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"... To identify proteins that are strongly associated with Alzheimer’s diseases and cognitive decline, ... [researchers] performed a large-scale proteomic analysis (measuring more than 7,000 proteins per sample) on the cerebrospinal fluid of more than 3,000 people with Alzheimer’s disease across Sweden, Finland, and the US.
The team also had access to detailed information on the cognitive status of the individuals over multiple years, their age, sex, Aβ and tau biomarkers, and Alzheimer’s disease risk genes. They observed changes in the expression of hundreds of proteins with respect to cognitive impairment, the most significant of which were proteins present at neuronal connections, or synapses. Using machine learning, the researchers arrived at a new signature of cognitive impairment—a ratio of two synaptic proteins, YWHAG:NPTX2. ...
team observed that an increase in YWHAG:NPTX2 was a robust predictor of cognitive decline across all cohorts, suggesting its potential use in clinical settings. Individuals with high YWHAG:NPTX2 had a 15-times higher risk of suffering cognitive decline than those with a low ratio. ... Moreover, individuals with high levels of tau tangles had high YWHAG:NPTX2, but the reverse was not true, indicating the ratio of these proteins changes before tau tangles appear in Alzheimer’s disease.
The team wanted to know if the ratio between YWHAG and NPTX2 could predict the progression of Alzheimer’s disease in people with a diagnosis or those with a genetic risk of the disease. They determined that YWHAG:NPTX2 starts increasing 30 years before plaques and tangles form. While everyone showed an age related increase in YWHAG:NPTX2, individuals with Alzheimer’s disease-associated genes had a steeper rise in the ratio. Symptoms in these people generally manifested 20 years after YWHAG:NPTX2 increased. ..."
From the abstract:
"Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20–40% of the variance in AD-related cognitive impairment (CI).
To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case–control cohorts.
Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals.
CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and
A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10–16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex.
We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2.
Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus 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."
A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease (open access)
Fig. 1: The CSF YWHAG:NPTX2 ratio explains a substantial proportion of variance in CI beyond amyloid and tau in AD.
Fig. 4: CSF YWHAG:NPTX2 ratio predicts future tau accumulation and cognitive decline beyond Aβ, tau, NfL, GAP-43 and Ng.
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