepts and age‐related slopes) adjusting for sex, education, cohort, and the number of prior exposures to the cognitive battery. In primary analyses, the predictors of interest included the biomarker group and its interaction with age to investigate whether longitudinal PACC‐3 trajectories differed between biomarker groups. Secondary models added one of the following biomarkers for neurodegeneration and its interaction with age: neurofilament light chain (NfL), neurogranin, or alpha‐synuclein. Models were compared against the primary model using the Akaike information criterion and log likelihood ratio tests.ResultThe results from the primary model indicated a significant biomarker group×time interaction (P<.001, Figure 2). Tukey‐adjusted pairwise comparisons indicated that the A+ groups (A+T‐ and A+T+) had significantly different PACC‐3 trajectories compared with the A‐T‐ group (P<.0001, Figure 2). Comparison of the simple age‐related slopes suggest that the A+T+ group was declining approximately 3.6 times faster compared with those without elevated biomarkers. Higher NfL, but not neurogranin or alpha‐synuclein, was associated with PACC‐3 decline after accounting for AT(+/‐) status (Table 2).ConclusionIn this preclinical sample, cognitive decline was evident in A+ groups. Secondary analyses suggest that NfL may contribute additional value to the AT(neurodegeneration) framework in explaining cognitive decline before the onset of dementia.