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

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) (Aβ 42 /Aβ 40 , p-tau 181 , p-tau 217 , Aβ 42 /p-tau 181 and Aβ 42 /p-tau 217 ) and three plasma (p-tau 217 , p-tau 217 /Aβ 42 and Aβ 42 /Aβ 40 ) 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 Aβ 42 /Aβ 40 decreased at the second quartile of Aβ burden ( p< 0.001), whereas p-tau 181 ( p< 0.01) and p-tau 217 ( p< 0.001) increased only from the third quartile. CSF Aβ 42 /Aβ 40 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-tau 217 and Aβ 42 /p-tau 217 consistently showed higher accuracy than their p-tau 181 counterparts across Aβ and tau pathology scores. Plasma p-tau 217 and p-tau 217 /Aβ 42 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 Aβ 42 /Aβ 40 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.