CSF pTDP-43 across the Alzheimer's spectrum: Links to amyloid, APOE and vasculopathy

Accumulation of phosphorylated TDP-43 (pTDP-43) has been linked to cognitive decline and medial temporal lobe atrophy in Alzheimer's disease (AD), as well as to vascular pathology in individuals with TDP-43 proteinopathy. Our previous findings demonstrated that small perivascular pTDP-43 inclusions are associated with reduced expression of molecules critical for maintaining vascular integrity and function. To further explore the interplay between pTDP-43, amyloid beta (Aβ), and cerebrovascular pathology, we analyzed pTDP-43 levels in cerebrospinal fluid (CSF) samples from patients diagnosed with mild cognitive impairment (MCI), AD, and vascular dementia (VaD).

The study included non-demented controls (NC, n = 47), patients with stable MCI (sMCI, n = 55), MCI-AD (patients who later developed AD, n = 32), AD (n = 64), and VaD (n = 30) from a cohort in which markers of Aβ pathology, vasculopathy, and APOE genotypes had previously been determined. Levels of CSF pTDP-43 were measured using an in-house ELISA. Correlations were analyzed between CSF pTDP-43 and biomarkers of Aβ pathology (Aβ40, Aβ42, Aβ40/Aβ42), vascular integrity (sICAM-1, sVCAM-1, VEGF, sFLt-1), and blood-brain barrier permeability (Q-albumin). Additionally, levels of pTDP-43 in postmortem CSF and pTDP-43 load in the hippocampus from cases with AD neuropathological changes (n = 7) were analyzed using the in-house ELISA and immunofluorescent stainings, respectively.

CSF pTDP-43 levels did not differ between diagnostic groups or APOE genotypes. CSF pTDP-43 correlated with Aβ markers in sMCI and VaD. Among the vascular integrity markers, only sFLt-1 correlated with pTDP-43 in VaD. CSF pTDP-43 levels trended to correlate negatively with hippocampal pTDP-43 load.

CSF pTDP-43 measured by ELISA cannot distinguish between MCI, AD, and VaD. However, it may reflect hippocampal pTDP-43 burden and is associated with some vascular and Aβ-related changes.