Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

Abstract

AbstractBackgroundFor optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.MethodWe included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables.ResultIn early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C).ConclusionSoluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.