Can phosphorylated tau (p‑tau) be elevated in Parkinson's disease?

Can P-tau Be Elevated in Parkinson's Disease?

Yes, phosphorylated tau (p-tau) can be elevated in Parkinson's disease, particularly in patients with cognitive impairment and dementia, though the elevations are typically modest compared to Alzheimer's disease and reflect different underlying pathophysiology.

Diagnostic Context: P-tau217 Specificity

The critical distinction is that p-tau217 specifically is highly specific to Alzheimer's disease pathology and is not significantly elevated in other tauopathies or neurodegenerative diseases, including Parkinson's disease 1. When using high-performing assays, elevated p-tau217 is essentially pathognomonic for Alzheimer's disease pathology 1. This means if you see elevated p-tau217 in a patient with parkinsonism, you should strongly consider concomitant Alzheimer's disease pathology rather than pure Parkinson's disease.

P-tau Elevations in Parkinson's Disease: The Evidence

CSF P-tau in PD with Dementia

• CSF p-tau (particularly p-tau181) is elevated in Parkinson's disease dementia (PDD) compared to cognitively normal PD patients, with a pooled standardized mean difference of 0.36 2
• CSF tau and phospho-tau levels are significantly higher in PDD than in non-demented PD patients and controls 3
• High CSF tau and phospho-tau in PD patients are associated with impaired memory and naming functions, suggesting underlying Alzheimer's disease-type pathology 3

Longitudinal Changes

• CSF phosphorylated tau levels increase over time in Parkinson's disease, with significant increases observed over 2 years 4
• Increases in phosphorylated tau over 2 years correlate with faster motor progression and faster cognitive decline in PD 4
• These increases are more pronounced in patients with longer disease duration (>5 years) 4

Plasma P-tau181 in PD

• Plasma p-tau181 does NOT effectively differentiate PD with mild cognitive impairment from cognitively normal PD, and does not predict progression to dementia in PD 5
• This contrasts with neurofilament light chain (NfL), which does differentiate cognitive states in PD 5

Clinical Algorithm for Interpreting Elevated P-tau in Parkinsonism

Step 1: Determine Which P-tau Assay Was Used

• If p-tau217 is elevated: This strongly indicates concomitant Alzheimer's disease pathology rather than pure Parkinson's disease 1
• If p-tau181 (CSF) is elevated: Consider mixed pathology (PD + AD) especially if cognitive impairment is present 2, 3
• If p-tau181 (plasma) is elevated: This has limited utility for differentiating cognitive states in PD 5

Step 2: Assess Cognitive Status

• In cognitively normal PD: Modest p-tau elevations may represent early mixed pathology or normal aging-related changes 6
• In PD with dementia: Elevated p-tau (especially with low Aβ42) strongly suggests concomitant Alzheimer's disease pathology contributing to cognitive decline 2, 3

Step 3: Consider Amyloid Status

• If both p-tau AND Aβ42 are abnormal: This indicates mixed PD-AD pathology 2, 3
• If p-tau is elevated but Aβ42 is normal: Consider primary age-related tauopathy or other non-AD causes 1

Critical Caveats and Pitfalls

Pathophysiological Considerations

• Tauopathy in PD may reflect different mechanisms than in AD: Animal models show that α-synuclein overexpression can induce tau hyperphosphorylation through activation of GSK-3β, creating Lewy body-like inclusions containing both proteins 7
• The presence of tau pathology in PD represents overlapping degenerative mechanisms between synucleinopathies and tauopathies 7

Threshold and Interpretation Issues

• Binary thresholds for p-tau positivity are somewhat artificial, as tau pathology exists on a continuum 6
• Almost all individuals over age 70 have some degree of tau pathology (Braak stages I-II), which may not be clinically significant 6
• Current tau PET tracers detect only widespread tau pathology (Braak stages ≥IV), while CSF p-tau can reflect earlier stages 6

Confounding Factors

• Cerebrovascular disease and cardiovascular disease are the most important biological confounders that may influence p-tau measurements 1, 8
• Age, creatinine levels, and depressive symptoms can also affect p-tau measurements 1, 8

When to Suspect Mixed Pathology

Actively consider concomitant Alzheimer's disease pathology in PD patients when:

• P-tau217 is elevated (highly specific for AD) 1
• CSF shows the AD signature: low Aβ42 + elevated t-tau + elevated p-tau 2, 3
• Cognitive impairment involves prominent cortical features (memory, naming deficits) rather than pure frontosubcortical dysfunction 3
• Cognitive decline is rapid or disproportionate to motor symptoms 4