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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282910 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia, neither of which can be effectively treated. There is growing evidence on vascular contributions to cognitive impairment and dementia such as AD, but their pathogenic molecular links are not defined yet. Notably, neurofibrillary tangles made of hyperphosphorylated tau (P-tau) are a hallmark lesion of AD, but are not found in VaD. Although brain ischemia induces some tau changes and tau knockout reduces stroke-induced acute brain damage, little is known about the role of tau in mediating progression from vascular insufficiency to later development of VaD. Cis P-tau is a pre-tangle pathology in AD and an early driver of neurodegeneration resulting from brain injury, but its role in AD treatment or in VaD is unknown. Here we identify cis P-tau as an antibody-neutralizable major common early driver of AD and VaD. We show that cis P-tau elimination using cis antibody not only prevents, but also treats AD-like neurodegeneration and memory loss in a hTau mouse model of AD. Purified cis P-tau causes and spreads neurodegeneration with behavioral changes when injected into wild-type mouse brains, but is prevented by cis antibody. Surprisingly, we also find robust cis P-tau with no evidence of tau tangles in human VaD brains and a mouse model of chronic cerebral hypoperfusion that mimics key aspects of clinical VaD. Cis mAb treatment of hypoperfusive mice for 1 or 6 months blocks VaD-like neuropathological and functional outcomes. Single-cell transcriptomic profiling reveals that cerebral hypoperfusion induces numerous global changes in diverse brain cells including those of human AD brains. Remarkably, ~90% of these global changes are fully recovered with cis antibody, correlating with tau expression in cells. Thus, cis P-tau is a major common early driver of AD and VaD, and cis antibody has a potential role in the early detection, prevention and treatment of these devastating diseases.

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

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