This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Potential Conflicts of Interest S.E.S. has a family member with stock in Eli Lilly, which is developing drugs for Alzheimer disease. D.L.G. is a full time employee at Biogen, which funded this study and is developing drugs for Alzheimer disease. L.M.S. receives research support from Eli Lilly, Hoffman LaRoche, MJFox Foundation for Parkinson's Research for Biofind study and has served as consultant and/or advisory boards for Roche Diagnostics and Eli Lilly. He provides quality control oversight for Roche Elecsys immunoassays in the ADNI study. J.J.H. is on the advisory board and consults for both Biogen and Lundbeck A/S. T.L.S.B. consults for Eli Lilly and receives research funding from Avid Radiopharmaceuticals. J.L. reports personal fees from Aesku, Bayer Vital, the Willi Gross Foundation, Axon Neuroscience, and Ionis Pharmaceuticals. He has received non-financial support from AbbVie that is outside the submitted work. D.M.H. co-founded and is on the scientific advisory board of C 2 N Diagnostics. D.M.H. consults for Genentech, AbbVie, Eli Lilly, Proclara, and Denali. Washington University receives research grants to the lab of D.M.H. from C2N Diagnostics, Eli Lilly, AbbVie, and Denali. J.H.L. reports being named on patents related to the use of VILIP-1. These are being managed by Washington University in accordance with University policy. J.H.L. is a co-inventor on patent 11/630582 (2005) (Markers for brain damage) and patent 60957132 (2008) (Alzheimer's diagnosis). J.C.M. has or is currently participating in clinical trials of anti-dementia drugs sponsored by Janssen Immunotherapy, Eli Lilly and Company, and Pfizer. He has served as a consultant for or has received speaking honoraria from Eisai, Esteve, Janssen Alzheimer Immunotherapy Program/Elan, GlaxoSmithKline, Novartis, and Pfizer. He receives research support from Eli Lilly/Avid Radiopharmaceuticals. R.J.B. co-founded and is on the scientific advisory board of C 2 N Diagnostics. He consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. A.M.F. has received research funding from Biogen, Fujirebio and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech and AbbVie and also consults for Araclon/Griffols and DiamiR.

Objective:To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231) and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.Methods:Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status and cognitive status. Each participant underwent blood and cerebrospinal fluid (CSF) collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.Results:There were 76 matched pairs of AA and NHW participants (n=152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers and 91% were cognitively normal. AA were less likely than NHW to have brain amyloidosis by CSF Aβ42/Aβ40 (22% versus 43% positive, p = 0.003). The Receiver Operating Characteristic Area Under the Curve (ROC AUC) of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% confidence intervals [CI] 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231 or Nfl, AA had a lower probability of CSF Aβ42/Aβ40 positivity (Odds Ratio [OR] 0.31 [95% CI 0.13-0.73], OR 0.30 [0.13-0.71]) and OR 0.27 [0.12-0.64], respectively. Models of amyloid PET status yielded similar findings.Conclusions:Models predicting brain amyloidosis using a high performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA.

Objectives:To determine whether neuronal and neuroaxonal injury, neuroinflammation and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.Methods:Biomarkers of neuronal (total-tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40) and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n=34) or LGI1/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scores were evaluated in a subset (n=20) of longitudinally followed patients.Results:Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, while markers of neuronal injury and synaptic function were stable (total-tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated cases from cognitively normal individuals (AUC=0.99; 95%CI: 0.97, >0.99). Younger age (ρ=-0.56; p=0.01), lower VILIP-1 (ρ=-0.60; p<0.01) and SNAP-25 (ρ=-0.54; p=0.01), and higher log10(YKL-40/SNAP-25) [(ρ=0.48; p=0.04] associated with greater disease severity (higher modified Rankin Score) in prospectively followed patients. Higher YKL-40 (ρ=0.60; p=0.02) and neurogranin (ρ=0.55; p=0.03) at presentation were associated with higher modified Rankin Scores 12-months following hospital discharge.Conclusions:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, despite neuroaxonal compromise. Low-levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.

ObjectiveTo evaluate for racial differences in triggering receptor expressed on myeloid cells 2 (TREM2), a key immune mediator in Alzheimer disease, the levels of CSF soluble TREM2 (sTREM2), and the frequency of associated genetic variants were compared in groups of individuals who self-reported their race as African American (AA) or non-Hispanic White (NHW).MethodsCommunity-dwelling older research participants underwent measurement of CSF sTREM2 concentrations and genetic analyses.ResultsThe primary cohort included 91 AAs and 868 NHWs. CSF sTREM2 levels were lower in the AA compared with the NHW group (1,336 ± 470 vs 1,856 ± 624 pg/mL, p < 0.0001). AAs were more likely to carry TREM2 coding variants (15% vs 3%, p < 0.0001), which were associated with lower CSF sTREM2. AAs were less likely to carry the rs1582763 minor allele (8% vs 37%, p < 0.0001), located near MS4A4A, which was associated with higher CSF sTREM2. These findings were replicated in an independent cohort of 23 AAs and 917 NHWs: CSF sTREM2 levels were lower in the AA group (p = 0.03), AAs were more likely to carry coding TREM2 variants (22% vs 4%, p = 0.002), and AAs were less likely to carry the rs1582763 minor allele (16% vs 37%, p = 0.003).ConclusionsOn average, AAs had lower CSF sTREM2 levels compared with NHWs, potentially because AAs are more likely to carry genetic variants associated with lower CSF sTREM2 levels. Importantly, CSF sTREM2 reflects TREM2-mediated microglial activity, a critical step in the immune response to amyloid plaques. These findings suggest that race may be associated with risk for genetic variants that influence Alzheimer disease–related inflammation.

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Introduction Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late‐onset AD (LOAD) and autosomal‐dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Methods CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho‐tau181 (p‐tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase‐3‐like protein 1 (YKL‐40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal‐associated protein 25 (SNAP‐25), and visinin‐like protein 1 (VILIP‐1) were assessed in CSF from 44 adults with DS from the Alzheimer's Biomarker Consortium–Down Syndrome study. Biomarker levels were evaluated by cognitive status, age, and apolipoprotein E gene ( APOE ) ε4 carrier status. Results Biomarker abnormalities indicative of amyloid deposition, tauopathy, neurodegeneration, synaptic dysfunction, and neuroinflammation were associated with increased cognitive impairment. Age and APOE ε4 status influenced some biomarkers. Discussion The profile of many established and emerging CSF biomarkers of AD in a cohort of adults with DS was similar to that reported in LOAD and ADAD, while some differences were observed.

Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31–513). Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aβ 40 at presentation (rho = –0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66). Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.