By virtue of being less heterogeneous than clinical diagnoses and more directly affected by genetic variation, endophenotypes not only offers the advantage of providing a functional link between the variants identified and trait but also increase the statistical power of genetic studies. Our group has pioneer the employment of cerebrospinal fluid (CSF) tau, phospho-tau (ptau) and Aβ levels as quantitative trait for genetic studies to identify novel variants implicated in Alzheimer’s disease (AD). We plan to analyze a comprehensive panel of analytes (n>1300) to identify novel biomarkers and endophenotypes for AD and other complex traits. We will employ Mendelian randomization techniques to estimate their causal effect on AD, and extend our analyses to other complex traits such as Stroke, Multiple Sclerosis, bipolar disorder and others reported in the NHGRI GWAS catalog. In addition, we will evaluate predictive models than accommodate multiple analytes to increase their accuracy by representing the distinct pathways affected by AD.

In this study, we will leverage a unique resource that includes the study of more than 1300 proteins in plasma, CSF and brain tissue for a large number of very well clinically (longitudinal clinical information about disease and cognition) and genetically characterized participants (GWAS, genome-chip and whole-exome and whole-genome sequences). The goals of this study are: 1) to identify novel biomarkers for AD and other complex traits, 2) to identify independent and/or combinatorial plasma, CSF and brain analytes that predict AD risk, age at onset or rate of disease progression; 3) to use protein levels to identify novel variants, genes and pathways associated with AD; and 4) to employ genetic variants to improve biomarker prediction accuracy.

Plots of AD related protein biomarkers


  1. Deming Y, Black K, Carrell D, Cai Y, Del-Aguila JL, Fernandez MV, Budde J, Ma S, Saef B, Howells B, Bertelsen S, Huang KL, Sutphen CL, Tarawneh R, Fagan AM, Holtzman DM, MorrisJC, Goate AM, Dougherty JD, Cruchaga C.  Chitinase-3-like 1 protein (CHI3L1) locus Influences cerebrospinal fluid levels of YKL-40.  BMC Neurol 2016; 16(1):217. PMCID:  PMC5105244
  2. Deming Y, Xia J, Cai Y, Lord J, Del-Aguila JL, Fernandez MV, Carrell D, Black K, Budde J, Ma S, Saef B, Howells B, Bertelsen S, Bailey M, Ridge PG, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Holtzman D, Morris JC, Bales K, Pickering EH, Lee JM, Heitsch L, Kauwe J, Goate A, Piccio L, Cruchaga C. Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits. Sci Rep. 2016; 6: 18092. PMCID: PMC4698720
  3. Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C.  Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.  Acta Neuropathol 2016; 131(6):925-33.  PMCID: PMC4867123
  4. Deming Y, Xia J, Cai Y, Lord J, Holmans P, Bertelsen S, Holtzman D, Morris JC, Bales K, Pickering EH, Kauwe J, Goate A, Cruchaga C; Alzheimer’s Disease Neuroimaging Initiative (ADNI).  A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin. Neurobiol Aging 2016; 37:208.  PMCID:  PMC5118651
  5. Kauwe JS, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL, Staley LA, Karch CM, Harari O, Cruchaga C, Ainscough BJ, Bales K, Pickering EH, Bertelsen S; the Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Holtzman DM, Morris JC, Goate AM. Genome-Wide Association Study of CSF Levels of 59 Alzheimer’s Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation. PloS Genet 2014; 10(10):e1004758. PMCID: PMC4207667.