Synergistic associations of amyloid-β and phosphorylated tau with tau aggregation and cognitive decline in Alzheimer's disease

Abstract

Background: The pathological hallmarks of Alzheimer's disease (AD) include the amyloid-β (Aβ) plaques and phosphorylated tau (p-tau) forming neurofibrillary tangles. Understanding the pathophysiological cascade related to Aβ and tau process is crucial. Objective: To investigate the impact of Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) p-tau on tau pathology and cognitive decline in AD. Methods: We analyzed 319 older individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent Aβ (18F-florbetapir or 18F-florbetaben) and tau (18F-flortaucipir) PET scans, along with CSF and cognitive assessments. Aβ positivity (A+) was determined by global standardized uptake value ratio thresholds of ≥1.11 for 18F-florbetapir or ≥1.08 for 18F-florbetaben, while p-tau positivity (T+) was defined as CSF p-tau181 levels ≥23 pg/ml. Linear mixed regression models were used to assess the effects of PET Aβ and CSF p-tau181 levels on tau accumulation in predefined Braak regions and cognitive function over time. Results: Our results revealed significant differences in PET tau pathology and cognitive decline between A + and A− individuals. We observed that interactions between Aβ and p-tau proteins were associated with tau accumulation and cognitive decline. Additionally, A−/T + individuals exhibited higher levels of tau accumulation in all Braak regions compared to A−/T− counterparts, suggesting a potential independent role of p-tau in tau pathology in the absence of Aβ. Conclusions: Our findings suggest that Aβ positivity and elevated CSF p-tau181 levels were associated with tau accumulation and cognitive decline, highlighting the relevance of soluble p-tau as a potential biomarker for further investigation.