In‐vivo plasma biomarker concentrations correlate with postmortem AD‐neuropathology in the oldest old

Abstract Background There has been ongoing uncertainty to what extent plasma biomarkers are representative of neuropathological markers of AD pathology in the oldest old. A complicating factor is that with increasing age, Aβ‐ and Tau pathologies accumulate in the brains of cognitively healthy individuals to highly variable levels (Zhang & Ganz et al., 2022). The unique availability of both antemortem plasma biomarker concentrations and postmortem neuropathology in self‐reported cognitively healthy oldest old, offers a chance to explore whether levels of plasma biomarkers can serve as in‐vivo proxy of AD neuropathology. Methods We evaluated postmortem neuropathology of 48 centenarian brains, with a median MMSE score of 26 (range:16–30) at blood draw. We quantified plasma biomarkers Aβ 40 , Aβ 42 , Aβ 42/40 , pTau181, NfL and GFAP on the Simoa platform. The median interval between blood‐sample collection and brain donation was 1.3 (range:0–5.1) years. In addition to conventional spatio‐temporal staging systems such as Thal‐Aβ phase (median 2, range:0‐5) and Braak‐NFT stage (median 3, range:2‐5), we also quantified pathological load by measuring the percentage area of immunopositivity for total Aβ (range:0–9.0%), Aβ 40 (range:0–3.3%), Aβ 42 (range:0–11.5%), pTau‐217 (range:0–1.8%) and AT8 (pTau‐202/205; range:0–49.2%) in the cortex of the temporal pole. Partial Spearman correlations were conducted adjusted for age, sex, and time interval. Results Plasma pTau‐181 correlated with Aβ pathology loads, namely Aβ 40 (r=0.48, p<0.001), Aβ 42 (r=0.41, p=0.005) and total Aβ (r=0.48, p<0.001), as well as with spatio‐temporal Thal‐Aβ phase (r=0.45, p=0.003). Plasma pTau‐181 correlated with quantitative pTau pathology loads, specifically pTau‐217 (r=0.48, p=0.001) and AT8 (r=0.41, p=0.005), but not with spatio‐temporal Braak‐NFT stage (r=0.17, p=0.290). Furthermore, both plasma NfL and plasma GFAP also correlated with pTau‐217 load in the brain (r=0.30, p=0.0496; r=0.30, p=0.044, respectively). Plasma Aβ 40 , Aβ 42 , Aβ 42/40 did not correlate with any neuropathology measure. Conclusions Results reveals plasma pTau‐181, but not plasma Aβ, as a reliable indicator for both Aβ and pTau pathology loads in the temporal pole of the oldest old. The 100‐plus study cohort provides a promising opportunity to study the correlation between different pTau epitopes and the presence of pTau levels, as well as the presence of Tau pathology, including NFTs, neuropil threads, pre‐tangles and ARTAG.