How do core 2 biomarkers, such as tau (tau protein) PET (Positron Emission Tomography) and specific CSF (Cerebrospinal Fluid) tau species, prognosticate Alzheimer's disease (AD)?

Core 2 Biomarkers in Alzheimer's Disease Prognostication

Core 2 biomarkers (tau PET and specific CSF/plasma tau species including p-tau 205, MTBR-243, and non-phosphorylated tau fragments) primarily provide prognostic information about disease stage and predict the rate of cognitive decline and brain atrophy, rather than serving as primary diagnostic tools. 1

Diagnostic vs. Prognostic Role

Core 2 biomarkers increase confidence that AD pathology is contributing to clinical symptoms but are not required for establishing an AD diagnosis. 2 The 2025 Alzheimer's Association guidelines clearly distinguish Core 2 from Core 1 biomarkers:

• Core 1 biomarkers (Aβ and hyperphosphorylated tau species p-tau 217, p-tau 181, p-tau 231) establish the biological diagnosis of AD 1, 2
• Core 2 biomarkers (tau PET, p-tau 205, MTBR-243, non-phosphorylated tau fragments) reflect AD tau proteinopathy and provide staging and prognostic information 1

Prognostic Capabilities of Core 2 Biomarkers

Tau PET Imaging

Tau PET demonstrates the strongest associations with cognitive decline and neurodegeneration markers compared to other biomarker modalities. 3

• Baseline tau PET binding predicts subsequent cognitive decline in domain-specific brain regions with strong anatomical correspondence (e.g., temporal tau binding predicts memory decline) 4
• Tau PET signal correlates more strongly with cognitive performance and cortical thickness than CSF or plasma tau biomarkers 3
• Higher baseline tau tracer binding predicts subsequent regional brain atrophy progression over 2 years, particularly in temporal, parietal, and frontal association cortices 4
• Tau PET outperforms amyloid PET, structural MRI, and CSF biomarkers in predicting rate of cognitive decline 4

CSF Core 2 Tau Species

Novel CSF tau biomarkers (p-tau 205, MTBR-243) enable biological disease staging that predicts clinical progression. 5

• A five-stage CSF biomarker model (ordered: Aβ42/40 → p-tau 217 → p-tau 205 → MTBR-243 → total tau) accurately stages disease progression across the AD continuum 5
• Higher CSF stages at baseline are associated with increased hazard ratio for clinical decline 5
• CSF stages align with longitudinal biomarker changes and correlate with Aβ-PET, tau-PET, and neurodegeneration markers 5

Biological Staging Framework

The 2025 NIA-AA criteria incorporate Core 2 biomarkers into a biological staging system: 1

• Stage A: Amyloid-positive only
• Stage B: Amyloid-positive + tau-positive in medial temporal lobe
• Stage C: Amyloid-positive + tau-positive with moderate neocortical involvement
• Stage D: Amyloid-positive + tau-positive with high neocortical involvement

Higher biological stages (C and D) indicate more advanced tau pathology and predict faster progression to dementia. 1

Differential Information Provided by Core 2 vs. Core 1

Core 1 and Core 2 biomarkers convey partly independent prognostic information: 3

• CSF and plasma p-tau 181 and p-tau 217 (Core 1) are more tightly linked with early AD markers, particularly Aβ pathology, age, and APOE ε4 carriership 3
• Tau PET (Core 2) shows stronger associations with downstream markers of disease progression including cognitive impairment and neurodegeneration 3
• Concordance between tau PET and fluid biomarkers ranges from 66-95%, indicating they capture different aspects of tau pathology 3

Clinical Application for Prognosis

When both Core 1 (Aβ + hyperphosphorylated tau) and Core 2 biomarkers are positive, the likelihood of MCI progressing to dementia is high. 1

The prognostic framework for MCI due to AD: 1

• High likelihood of progression: Both Aβ biomarkers AND neuronal injury markers (including CSF tau) are positive
• Intermediate likelihood: One biomarker category positive, the other untested or conflicting results
• Low likelihood: Both Aβ and neuronal injury biomarkers absent

Important Caveats

The prognostic value of biomarkers has limitations due to high inter-individual variability in decline rates among biomarker-positive individuals. 1 The 2021 International Working Group noted that Cochrane reviews consistently found insufficient evidence to recommend routine biomarker use solely for predicting "will my patient decline?" in clinical practice 1

Core 2 biomarkers are most valuable when integrated with Core 1 biomarkers and clinical assessment rather than used in isolation for prognostication. 1 Together with low CSF Aβ42, elevated CSF tau provides high likelihood of progression to AD dementia in MCI patients 1