A cerebrospinal fluid synaptic protein biomarker ratio showed robust prediction of cognitive resilience vs progressive cognitive impairment in patients with Alzheimer's disease, explaining substantial cognitive impairment variance beyond traditional amyloid and tau markers, according to recently published research.
Researchers from Stanford University, Washington University, and other international institutions found that the cerebrospinal fluid (CSF) YWHAG:NPTX2 protein ratio explains 27% of cognitive impairment variance beyond CSF pTau181/β42, 11% beyond tau positron-emission tomography imaging, and 28% beyond other neurodegeneration markers in amyloid-positive and phosphorylated tau–positive individuals.
Using CSF proteomics on 3,397 individuals from 6 prospective Alzheimer's disease (AD) case-control cohorts (including the Alzheimer’s Disease Neuroimaging Initiative, Knight-Alzheimer’s Disease Research Center, and Stanford), investigators identified synaptic proteins as the strongest correlates of cognitive impairment, independent of amyloid-beta and tau pathology.
"Rates of cognitive decline in [AD] are extremely heterogeneous. Although biomarkers for amyloid-beta and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20% to 40% of the variance in AD-related cognitive impairment," the authors noted in Nature Medicine.
Key Findings
The CSF YWHAG:NPTX2 ratio showed predictive capacity for future disease progression. It predicted conversion from amyloid-positive, phosphorylated tau–positive cognitively normal to mild cognitive impairment, with a standard deviation increase hazard ratio (HR) of 3.0 (P = 7.0 × 10⁻⁴). It also predicted conversion from mild cognitive impairment to dementia, with a standard deviation increase HR of 2.2 (P = 8.2 × 10⁻¹⁶) over a 15-year follow-up.
These associations remained significant after adjusting for CSF pTau181/β42, CSF neurofilament light chain, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 dose, and sex.
The study also revealed that YWHAG:NPTX2 increases with normal aging and appears elevated approximately 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. The authors derived five discrete YWHAG:NPTX2 groups that strongly predict future cognitive outcomes.
Additionally, the researchers developed a plasma proteomic signature of cognitive impairment, evaluated in 13,401 samples, which partially recapitulated CSF YWHAG:NPTX2, demonstrating its robustness and potential scalability for clinical application.
Clinical Implications
"Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience vs AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement, and further implicate synapse dysfunction as a core driver of AD dementia," the researchers concluded.
The CSF YWHAG:NPTX2 ratio specifically integrates the neuronal pentraxin NPTX2, which regulates homeostatic scaling of excitatory synapses on parvalbumin interneurons to prevent neuronal network hyperactivity, and YWHAG, a 14-3-3 protein that localizes in neuron bodies and synapses.
The authors proposed that CSF YWHAG:NPTX2 is likely a measure of synapse dysfunction related to loss of NPTX2-driven homeostatic scaling and YWHAG-driven tau toxicity, pointing to synapse dysfunction as a promising therapeutic target for cognitive resilience in Alzheimer's disease.
In a clinical context, CSF YWHAG:NPTX2 demonstrated improved performance compared to established biomarkers in predicting future cognitive outcomes, potentially aiding in clinical trial target patient selection and therapeutic efficacy evaluation.
Disclosures can be found in the study.