biostudies-literatureOh HSNCATS NIH HHSEuropean Research CouncilNIA NIH HHSNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)1592-1603https://www.ebi.ac.uk/biostudies/studies/S-EPMC12092275biostudies-literatureUnknown31(5)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, growthNature medicineA cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease.PMC1209227575N92022D00003R01 AG015819U01 AG061356AG07225575N92022D0000475N92022D0000175N92022D00002UL1 TR003142R01 AG072255P30 AG066515U01 HL096917P50 AG04736675N92022D00005U24 AG021886U01 HL096902101096455P30 AG072975R01 AG044546U01 AG046152P30AG066515P30 AG066444U01 AG058922R21 AG058859R01 AG048076P30 AG010161RF1 AG074007RF1 AG058501RF1 AG053303U01 HL096814U01 HL096899U01 HL096812P01 AG026276R01 AG017917K99 AG088304P01 AG003991F32 AG079666Guldner IHLeinonen VDuggan MRLipponen AKarlsson LZhu ZFranzmeier NMormino EZetterberg HWyss-Coray TFarinas AOh HSShen YLe Guen YUrey DYTimsina JChen JHansson OEhrenberg AJWagner ADLuikku AJYang CWestern DAli MWalker KAPoston KLCruchaga CCoresh JChannappa DGottesman RFBennett DAMorshed NStevens BHiltunen MTrelle AHerukka SKRauramaa TWilson ENfalseA cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease.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, growth2025-01-01T00:00:00Z2025 May2026-06-02T17:56:29.365Z2026-04-18T03:11:55.752ZS-EPMC120922754016472410.1038/s41591-025-03565-2