Cerebrospinal fluid (CSF) biomarkers for amyloid-beta (Aβ) and tau have improved Alzheimer’s disease (AD) diagnosis; however, these biomarkers only explain 20–40% of the variance in cognitive impairment in AD. FunGen-AD investigator Carlos Cruchaga at the Washington University School of Medicine and a group of international researchers analyzed CSF proteins to identify novel biomarkers of cognitive impairment in AD. This proteomic analysis was conducted on 3,397 individuals from six prospective AD case-control cohorts.
The analysis identified synapse proteins as the strongest correlates of cognitive impairment independent of Aβ and tau. Researchers then trained a machine learning model to predict cognitive impairment severity based on the synapse proteins that changed significantly with cognitive impairment. The model identified a 1:1 difference between the synapse proteins YWHAG (upregulated in the proteomics analysis) and NPTX2 (downregulated). Further analysis showed that this YWHAG:NPTX2 synapse protein ratio explained 27% of cognitive impairment variance beyond CSF biomarker pTau181:Aβ42, 11% beyond positron emission tomography, and 28% beyond neurodegeneration markers in amyloid-positive and phosphorylated tau-positive individuals. The YWHAG:NPTX2 synapse protein ratio increases with normal aging 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations.
Researchers also developed a plasma proteomic signature of cognitive impairment. An evaluation of over 13,000 CSF samples partially recapitulated the YWHAG:NPTX2 ratio, indicating that this ratio is a robust prognostic biomarker for cognitive impairment in AD. Overall, the study highlights the YWHAG:NPTX2 synapse protein ratio as a biomarker of cognitive impairment in AD and indicates that synapse dysfunction is a core driver of AD, making it a promising therapeutic target.
This research, partially supported by FunGen-AD grant RF1AG058501, is published in Nature Medicine here. You can read more about these research findings at the following links:
- New Biomarker May Predict Alzheimer’s Cognitive Decline (Conexiant)
- Protein ratio in cerebrospinal fluid outperforms traditional biomarkers in predicting Alzheimer’s cognitive decline (Medical Xpress)