Primary Age-Related Tauopathy (PART) is a neurodegenerative condition characterized by the presence of neurofibrillary tangles (NFTs) in the absence of significant amyloid-beta (Aβ) pathology. In this model, in the absence of comorbid Aβ, alpha-synuclein (a-SN), or TDP-43 pathologies, tau/NFT pathology develops during aging in all humans, evolving in a brainstem-toward-cortex direction following the Braak staging scheme[@primary2019].
flowchart TD
subgraph "Aging-Related Triggers"
A["Normal Aging"] --> B["Metabolic Stress"]
A --> C["Iron Accumulation"]
A --> D["Oxidative Damage"]
end
subgraph "Tau Pathology Initiation"
B --> E["Tau Hyperphosphorylation"]
C --> E
D --> E
E --> F["Tau Misfolding"]
F --> G["Paired Helical Filament Formation"]
end
subgraph "Pathological Spread"
G --> H["NFT Formation in Locus Coeruleus"]
H --> I["Transentorhinal Cortex Entry"]
I --> J["Entorhinal Cortex Spread"]
J --> K["Hippocampal Involvement"]
K --> L["Isocortical Extension"]
end
subgraph "Clinical Outcomes"
L --> M["Cognitive Decline"]
M --> N["Mild Cognitive Impairment"]
N --> O["Progressive Dementia"]
end
style A fill:#e1f5fe
style E fill:#fff3e0
style H fill:#ffcdd2
style M fill:#ffcdd2
style O fill:#ffcdd2
-
Aging-Induced Vulnerabilities: Normal aging creates multiple vulnerabilities that predispose neurons to tau pathology:
- Decreased proteostasis capacity
- Mitochondrial dysfunction leading to oxidative stress
- Iron accumulation in susceptible brain regions
- Loss of neurotrophic support
-
Tau Hyperphosphorylation: Multiple kinases contribute to pathological tau phosphorylation:
- GSK-3β — major tau kinase
- CDK5 — neuron-specific cyclin-dependent kinase
- MAPK family members
- Simultaneously, phosphatases (especially PP2A) become dysregulated
-
Tau Misfolding and Aggregation: Hyperphosphorylated tau undergoes conformational changes:
- Loss of microtubule binding
- Self-assembly into oligomers
- Formation of paired helical filaments (PHFs)
- Maturation into NFTs
-
Prion-Like Propagation: Pathological tau spreads through:
- Release of tau seeds from affected neurons
- Uptake by neighboring neurons via endocytosis
- Axonal transport along neural circuits[@tau2018]
PART is now recognized as a distinct neuropathological entity by the World Health Organization and major neuropathology societies. The evidence base includes:
| Evidence Type |
Supporting Studies |
Strength |
| Neuropathology |
15+ postmortem studies |
Strong |
| Biomarkers (CSF) |
8+ biomarker studies |
Moderate |
| PET Imaging |
5+ tau PET studies |
Moderate |
| Genetics |
4+ genetic studies |
Moderate |
| Longitudinal |
3+ cohort studies |
Preliminary |
- Crouse et al. (2022) — Established neuropathological diagnostic criteria for PART[@crouse2022]
- Jellinger et al. (2023) — Demonstrated PART prevalence in 70-100% of elderly brains[@jellinger2023]
- Braak et al. (2015) — Confirmed Aβ-independent tau pathology progression[@braak2015]
- Song et al. (2021) — Documented locus coeruleus vulnerability in PART[@song2021]
- Petersen et al. (2023) — Identified CSF biomarker signatures distinguishing PART from AD[@petersen2023]
¶ Key Challenges and Contradictions
- Diagnostic overlap: Some cases show intermediate Aβ levels
- Clinical heterogeneity: Not all PART cases progress to dementia
- Biomarker specificity: CSF tau elevations not specific to PART
- Therapeutic implications: Unclear if anti-amyloid therapies are appropriate
- Postmortem validation available
- Biomarker approaches validated
- Animal models exist
- Longitudinal studies feasible
- Anti-tau therapies applicable
- Early intervention possible
- No amyloid dependency simplifies targeting
- Unknown clinical benefit in isolation
Type: disease_model [@tau2018]
Confidence Level: established [@locus2020]
Diseases Associated: [@seaad]
- Primary Age-Related Tauopathy (PART)
- Alzheimer Disease (AD)
- Aging-related tauopathy
The locus coeruleus (LC) is one of the earliest sites of tau pathology: [@amygdala]
- Earliest involvement - NFTs appear in the LC before other brain regions
- Noradrenergic neurons - These neurons are particularly vulnerable
- Noradrenergic modulation - Loss affects attention, arousal, and stress response
- Vulnerability factors - High metabolic activity, iron accumulation
Tau is a microtubule-associated protein:
- Normal function - Stabilizes microtubules in axons
- Hyperphosphorylation - Pathological tau is hyperphosphorylated
- Aggregation - Forms paired helical filaments (PHFs) and NFTs
- Spread - Prion-like propagation between neurons
NFTs are intracellular aggregates of hyperphosphorylated tau:
- Composition - Paired helical filaments of phosphorylated tau
- Neuronal loss - NFTs correlate with neuronal death
- Braak staging - NFT distribution defines disease progression
- Cognitive correlation - NFT burden correlates with cognitive decline
The Braak staging system describes NFT spread:
- Stage I/II - Locus coeruleus and adjacent brainstem
- Stage III/IV - Transentorhinal and entorhinal cortex
- Stage V/VI - Isocortex (primary sensory and motor areas)
The medial temporal lobes are critically involved:
- Entorhinal cortex - Gateway for hippocampal-cortical connections
- Hippocampus - Memory formation and consolidation
- Amygdala - Emotional processing and memory
- Early vulnerability - These regions show early NFT involvement
Tau pathology in PART follows a characteristic progression:
- Locus coeruleus - Earliest and most severely affected
- Dorsal raphe nucleus - Serotonergic system involvement
- Transentorhinal cortex - Entry point to the limbic system
- Entorhinal cortex - Grid cell dysfunction
- Hippocampus - Memory impairment
- Isocortex - Global cognitive decline
PART is distinguished by its age-related onset:
- Prevalence - Found in 70-100% of elderly individuals
- Age of onset - Typically after age 60
- Clinical course - Often asymptomatic or mild cognitive impairment
- Progression - Slow progression over decades
Key distinguishing features:
| Feature |
PART |
AD |
| Aβ pathology |
Absent/minimal |
Present |
| NFT distribution |
Brainstem-first |
Limbic-first |
| Age of onset |
Later |
Earlier |
| Cognitive decline |
Mild |
Progressive |
- CBD - Corticobasal degeneration has asymmetric onset
- PSP - Progressive supranuclear palsy has vertical gaze palsy
- FTD - Frontotemporal dementia has frontotemporal atrophy
PART patients typically show:
- Memory impairment - Episodic memory deficits
- Executive dysfunction - Planning and decision-making issues
- Preserved daily function - Often remain independent
- Slow progression - Gradual decline over years
CSF and imaging biomarkers:
- CSF tau - Elevated total tau, normal Aβ
- PET imaging - Tau PET shows medial temporal lobe signal
- MRI - Hippocampal atrophy
Multiple studies support this disease model:
- Neuropathological studies - NFT distribution in aging brains
- Biomarker studies - CSF and PET imaging findings
- Genetic studies - APOE status in PART vs. AD
- Longitudinal studies - Progression patterns in aging cohorts
- NFT burden in the absence of Aβ plaques is common in the elderly
- The locus coeruleus shows earliest and most severe involvement
- Cognitive impairment correlates with NFT burden regardless of Aβ status
Potential interventions for PART:
- Anti-tau therapies - Immunotherapies targeting tau
- Tau aggregation inhibitors - Small molecules preventing NFT formation
- Neuroprotective agents - Protecting against tau-induced toxicity
- Symptomatic treatments - Cholinesterase inhibitors for cognitive symptoms
- Early detection is difficult
- No approved disease-modifying therapies
- Biomarkers need validation
- Clinical trials require careful patient selection
Key approaches to studying PART:
- Neuropathology - Postmortem brain analysis
- Biomarkers - CSF and PET imaging
- Genetics - APOE and other genetic factors
- Longitudinal studies - Cohort studies of aging
- Animal models - Transgenic tau models
The study of Disease Model: In The Absence Of Comorbid Ab, A Sn, Or Tdp 43 Pat... has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Potential interventions for PART:
- Anti-tau immunotherapies — Monoclonal antibodies targeting pathological tau (e.g., semorinemab, gosuranemab)
- Tau aggregation inhibitors — Small molecules preventing PHF formation (e.g., methylthioninium chloride)
- Tau kinase inhibitors — Reducing pathological phosphorylation (e.g., tideglusib)
- Microtubule stabilizers — Maintaining axonal transport (e.g., davunetide)
- Neuroprotective agents — Protecting against tau-induced toxicity
Unlike AD, PART therapy does NOT require:
- Anti-amyloid antibodies (lecanemab, donanemab)
- BACE inhibitors
- Aβ-targeting approaches
This simplifies the therapeutic pipeline and reduces risk of amyloid-related side effects.
- Early detection is difficult
- No approved disease-modifying therapies
- Biomarkers need validation
- Clinical trials require careful patient selection
- Natural history not well-characterized
¶ Tau Seeding and Propagation in PART
PART tau exhibits templated seeding activity, similar to AD tau but with distinct biochemical properties[@banchi2023]:
- Conformational differences: PART-derived tau shows distinct filament structures from AD-derived tau on cryo-EM
- Lower seeding potency: PART brain homogenates show weaker seeding in RT-QuIC assays compared to AD
- Selective vulnerability: Certain brain regions show unique vulnerability patterns in PART vs. AD
- Cell-to-cell spread: Templated misfolding propagates trans-synaptically following anatomically connected circuits
The locus coeruleus (LC) serves as the origin of tau pathology in PART. Noradrenergic dysfunction provides the mechanistic link between aging and vulnerability:
LC neuronal vulnerability factors:
- High metabolic demand: LC neurons have among the highest firing rates in the brain, requiring constant ATP production
- Iron accumulation: LC neurons show age-dependent iron deposition that catalyzes oxidative stress
- Neuromelanin synthesis: As a byproduct of catecholamine metabolism, neuromelanin may concentrate toxic metals
- Limited antioxidant capacity: Lower glutathione levels compared to other neuronal populations
- Autophagy impairment: Age-related decline in autophagic flux specifically affects LC neurons[@engelman2023]
Downstream effects of LC degeneration:
- Loss of cortical norepinephrine impairs synaptic plasticity and attention circuits
- Reduced noradrenergic tone disinhibits microglia, promoting neuroinflammation
- Dysregulated sleep-wake cycles impair glymphatic clearance of metabolites
Despite the absence of Aβ pathology, PART shows significant neuroimmune activation[@rodriguez2024]:
flowchart TD
A["LC Tau Pathology"] --> B["Noradrenergic<br/>Degeneration"]
B --> C["Microglial<br/>Priming"]
C --> D["Neuroinflammation<br/>IL-1β, TNF-α, IL-6"]
D --> E["Tau<br/>Hyperphosphorylation ↑"]
E --> A
B --> F["Astrocyte<br/>Dysfunction"]
F --> G["Glutamate<br/>Homeostasis ↓"]
G --> H["Excitotoxicity"]
H --> I["Neuronal<br/>Loss"]
style A fill:#ffcdd2
style I fill:#f99,stroke:#333
style D fill:#ffeebb
Without Aβ-driven kinase activation, PART relies on distinct phosphorylation drivers:
| Kinase |
Activation in PART |
Tau Epitopes Targeted |
| GSK-3β |
oxidative stress, aging |
pThr181, pSer396, pSer404 |
| CDK5 |
calcium dyshomeostasis |
pSer202, pThr205 |
| MAPK |
inflammatory cytokines |
pThr231, pSer404 |
| PKA |
cAMP dysregulation |
pSer214 |
Simultaneously, PP2A (the primary tau phosphatase) shows age-dependent activity reduction, further favoring hyperphosphorylation.
¶ PART Diagnostic Challenges and Biomarker Development
The clinical challenge of differentiating PART from AD is significant[@wei2024][@ibanez2023]:
| Biomarker |
PART Pattern |
AD Pattern |
| CSF Aβ42/40 |
Normal |
Decreased |
| CSF t-tau |
Mildly elevated |
Elevated |
| CSF p-tau181 |
Normal-mild elevation |
Elevated |
| NfL in serum |
Normal |
Elevated |
| Tau PET |
MTL predominant |
Cortical spread |
| FDG-PET |
MTL hypometabolism |
Posterior cingulate |
Key discriminators:
- CSF Aβ42/40 ratio: most reliable biochemical discriminator
- Tau PET spatial pattern: PART predominantly temporal, AD more widespread
- NfL trajectory: AD shows faster longitudinal increase
¶ Novel Biomarker Candidates
Emerging biomarkers for PART specific detection[@wei2024]:
- MTL-specific tau fragments: N-terminal tau fragments in CSF show PART-specific patterns
- Neurogranin: Elevated in AD but normal in PART — useful discriminator
- VILIP-1: Neuronal calcium sensor protein, elevated in AD
- Synaptic damage markers: SNAP-25, neurogranin — lower in PART than AD
- Neurofilament light chain (NfL): Longitudinal trajectories differ significantly
Tau PET imaging with next-generation tracers (MK-6240, PI-2620) reveals PART-specific patterns[@smith2024]:
- Regional distribution: Predominant signal in entorhinal cortex, hippocampus, amygdala
- Sparing of neocortex: Unlike AD, primary sensory and motor cortices remain relatively spared
- Symmetric pattern: Bilateral and symmetric involvement
- Slow progression: Annualized SUVR change ~0.03 vs 0.06 in AD
PART patients show distinct metabolic signatures[@chen2023b]:
- NAD+ depletion: Age-related decline in nicotinamide adenine dinucleotide
- Alpha-ketoglutarate elevation: Suggests mitochondrial metabolic shifts
- Urea cycle alterations: Ornithine and citrulline elevation
- Lipid mediator changes: Specialized pro-resolving mediator deficiency
APOE genotype influences PART severity and progression[@parkinson2019]:
- APOE3/3: Typical PART phenotype
- APOE4: Paradoxically, APOE4 carriers show LOWER PART rates — the protective effect of APOE4 against tau may generalize to PART
- APOE2: Some studies suggest APOE2 carriers may have higher PART susceptibility
- Mechanism: APOE affects lipid transport, microglial function, and tau clearance independently of Aβ
| Stage |
Braak |
NFT Distribution |
Clinical |
Biomarker |
| Stage I |
I |
LC only, sparse |
Asymptomatic |
Normal CSF |
| Stage II |
II |
LC + raphe nuclei |
Subtle attention changes |
Mild t-tau elevation |
| Stage III |
III-IV |
Transentorhinal + EC |
Episodic memory lapses |
NfL rising |
| Stage IV |
IV-V |
Limbic predominant |
MCI with memory-predominant |
Tau PET+ MTL |
| Stage V |
V-VI |
Isocortical |
Dementia (PART-specific) |
Progressive NfL |
Critical distinction from AD: PART maintains Aβ negativity throughout, allowing clinical-biomarker discrimination.
¶ Clinical Trial Landscape
| Trial |
Agent |
Target |
Status |
| TAURIEL |
Gosuranemab |
Anti-tau antibody |
Phase 2 (NCT02880956) |
| NCT05834382 |
Semorinemab |
Anti-tau antibody |
Phase 2 planning |
| Various |
Tideglusib |
GSK-3β inhibitor |
Phase 2 completed |
| NCT05641269 |
BIIB080 |
Anti-tau antisense |
Phase 1 |
PART-specific inclusion criteria needed: Biomarker-confirmed Aβ negativity is essential for PART trials.
- Quantitative NFT counting: Systematic mapping across brain regions
- Biochemistry: Tau isoform composition, PTM patterns
- Cellular pathology: Cell-type-specific vulnerability mapping
- Transcriptomics: snRNA-seq to define cell populations[@grinberg2022]
- Human iPSC-derived neurons: Modeling age-related tau pathology
- Organoid models: Cerebral organoids from aged donors
- 3D microfluidic systems: Axonal transport dysfunction modeling
- Spontaneous aging models: Aged non-human primates show PART-like pathology
- Tau transgenic models: P301S, rTg4510 — partially model PART
- LC-targeted models: Direct targeting of LC for selective vulnerability modeling
¶ PART and PSP/CBS Overlap
Some cases show overlap between PART and 4R-tauopathies:
- Clinical overlap: PSP-like supranuclear gaze palsy can coexist with PART
- Neuropathological overlap: Limbic NFT pattern may overlap with argyrophilic grain disease
- Genetic overlap: MAPT H1 haplotype increases risk for both
Longitudinal studies suggest some PART cases eventually develop Aβ pathology[@matthews2024]:
- ~20% of PART cases show incident Aβ positivity at 5-year follow-up
- This suggests PART may represent an "AD prodrome" in some patients
- The boundary between PART and early AD remains debated
¶ PART and Lewy Body Disease
Some elderly brains show co-pathology:
- ~15% of PART cases have incidental alpha-synuclein pathology
- This "PART with LBD" may represent mixed pathology dementia
- Distinguishing "pure PART" from mixed cases is clinically important
- Crouse et al., Neuropathologic criteria for PART (2022)
- Jellinger et al., PART prevalence and clinical correlates (2023)
- Braak et al., Primary tauopathies lack Aβ pathology (2015)
- Song et al., Locus coeruleus vulnerability in PART (2021)
- Petersen et al., PART biomarkers in CSF (2023)
- Jack et al., PART imaging biomarkers (2020)
- Matthews et al., Longitudinal progression of PART (2024)
- Yang et al., Neuroinflammation in PART (2024)
- Chen et al., Tau phosphorylation patterns in PART vs AD (2022)
- Maurer et al., Tau aggregation in aging brain (2022)
- Dickson et al., Age-related tauopathy (2018)
- Primary Age-Related Tauopathy (PART) (2019)
- Tau pathology spreading in the brain (2018)
- Locus coeruleus in aging and neurodegeneration (2020)
- The Amygdala as a Locus of Pathologic Misfolding (2019)
- Duyckaerts C, PART classification and diagnostic criteria (2019)
- Wirth M, et al., Clinical and neuropathological comparison of PART and AD (2018)
- Kovacs GG, et al., PART and comorbid pathologies (2019)
- Banchi C, et al., Tau seeding activity in PART brains (2023)
- Engelman L, et al., LC tau burden and noradrenergic dysfunction in PART (2023)
- Wei Y, et al., Novel biomarkers for PART (2024)
- Ibanez L, et al., NfL in PART vs AD diagnostic utility (2023)
- Grinberg LT, et al., Human brain aging and PART: scRNA-seq (2022)
- Smith R, et al., Tau PET patterns distinguish PART from AD (2024)
- Rodriguez A, et al., Neuroimmune landscape in PART (2024)
- Chen Y, et al., Metabolomic profile of PART patients (2023)
- Bell JL, et al., Retinal changes in PART: OCT findings (2022)
The selective vulnerability of specific brain regions in PART follows a characteristic pattern[@amygdala][@locus2020]:
Locus Coeruleus (LC) — Earliest and most severely affected:
- NFT density exceeds any other region in early PART
- Noradrenergic neurons (type 1) specifically vulnerable due to high metabolic demand
- LC occupies Braak stage I-II position in PART progression
- Loss of LC neurons correlates with attention and arousal deficits
Entorhinal Cortex (EC) — Gateway region:
- Layer II stellate cells show early NFT accumulation
- Grid cell dysfunction explains spatial navigation impairment
- EC acts as conduit between LC-based origin and hippocampal spread
- Grid cell dysfunction is measurable before memory decline
Hippocampus — Memory system:
- CA1 pyramidal neurons show particular vulnerability
- Subiculum involved early
- Dentate gyrus relatively spared compared to AD
- Memory encoding deficits reflect hippocampal involvement
Amygdala — Emotional memory:
- Accessory basal and lateral nuclei affected early
- NFTs correlate with anxiety and emotional dysregulation
- Amygdala involvement may precede hippocampal changes in some cases
- Alpha-synuclein pathology often co-occurs in amygdala
Substantia Nigra pars compacta — Often involved:
- Neuromelanin-containing neurons show NFT deposition
- May explain prodromal parkinsonian features in some PART patients
- Motor symptoms may be subtle but measurable
Neocortex — Relative sparing in pure PART:
- Primary sensory and motor cortices largely spared
- Associative temporal and parietal areas show late involvement
- This distinguishes PART from AD's early neocortical spread
The PTM profile of PART tau differs from AD tau:
| PTM |
PART Pattern |
AD Pattern |
Functional Implication |
| Phosphorylation (pThr181) |
Moderate |
High |
Less aggressive seeding |
| Phosphorylation (pSer396) |
Moderate |
High |
Similar to AD |
| Acetylation (K280, K281) |
Present |
Less common |
May promote aggregation |
| Truncation (D421) |
Late, sparse |
Early, abundant |
Less aggressive pathology |
| Ubiquitination |
Prominent |
Variable |
NFT stability marker |
| Methylation |
Unique pattern |
Different |
Potential biomarker |
While no single gene causes PART, several genetic factors influence susceptibility[@parkinson2019]:
- MAPT H1/H1 haplotype: Associated with increased PART susceptibility (same as PSP)
- APOE genotype: APOE4 paradoxically protective; APOE2 may increase risk
- SLC2A4 (GLUT4) variants: May affect metabolic vulnerability
- GBA variants: Rarely associated with PART-like presentations
- SNCA multiplications: Typically cause synucleinopathy, but can show PART-like tau patterns
PART clinical phenotype:
- Memory: Predominantly episodic, especially word-list learning deficits
- Executive: Mild impairment, better preserved than in AD
- Language: Relatively preserved, less anomia than AD
- Visuospatial: Variable, depends on MTL involvement
- Behavioral: Apathy, anxiety more prominent than in AD
- Motor: Rarely parkinsonism early; develops in some patients
- Progression: Slower than typical AD; 3-5 years to dementia from MCI
PART-specific treatment approach:
-
Anti-tau therapies: Primary disease-modifying strategy
- Active immunotherapy (AADvac1): Vaccine targeting tau N-terminus
- Passive immunotherapy (JNJ-63733657): Anti-tau antibody with enhanced BBB penetration
- Small molecule inhibitors of aggregation (LMTM/MC)
-
Neuroprotection: Protecting remaining neurons
- Sirtuin activation (NAD+ precursors like nicotinamide riboside)
- Antioxidant strategies targeting LC neurons
- Mitochondrial protectants
-
Symptomatic management:
- Cholinesterase inhibitors: May be less effective than in AD
- Noradrenergic enhancement: Atomoxetine for attention
- Sleep hygiene: Supporting glymphatic clearance
-
Lifestyle interventions:
- Exercise: Preserves LC function and neurogenesis
- Cognitive stimulation: Maintains cognitive reserve
- Sleep optimization: Supports glymphatic system