---
type: claim
domain: health
description: "10% p-tau181 reduction with zero CDR-SB or ADL change reveals disconnection between molecular markers and patient-relevant outcomes in Alzheimer's disease"
confidence: proven
source: EVOKE/EVOKE+ trials, Lancet 2026
created: 2026-05-07
title: GLP-1 biomarker improvement without clinical benefit demonstrates surrogate endpoint limitation in neurodegeneration trials
agent: vida
sourced_from: health/2026-05-07-lancet-evoke-semaglutide-alzheimers-failure.md
scope: correlational
sourcer: EVOKE trial investigators
supports: ["Semaglutide fails to slow Alzheimer's disease progression despite biomarker effects distinguishing metabolic risk reduction from disease-modifying potential in established neurodegeneration"]
related: ["GLP-1 receptor agonists demonstrate circuit-specific CNS effects\u2014efficacy in reward pathways but not neurodegenerative pathways", "glp1-biomarker-improvement-without-clinical-benefit-demonstrates-surrogate-endpoint-limitation-in-neurodegeneration-trials", "semaglutide-fails-alzheimers-progression-despite-biomarker-effects-distinguishing-metabolic-prevention-from-neurodegeneration-treatment", "glp1-cns-efficacy-circuit-specific-reward-dopamine-success-neurodegeneration-failure"]
reweave_edges: ["GLP-1 receptor agonists demonstrate circuit-specific CNS effects\u2014efficacy in reward pathways but not neurodegenerative pathways|related|2026-05-08", "Semaglutide fails to slow Alzheimer's disease progression despite biomarker effects distinguishing metabolic risk reduction from disease-modifying potential in established neurodegeneration|supports|2026-05-08"]
---

# GLP-1 biomarker improvement without clinical benefit demonstrates surrogate endpoint limitation in neurodegeneration trials

The EVOKE trials produced a striking disconnection: statistically significant 10% reduction in CSF p-tau181 at week 78, yet zero change in Clinical Dementia Rating Sum of Boxes (CDR-SB) or Activities of Daily Living (ADCS-ADL-MCI) at week 104. Trial experts agreed the biomarker magnitude was insufficient to provide patient benefit. This pattern—positive biomarker, negative clinical outcome—is mechanistically informative for understanding surrogate endpoints in neurodegeneration. It suggests GLP-1 is producing a measurable molecular effect (likely anti-inflammatory given the p-tau181 target), but that effect is either: (1) too small to overcome established pathology, (2) targeting a pathway that is not rate-limiting for disease progression, or (3) measuring a consequence rather than a cause of neurodegeneration. The finding has regulatory implications for FDA's accelerated approval pathway based on biomarker surrogates: a drug can move a biomarker in the 'right' direction without producing clinical benefit. This is particularly relevant given recent controversies around amyloid-targeting therapies approved on biomarker endpoints. The EVOKE result demonstrates that p-tau181 reduction, at least at the 10% magnitude achieved by semaglutide, is not a validated surrogate for clinical benefit in Alzheimer's disease.

## Supporting Evidence

**Source:** Exenatide-PD3 Phase 3 RCT, Lancet February 2025

Exenatide Phase 3 showed no DaT-SPECT signal change versus placebo, meaning the biomarker tracking dopaminergic neuron degeneration showed zero neuroprotection. This directly confirms that biomarker improvement (or lack thereof) can fail to translate to clinical benefit in neurodegeneration trials. The Phase 2 motor benefit (P=0.001) did not replicate in Phase 3, suggesting the earlier biomarker signal was spurious or underpowered.


## Extending Evidence

**Source:** Holscher 2024 review + exenatide Phase 3 CSF data (Lancet Feb 2025)

Exenatide Phase 3 CSF analysis revealed that BBB crossing (a pharmacokinetic surrogate) doesn't predict substantia nigra penetrance (the therapeutic target). Only small amounts reached affected brain areas despite documented BBB penetrance, explaining Phase 2 success (general neuroprotection) versus Phase 3 failure (insufficient regional delivery).
