Dr. Anne Fagan, PhD, the Fluid Biomarker Core Leader of the Knight Alzheimer Disease Research Center (ADRC), is a Professor of Neurology at Washington University School of Medicine in St. Louis. She has been involved in fluid biomarker research since 1997 at which time she and her colleagues Drs. David Holtzman and John Morris initiated visionary, longitudinal studies investigating the potential of a variety of fluid measures as biomarkers of preclinical (prior to dementia symptoms) AD pathology in elderly and at-risk middle-aged individuals. Evaluation of fluid biomarkers in individuals with autosomal dominant AD (ADAD) gene mutations (Dominantly Inherited Alzheimer Network, DIAN) and its associated DIAN Trials Unit (DIAN TU) soon followed, as well as expansion evaluating fluid biomarkers in AD due to Down syndrome (Alzheimer Biomarker Consortium – Down Syndrome [ABC-DS]) and early-onset AD (Longitudinal Early-Onset Alzheimer’s Disease Study, [LEADS]).

Dr. Fagan’s primary research interests/findings include:

1. Biomarkers in CSF (and more recently, plasma) are useful for identifying underlying AD pathology defined by amyloid and tau positron emission tomography (PET) and brain volumetric measures defined by magnetic resonance imaging (MRI). These data validate the use of CSF (and potentially plasma) markers for disease diagnosis, staging, prognosis and eventual therapeutic efficacy.
   • Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006, 59:512-9.
   • Gordon BA, Friedrichsen K, Brier M, Blazey T, Su Y, et al. The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain. 2016 Aug;139(Pt 8):2249-60. PMCID:PMC4958902
   • Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, et al., Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017,13:841-849. PMCID:PMC5567785
   • Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R et al, Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 2018 Mar 2. pii:S1552-5260(18)30039-6. PMCID:PMC6119652
2. CSF biomarkers are useful for staging individuals during the preclinical/asymptomatic period. The concept of AD as a long, progressive disease that begins several decades prior to clinical symptoms was facilitated by the development of fluid and imaging biomarkers, prompting the proposal of defined diagnostic criteria to include biomarker results. Biomarker profiles observed in LOAD, ADAD and AD due to Down syndrome were instrumental in the crafting/validation of these proposed stages. Such findings are now informing the design and evaluation of prevention trials in AD.
   • Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013, 12:957-65. PMCID: PMC3904678.
   • Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med. 2014, 6:226ra30. PMCID: PMC4038930.
   • Sutphen CL, Jasielec MS, Shah AR, Macy EM, Xiong C, et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol. 2015, 72:1029-42. PMCID:PMC4570860.
   • Fagan AM, Henson RL, Li Y, Boerwinkle AH, Xiong C, et al. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study. Lancet Neurol. 2021 Aug;20(8):615-626. NIHMS1730890.
3. CSF biomarkers are useful for predicting future cognitive decline in early and pre-symptomatic stages. The critical element required for establishing biomarker validity and utility in early disease stages is its ability to predict future dementia. CSF biomarkers have been shown to predict which cognitively normal individuals will develop cognitive abnormalities within a few years. This information is important clinical trial design for shortening trial duration and reducing cost.
   • Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, et al. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007, 64:343-9.
   • Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, et al. Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol. 2009, 66:638-45. PMCID: PMC2759394
   • Roe CM, Fagan AM, Grant EA, Marcus DS, Benzinger TL, et al. Cerebrospinal fluid biomarkers, education, brain volume, and future cognition. Arch Neurol. 2011, 68:1145-51. PMCID: PMC3203689.
   • Schindler SE, Jasielec MS, Weng H, Hassenstab JJ, Grober E, et al., Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease. Neurobiol Aging. 2017, 56:25-32. PMCID:PMC5505233
4. Despite the utility of established CSF analytes for identifying core AD pathologies and predicting cognitive decline, there still remains a need for markers of additional pathogenic processes (e.g., neuroinflammation and synaptic/neuronal stress and dysfunction). We have reported on several novel markers of neuronal injury and neuroinflammation (e.g., VILIP-1, Ng, YKL-40, SNAP-25) whose levels differ among clinical groups and, when combined with markers of amyloid, predict future cognitive decline.
   • Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biol Psychiatry. 2010, 68:903-12. PMCID: PMC3011944.
   • Kester MI, Teunissen CE, Crimmins DL, Herries EM, Ladenson JH, et al. Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol. 2015 Sep 14:1-7. PMCID: PMC4694558
   • Sutphen CL, McCue L, Herries EM, Xiong C, Ladenson JH, Holtzman DM, et al. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease. Alzheimers Dement. 2018, 14(7):869-879. PMCID: PMC6110083
   • Schindler SE, Li Y, Todd KW, Herries EM, Henson RL, et al. Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease. Alzheimers Dement. 2019 15:655-665. PMCID: PMC6511459.
5. Bringing validated biomarkers to clinical practice requires global biomarker standardization efforts. Although CSF biomarkers exhibit excellent diagnostic and prognostic utility when used in research settings, their potential use for individual patient care is limited by inconsistent protocols for sample collection and processing and unacceptable variability in current assay performance. To address these inadequacies, my laboratory has collaborated with domestic and international high-level AD research and clinical labs to formally investigate the within- and between-lab sources of assay variability.
   • Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011, 7:386-395.e6. PMCID: PMC3710290
   • Fagan AM, Shaw LM, Xiong C, Vanderstichele H, Mintun MA, et al. Comparison of analytical platforms for cerebrospinal fluid measures of β-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. Arch Neurol. 2011, 68:1137-44. PMCID: PMC3154969.
   • Mattsson N, Andreasson U, Persson S, Carrillo MC, Collins S, et al. CSF biomarker variability in the Alzheimer's Association quality control program. Alzheimers Dement. 2013, 9:251-61. PMCID: PMC3707386
   • Schindler SE, Sutphen CL, Teunissen C, McCue LM, Morris JC, et al., Upward drift in cerebrospinal fluid amyloid β 42 assay values for more than 10 years. Alzheimers Dement. 2018, 14:62-70. PMCID:PMC5750131

Dr. Fagan is the 2019 recipient of the Fellows Award from the Academy of Science – St. Louis in recognition of her “outstanding achievement in science.” A complete list of Dr. Fagan’s published work can be found in her National Library of Medicine My Bibliography page. 

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