Amelia Farinas
Ph.D. Student in Neurosciences, admitted Autumn 2020
All Publications
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A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease.
Nature medicine
2025
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.
View details for DOI 10.1038/s41591-025-03565-2
View details for PubMedID 40164724
View details for PubMedCentralID 8574196
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Glia detect and transiently protect against dendrite substructure disruption in C. elegans.
Nature communications
2025; 16 (1): 79
Abstract
Glia assess axon structure to modulate myelination and axon repair. Whether glia similarly detect dendrites and their substructures is not well understood. Here we show that glia monitor the integrity of dendrite substructures and transiently protect them against perturbations. We demonstrate that disruption of C. elegans sensory neuron dendrite cilia elicits acute glial responses, including increased accumulation of glia-derived extracellular matrix around cilia, changes in gene expression, and alteration of secreted protein repertoire. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, physically interact, and exhibit mutually-dependent localization to and around cilia, respectively. Glial responses to dendrite cilia disruption transiently protect against damage. Thus, our studies uncover a homeostatic, protective, dendrite-glia signaling interaction regulating dendrite substructure integrity.
View details for DOI 10.1038/s41467-024-55674-0
View details for PubMedID 39747235
View details for PubMedCentralID PMC11696001