Implication of tau propagation on neurodegeneration in Alzheimer's disease

Abstract

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

Keywords: Alzheimer’s disease; PET; amyloid; fMRI; neurodegeneration; propagation; tau.

Figure 1

Proposed mechanisms for tau propagation. Highlighted are the findings that tau propagates predominantly in its oligomeric and short-fibril forms, with misfolded and hyperphosphorylated forms propagating in smaller proportions (Colom-Cadena et al., 2023). Tau monomers and long fibrils do not appear to propagate from cell to cell (Wu et al., 2013).

Figure 2

Representation of four distinct tau propagation patterns as determined by PET in a cross-sectional analysis (n = 2,324) (Vogel et al., 2021), with AD progression presented from left to right. The prevalence of each pattern in the analysis is indicated below the pattern names. Only the left side of the brain is shown, with the interior faces of sagittal cuts above their respective arrows. Different points of origin are highlighted in each of the defined patterns. Limbic propagation most closely resembles patterns reported by Braak and Braak (1991). Figure adapted from Vogel et al. (2021).