====== Tau Proteinopathy ====== [[Tau]] [[proteinopathy]] refers to a group of [[neurodegenerative disease]]s characterized by abnormal [[accumulation]], misfolding, or hyperphosphorylation of [[tau protein]] within neurons or [[glial cell]]s. [[Tau]] is a microtubule-associated protein that stabilizes microtubules in [[neuron]]s. In disease states, tau becomes dysfunctional and forms neurofibrillary tangles (NFTs), leading to neuronal dysfunction and death. ---- ====== Tau Proteinopathy vs Tau Pathology ====== Both terms are correct but used in different contexts. Below is a comparative summary: ^ Term ^ Definition ^ Typical Use Context ^ | **Tau proteinopathy** | A neurodegenerative disease characterized by abnormal tau aggregation. | Neuropathological diagnosis, disease classification | | **[[Tau pathology]]** | The presence of abnormal tau protein (e.g., hyperphosphorylated, aggregated), regardless of specific disease. | Imaging, biomarkers, histological reports | ===== ✅ Tau Proteinopathy ===== **Definition**: A class of neurodegenerative diseases characterized by tau protein misfolding, hyperphosphorylation, and aggregation into neurofibrillary tangles (NFTs). **Examples**: * [[Alzheimer’s disease]] (mixed proteinopathy) * Progressive supranuclear palsy (PSP) * Corticobasal degeneration (CBD) * Pick’s disease **Use**: * In diagnostic classifications * In neuropathology reports * In research defining disease entities ===== ✅ Tau Pathology ===== **Definition**: Refers to the histological or biochemical presence of abnormal tau in the brain tissue, cerebrospinal fluid (CSF), or via PET imaging. **Examples**: * Elevated phospho-tau in CSF * Positive tau-PET imaging * Detection of neurofibrillary tangles on microscopy **Use**: * Describing findings in research or clinical imaging * Monitoring disease progression * Biomarker studies ===== 🔍 Summary Table ===== ^ Aspect ^ Tau Proteinopathy ^ Tau Pathology ^ | Scope | Disease entity | Pathological process | | Formality | More specific and formal | Descriptive and broad | | Field | Neuropathology, taxonomy | Clinical, biomarker, imaging studies | | Usage example | “CBD is a 4R tau proteinopathy.” | “Tau pathology was evident in PET scan.” | ====== Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex ====== **Type of study:** Observational, large-scale multisite neuroimaging (tau PET) meta-analysis **First author et al.:** Ossenkoppele et al. **Affiliation:** Amsterdam UMC, Alzheimer Center Amsterdam (Amsterdam, The Netherlands) **Journal:** Nature Neuroscience **Purpose:** To quantify how [[tau PET]] positivity varies by age, cognitive status (CU, MCI, dementia), Aβ status, APOE ε4 carriage, and sex, using 12,048 participants across 42 cohorts. **Conclusions:** * Among cognitively unimpaired (CU), tau positivity increases modestly with age: from 1.1 % to 4.4 % in Aβ–, versus 17.4 % to 22.2 % in Aβ+. * In MCI and dementia, tau positivity decreases with age (e.g., MCI: 68 → 53 %; dementia: 91.5 → 74.6 %). * APOE ε4 accelerates onset of both Aβ and tau pathology by decades. * Female sex also confers higher tau positivity risk across groups. * Findings were validated using an independent autopsy dataset (n ≈ 5,072). ---- === Critical Review === **Strengths:** - Extremely large, international sample (n = 12,048), with independent replication (n = 5,072) — excellent statistical power and generalizability. - Multi-variable modeling allows disentangling effects of age, Aβ, APOE, and sex. - Use of both in vivo PET and autopsy data strengthens validity. **Concerns:** - **Heterogeneity and harmonization:** Forty-two cohorts used various tracers, PET protocols, and tau positivity thresholds. The authors note harmonization efforts but residual bias may remain. - **Cross-sectional design:** Unable to track individual progression; age-related decline in positivity among MCI/dementia may reflect cohort effects or survival bias, not actual biology. - **Covariate control:** It’s unclear if vascular risk, education, or clinical severity were adjusted; these could influence tau deposition. - **Sex difference interpretation:** Higher tau PET in women may reflect hormonal or social factors; causality remains untested here. - **Threshold effects:** Reporting across positivity thresholds can amplify small measurement variances—continuous measures might yield more nuanced insights. Overall, while methodologically robust, the paper’s translation into clinical prognostication requires attention to inter-cohort variability and longitudinal dynamics. ---- === Final Verdict === - **Score:** 8.0/10 - Large scale and replication are major strengths; cross-sectional design and heterogeneity limit mechanistic inference. === Takeaway for neurosurgeons === - [[APOE]] ε4 carriers and Aβ+ individuals, especially women over 60, have elevated risk of early tau accumulation—consider when interpreting PET scans and risk stratification. - Modest tau positivity in older CU may signal preclinical [[Alzheimer’s disease]]; high positivity in MCI/dementia supports AD pathology, but age-specific prevalence should inform biomarker interpretation. === Bottom Line === This study delivers a refined, population-based template for tau PET positivity, stratified by key risk modifiers. While providing valuable benchmarks, longitudinal validation and standardization are needed to translate findings into routine diagnostics. ---- **CITATION:** Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid‑β status, APOE genotype and sex. Ossenkoppele R et al. *Nat Neurosci*. 2025 Jul 16. doi: 10.1038/s41593‑025‑02000‑6. Online ahead of print. **Corresponding author:** R. Ossenkoppele **PubMed PMID:** 40670684