CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum.

Background: Soluble Aβ dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aβ drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aβ and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum. Method: The first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aβ42, Aβ40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aβ42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aβ status (CSF Aβ42/40 < 0.071) on brain structure was determined. Result: Table 1 shows sample's characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aβ42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aβ status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aβ42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2). Conclusion: Independently of p‐tau, early Aβ dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aβ+ individuals. Pathophysiological alterations other than Aβ, but correlated with CSF Aβ levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages. [ABSTRACT FROM AUTHOR]