Surrogate Markers in Neuropathology

I. Framework / Classification

II. Biomarkers by Category

A. Amyloid / Aβ Markers (Alzheimer's Disease)

• CSF Aβ42: The first validated fluid biomarker for AD. Reduced CSF Aβ42 reflects sequestration of amyloid into plaques. The Aβ42/Aβ40 ratio corrects for inter-individual variability and shows higher concordance with amyloid PET than Aβ42 alone.
• Amyloid PET (florbetapir, florbetaben, flutemetamol): Directly images neuritic and diffuse Aβ plaques throughout the neocortex. A negative scan makes AD diagnosis unlikely; a positive scan confirms amyloid pathology for eligibility for anti-Aβ therapies (lecanemab, donanemab). About 25% of cognitively unimpaired older individuals have positive scans - likely representing preclinical AD.
• Blood plasma Aβ42/Aβ40 ratio: Emerging blood-based marker with good concordance with amyloid PET, enabling scalable screening.

B. Tau Markers

• CSF total tau (t-tau): Reflects general neuronal damage and is elevated in AD, CJD, and other degenerative disorders. Non-specific for AD.
• CSF phosphorylated tau (p-tau): Multiple isoforms are used:
  • p-tau181: Most validated; reflects NFT pathology; the ratio p-tau181/Aβ42 is a robust Core 1 AD biomarker.
  • p-tau217: Highest diagnostic accuracy for AD; shows >90% concordance with amyloid PET; FDA-cleared for assessing amyloid pathology in symptomatic adults (2025).
  • p-tau231: Becomes abnormal earliest in the AD continuum (even before amyloid PET positivity in some models).
  • p-tau205: Emerging marker of established tau pathology.
• Plasma p-tau217: Now measurable on automated platforms (Roche Elecsys, 2025); the plasma p-tau217/Aβ42 ratio is the leading blood-based surrogate for AD neuropathology.
• Tau PET (flortaucipir, [18F]MK-6240): Images fibrillar tau (neurofibrillary tangles) topographically. Tau PET Braak staging correlates with cognitive decline and disease stage. Particularly attractive as a surrogate endpoint in clinical trials targeting tau aggregation - the topographic spread of tau PET signal directly mirrors Braak neurofibrillary staging at autopsy.

C. Neurodegeneration / Axonal Injury Markers

• Neurofilament light chain (NfL): Structural axonal protein released into CSF and blood following axonal damage. Elevated in virtually all neurodegenerative diseases (AD, FTD, ALS, MS, PD, atypical Parkinsonisms). Non-specific but extremely sensitive as a marker of ongoing neurodegeneration. NfL is accepted by the FDA as a reasonably likely surrogate endpoint in SOD1-ALS clinical trials - a landmark regulatory milestone for fluid biomarkers in neuropathology.
• GFAP (Glial Fibrillary Acidic Protein): Astrocytic marker. Elevated plasma GFAP is a surrogate for astrocytic activation and neuroinflammation. Associated with Aβ pathology burden in AD and with disease severity. Also elevated in gliomas, traumatic brain injury, and MS.

D. Alpha-Synuclein Markers (Lewy Body / Synucleinopathy Spectrum)

• α-Synuclein Seed Amplification Assay (SAA) - including RT-QuIC (real-time quaking-induced conversion) and PMCA (protein misfolding cyclic amplification): These assays amplify misfolded α-synuclein "seeds" from CSF to detect Lewy body pathology with high sensitivity and specificity. Originally developed for prion diseases and adapted for synucleinopathies. The FDA has issued a Letter of Support for α-synuclein SAA use in clinical trials. Used to discriminate PD/DLB (SAA-positive) from MSA and PSP (typically SAA-negative).
• Plasma α-synuclein species: Still being validated.

E. TDP-43 Markers (ALS / FTD)

• TDP-43 is the pathological protein in ~97% of ALS and ~45% of FTD (FTLD-TDP). Traditional detection required post-mortem tissue. Emerging approaches include:
  • Plasma extracellular vesicle TDP-43 (diagnostic biomarker in FTD and ALS - Nat Med 2024).
  • Cryptic exon-encoded peptides in CSF: Novel surrogate of TDP-43 nuclear dysfunction; generated only when TDP-43 loses its normal RNA-splicing function. Shown to have high diagnostic performance (2024 studies in Science Translational Medicine).
  • CSF/plasma TDP-43 assays remain investigational.

F. Prion Disease Markers (CJD)

• 14-3-3 protein (CSF): A surrogate marker of rapid neuronal destruction. Elevated in CSF in ~90% of sporadic CJD cases. Not specific (also elevated in herpes encephalitis, stroke). Rapid progression with rigidity and myoclonus + elevated 14-3-3 strongly supports CJD diagnosis.
• CSF t-tau: Extremely elevated (often >10,000 pg/mL) in CJD - much higher than in AD.
• Real-time Quaking-Induced Conversion (RT-QuIC) of CSF: Detects misfolded prion protein seeds with ~96% sensitivity and near 100% specificity. Now the gold-standard pre-mortem surrogate test for CJD.
• MRI DWI (diffusion-weighted imaging): Cortical ribboning and basal ganglia hyperintensity on DWI are highly specific imaging surrogates for CJD.
• EEG: Periodic sharp wave complexes (1 Hz triphasic waves) are a classic surrogate electrophysiological marker in sporadic CJD.

G. Synaptic Markers

• Neurogranin (CSF): Postsynaptic protein; elevated CSF neurogranin reflects synaptic degeneration specifically in AD (less elevated in other dementias). Predicts cognitive decline. Classified as a Core 2 AD biomarker in the 2024 framework (becomes abnormal after Core 1 markers).
• SNAP-25, synaptotagmin-1, synapsin: Presynaptic markers under investigation.
• CSF synaptic protein panels: A CSF-based synaptic health index was reported in Nat Med (2025) as a predictor of cognitive resilience vs. decline in AD.

H. Neuroimaging Surrogates

III. Regulatory Significance

• Amyloid PET reduction was used for accelerated FDA approval of aducanumab (2021) - a controversial decision since clinical benefit was uncertain, underscoring that a neuropathological surrogate may not always predict clinical outcomes.
• Lecanemab (2023) and donanemab (2024) received full approval based on both amyloid PET surrogate data AND clinical efficacy.
• NfL is an accepted surrogate endpoint in SOD1-ALS trials.
• α-synuclein SAA has FDA Letter of Support for synucleinopathy trials.
• Plasma p-tau217/Aβ42 received FDA clearance in 2025 for assessing amyloid pathology in symptomatic adults.

IV. Summary Table