Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden

Abstract

Neuropathological validation studies of pathology-specific biomarkers for neurodegenerative diseases are essential but are often limited by long sampling-to-death intervals and the lack of semi-quantitative pathology measures. We assessed the associations of five cerebrospinal fluid (CSF) (Aβ42/Aβ40, p-tau181, p-tau217, Aβ42/p-tau181 and Aβ42/p-tau217) and three plasma (p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40) biomarkers with post-mortem Aβ and tau pathology burden in 250 participants with ante-mortem CSF (n=230) and/or plasma (n=101), affected by prion (n=162) or non-prion diseases (n=88). Aβ and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of Aβ and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5 months for CSF and 1 month for plasma. CSF Aβ42/Aβ40 decreased at the second quartile of Aβ burden (p<0.001), whereas p-tau181 (p<0.01) and p-tau217 (p<0.001) increased only from the third quartile. CSF Aβ42/Aβ40 achieved its highest accuracy at low/intermediate Aβ burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau217 and Aβ42/p-tau217 consistently showed higher accuracy than their p-tau181 counterparts across Aβ and tau pathology scores. Plasma p-tau217 and p-tau217/Aβ42 significantly increased in the highest Aβ and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer’s disease neuropathological continuum. CSF Aβ42/Aβ40 best reflects low/intermediate Aβ burden, while CSF p-tau markers are more closely related to high Aβ and intermediate tau load. Plasma markers primarily identify advanced Aβ and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of Aβ deposition.