Neocortical tau propagation is a mediator of clinical heterogeneity in Alzheimer's disease.

Heterogeneity in progression of clinical dementia obstructs the general therapeutic potential of current treatments for Alzheimer's disease (AD). Though the mechanisms of this heterogeneity remain unclear, the characterization of bioactive tau species and factors that regulate their seeding behavior might give valuable insight as pathological tau is well correlated with cognitive impairment. Here, we conducted an innovative investigation into the molecular basis of widespread, connectivity-based tau propagation that begins in the inferior temporal gyrus (ITG) and spreads to neocortical areas such as the prefrontal cortex (PFC). Biochemical analysis of human postmortem ITG and PFC tissues revealed individual variability in tau seeding, which correlated with cognitive decline, particularly in the ITG, a region known for promoting accelerated tau propagation. Notably, this study presents the first evidence that site-specific phosphorylation and isoform composition of both aggregation-prone high-molecular-weight (HMW) tau and the relatively unexplored, yet potentially crucial in AD progression low-molecular-weight (LMW) tau significantly contribute to tau propagation and cognitive decline. Our findings underscore the importance of comprehensively considering diverse tau forms including both HMW and LMW tau species in understanding AD progression. Additionally, these results are the first to identify distinct morphological strains within the AD brain associated with differing seeding propensity, potentially enabling patient stratification based on their tau profile. Furthermore, RNA-seq analyses of gene expression patterns in the ITG revealed molecular heterogeneity associated with tau seeding potential. Patients with higher levels of seed-competent tau displayed greater impairments in synaptic and neural plasticity, and increased neuroinflammation. This multidisciplinary study offers novel insights into various molecular mechanisms driving AD progression, suggesting potential molecular targets for early intervention and improved patient subtyping, which is critical for developing precision medicine approaches.