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

Molecular Psychiatry volume 30, pages 4194–4213 (2025)Cite this article

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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.

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Fig. 1: Tau seeding bioactivity correlates with cognitive decline in AD.
Fig. 2: AD brain lysates with elevated phospho-tau induce more tau seeding and higher order, more complex inclusion morphology.
Fig. 3: Phosphorylation of HMW-tau at specific sites associated with AD correlates with tau seeding.
Fig. 4: Tau seeding correlates with oligomeric 3R and 4R tau levels.
Fig. 5: HMW and LMW-phosphorylated tau and isoforms are associated with cognitive decline.
Fig. 6: Transcriptional changes in AD ITG associated with tau pathology and disease progression.
Fig. 7: Transcriptional dysregulation of synaptic transmission pathways in AD ITG.
Fig. 8: Identification and analysis of co-expression modules related to cognitive decline in AD.

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Data availability

Data supporting the findings of this study are available in the main text and supplementary information files. All other data generated in the study are available from the corresponding author on request. The RNA-seq datasets generated for the current study have been deposited in GEO under the accession ID: GSE282910.

Code availability

All codes used in this study will be made available upon request from the corresponding author.

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Acknowledgements

We thank the Alzheimer’s Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai, Mount Sinai Brain Bank (NIH NeuroBioBank), especially Dr. Vahram Haroutunian (Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA) and Banner Sun Health Research Institute, especially Dr. Thomas Beach and Dr. Geidy E. Serrano (Banner Sun Health Research Institute, Sun City, Arizona, USA) for providing human brain samples, and microscopy core at Icahn School of Medicine at Mount Sinai, especially Dr. Shilpa Dilip Kumar and Glenn Doherty. We thank Dr. Patrick Hof (Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA), Dr. Minghui Wang (Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA), Drs. Banshi Nath and Kaitlin Murtha (Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA) for their insightful comments and feedback. This work was supported by NIH Grants R01 AG063819 and R01 AG064020 (to A.C.P.), the DANA Foundation (to A.C.P.); the Alzheimer’s Association (to A.C.P.); the Sanford J Grossman Charitable Trust (to A.C.P.); Brian and Tania Higgins Charitable Foundation (to A.C.P.); the Carolyn and Eugene Mercy Research Gift (to A.C.P.); the Karen Strauss Cook Research Scholar Award (to A.C.P.); the Alzheimer’s New Jersey (to A.C.P); the Robert J. and Claire Pasarow Foundation (to A.C.P.); and NIH/NIA P30AG066514 Alzheimer’s Disease Research Center (to M.S.).

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Authors and Affiliations

  1. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Anjalika Chongtham, Marissa Farinas, Diede W. M. Broekaart, Joon Ho Seo & Ana C. Pereira

  2. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Anjalika Chongtham, Aarthi Ramakrishnan, Marissa Farinas, Diede W. M. Broekaart, Joon Ho Seo, Li Shen & Ana C. Pereira

  3. Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Carolyn W. Zhu

  4. James J. Peters VA Medical Center, Bronx, NY, USA

    Carolyn W. Zhu & Mary Sano

  5. Department of Psychiatry, Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Carolyn W. Zhu & Mary Sano

  6. Sanford Grossman Interdisciplinary Program I Neural Circuitry and Immune Function, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ana C. Pereira

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  1. Anjalika Chongtham
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Contributions

AC and ACP designed the research. AC and MF performed experiments. AC, AR, ACP, LS, MF, DB and JHS analyzed experiments. MS and CZ provided intellectual input while selecting subjects for the study. ACP and LS contributed reagents/analytic tools. AC wrote the manuscript. AC, ACP, LS, AR, MF, DB and CZ edited the manuscript. All authors provided feedback on the manuscript draft.

Corresponding author

Correspondence to Ana C. Pereira.

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Competing interests

ACP has patents unrelated to this work licensed to Neurobiopharma, LLC, serves on the scientific advisory board of Sinaptica Therapeutics and has served as a consultant to Eisai and Quanterix.

Ethics approval and consent to participate

For human brain tissue, written informed consent for post-mortem brain donation was obtained from the families of donors through the brain bank. Prior to their transfer to the Icahn School of Medicine at Mount Sinai, all samples were de-identified, thereby exempting them from the oversight of the Institutional Review Board (IRB).

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Chongtham, A., Ramakrishnan, A., Farinas, M. et al. Neocortical tau propagation is a mediator of clinical heterogeneity in Alzheimer’s disease. Mol Psychiatry 30, 4194–4213 (2025). https://doi.org/10.1038/s41380-025-02998-y

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