Neurotrophic Factors: Genetic Variation and Serum Levels in Brain Aging

Summary

Principal Investigator: S Seshadri
Abstract: DESCRIPTION (provided by applicant): Alzheimer disease (AD) imposes a substantial societal burden. Clinical AD likely results through the interaction of 3 factors: reserve, AD- and vascular pathology. Brain MRI and cognitive tests can identify proxy measures of reserve and subclinical markers (heritable endophenotypes) of AD- and vascular pathology. Neurotrophic factors (NTF) promote neuronal survival and function and are possible key determinants of reserve, the capacity that allows some persons to tolerate greater brain pathology without clinical symptoms. NTF also impact AD- and ischemia-related pathological processes. Experimental and clinical data suggest that circulating NTF levels are increased by a healthy diet and exercise, and decline with age. However, no prior study has comprehensively examined the clinical and genetic correlates of NTF in a community-based sample, or the association of NTF with brain aging and clinical AD. We hypothesize that genetic variation in the NTF pathway will be related to variation in serum NTF levels, and that lower circulating NTF levels will be associated with lower reserve, more cross-sectional evidence of brain aging on MRI and cognitive testing, greater longitudinal decline in these measures, and a higher risk of clinical dementia and AD. We propose to genotype a comprehensive panel of NTF and NTF receptors and measure serum levels of three NTF: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in the large, middle-aged to elderly, community-based, Framingham Heart Study (FHS) Original, Offspring and Omni cohorts. Serum levels of IGF1 have been measured by a collaborator. DNA, brain MRI and cognitive test measures are already available. We offer the following, interlinked specific aims: Aim 1: To examine the clinical and genetic correlates of NTF in all 3 FHS cohorts. Aim 2: To relate NTF serum levels and genetic variation in NTF pathway genes to cross-sectional measures on brain MRI and cognitive tests in the FHS Offspring and Omni cohorts. Aim 3: To prospectively relate baseline serum levels and genetic variation in NTF pathway genes to longitudinal changes in MRI and cognitive tests in the FHS Offspring and Omni. Aim 4: To prospectively relate baseline serum concentrations of NTF (measured in stored sera from 1992-94) and genetic variation in NTF pathway genes to risk of incident dementia and AD over a follow-up period of up to 16 years The proposed research should help us better understand the biological link between lifestyle and clinical dementia and the role of NTF in both subclinical brain aging and in the development of AD. PUBLIC HEALTH RELEVANCE: Neurotrophic factors (NTF) are important in brain development, in memory formation, and for the survival and healthy functioning of adult and aging neurons;circulating levels increase with exercise and a frugal diet, so NTF may also be the biological link between a healthy body and mind. We propose to study variation in NTF pathway genes and serum NTF levels in a longitudinally-followed community of over 5000 middle-aged and elderly adults (the Framingham Original, Offspring and Omni cohorts), and relate these data to baseline and 5-year follow-up measures of brain MRI and cognitive performance, as well as to the risk of developing clinical dementia and Alzheimer's disease over a 16 year follow-up period. This study will improve our understanding of the role the NTF pathway plays in healthy and abnormal aging, perhaps leading to improved prevention and treatment strategies to combat cognitive aging and the development of Alzheimer's disease.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study
    Jose Rafael Romero
    From the Department of Neurology J R R, A B, C S K, P A W, S S, School of Medicine and Department of Biostatistics S R P, A B, School of Public Health at Boston University, MA Department of Neurology, University of California, Davis C D Department of Neurology, Harvard Medical School, Boston, MA A V, S M R and NHLBI s Framingham Heart Study, Framingham, MA J R R, S R P, A B, C S K, P A W, S S
    Stroke 45:1492-4. 2014
  2. pmc Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study
    Thomas M van Himbergen
    Lipid Metabolism Laboratory, Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
    Arch Neurol 69:594-600. 2012
  3. pmc The Framingham Brain Donation Program: neuropathology along the cognitive continuum
    Rhoda Au
    Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Curr Alzheimer Res 9:673-86. 2012
  4. pmc Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology
    Patricia F Kao
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
    J Neuropathol Exp Neurol 71:654-64. 2012
  5. pmc Risk estimations, risk factors, and genetic variants associated with Alzheimer's disease in selected publications from the Framingham Heart Study
    Galit Weinstein
    Department of Neurology, Boston University School of Medicine, Boston, MA 20008, USA
    J Alzheimers Dis 33:S439-45. 2013
  6. pmc Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study
    Jose Rafael Romero
    Department of Neurology, School of Medicine, Boston University, 715 Albany Street, B 608, Boston, MA 02118 2526, USA
    Stroke 43:3091-4. 2012
  7. pmc Association of parental stroke with brain injury and cognitive measures in offspring: the Framingham Heart Study
    Galit Weinstein
    Boston University School of Medicine, Boston, MA 02118, USA
    Stroke 44:812-5. 2013
  8. pmc Ischemic stroke is associated with the ABO locus: the EuroCLOT study
    Frances M K Williams
    Department of Twin Research and Genetic Epidemiology, King s College London, United Kingdom
    Ann Neurol 73:16-31. 2013
  9. pmc APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline
    Katherine J Bangen
    Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, California Electronic address
    J Stroke Cerebrovasc Dis 22:1361-9. 2013
  10. pmc APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis
    Sabrina Schilling
    Department of Epidemiology, Raymond Poincare Hospital, University of Versailles St Quentin en Yvelines, Versailles, France
    Neurology 81:292-300. 2013

Scientific Experts

  • Angela L Jefferson
  • S Seshadri
  • Renate B Schnabel
  • Helena Schmidt
  • M Arfan Ikram
  • Stephanie Debette
  • Jane S Saczynski
  • Myriam Fornage
  • Anita L Destefano
  • Philip A Wolf
  • Rhoda Au
  • Charles DeCarli
  • Alexa S Beiser
  • Aleksandra Pikula
  • Galit Weinstein
  • Ramachandran S Vasan
  • Jose Rafael Romero
  • Alexa Beiser
  • Carlos S Kase
  • Sarah R Preis
  • Joshua C Bis
  • Tai C Chen
  • Seung Hoan Choi
  • Albert Hofman
  • Tamara B Harris
  • Margaret Kelly-Hayes
  • Ann C McKee
  • Jayandra J Himali
  • Renke Maas
  • Andrew J Westwood
  • Katherine J Bangen
  • Frances M K Williams
  • Sabrina Schilling
  • Anand Viswanathan
  • Philippe Amouyel
  • Bernard Mazoyer
  • Carole Dufouil
  • Christophe Tzourio
  • Thomas M van Himbergen
  • Patricia F Kao
  • Z S Tan
  • Monique M B Breteler
  • Ronenn Roubenoff
  • Ben A Oostra
  • Kathryn L Lunetta
  • Cornelia M van Duijn
  • Andre G Uitterlinden
  • Maaike Schuur
  • Emelia J Benjamin
  • Oscar L Lopez
  • Linda Broer
  • David A Bennett
  • Gary K Chen
  • Robert C Green
  • Sanford Auerbach
  • Gyungah Jun
  • Wolfgang Lieb
  • Friedrich Schulze
  • Edzard Schwedhelm
  • Rainer H Boger
  • Lewis E Braverman
  • Xue Mei He
  • Sergi Martínez-Ramírez
  • Demetrios Vorgas
  • Jonathan Rosand
  • Mark W Bondi
  • Mari Kaunisto
  • Rodney J Scott
  • Melissa Lamar
  • Veikko Salomaa
  • Lewis H Kuller
  • Unnur Thorsteinsdottir
  • Wei Wen
  • Demetrios Vorgias
  • Eugenio A Parati
  • David J Libon
  • Yi cheng Zhu
  • Thomas H Mosely
  • Anna Helgadottir
  • Karen L Furie
  • JAMES MESCHIA
  • Elizabeth G Holliday
  • Pankaj Sharma
  • Pirro G Hysi
  • Yu Ching Cheng
  • Daniel A Nation
  • Will Longstreth
  • Dylan Hodgkiss
  • Bruce Psaty
  • Braxton D Mitchell

Detail Information

Publications42

  1. pmc Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study
    Jose Rafael Romero
    From the Department of Neurology J R R, A B, C S K, P A W, S S, School of Medicine and Department of Biostatistics S R P, A B, School of Public Health at Boston University, MA Department of Neurology, University of California, Davis C D Department of Neurology, Harvard Medical School, Boston, MA A V, S M R and NHLBI s Framingham Heart Study, Framingham, MA J R R, S R P, A B, C S K, P A W, S S
    Stroke 45:1492-4. 2014
    ....
  2. pmc Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study
    Thomas M van Himbergen
    Lipid Metabolism Laboratory, Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
    Arch Neurol 69:594-600. 2012
    ....
  3. pmc The Framingham Brain Donation Program: neuropathology along the cognitive continuum
    Rhoda Au
    Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Curr Alzheimer Res 9:673-86. 2012
    ..We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score of 0.5 than in normal controls...
  4. pmc Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology
    Patricia F Kao
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
    J Neuropathol Exp Neurol 71:654-64. 2012
    ..In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline...
  5. pmc Risk estimations, risk factors, and genetic variants associated with Alzheimer's disease in selected publications from the Framingham Heart Study
    Galit Weinstein
    Department of Neurology, Boston University School of Medicine, Boston, MA 20008, USA
    J Alzheimers Dis 33:S439-45. 2013
    ..The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD...
  6. pmc Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study
    Jose Rafael Romero
    Department of Neurology, School of Medicine, Boston University, 715 Albany Street, B 608, Boston, MA 02118 2526, USA
    Stroke 43:3091-4. 2012
    ..We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMB, with possible regional specificity...
  7. pmc Association of parental stroke with brain injury and cognitive measures in offspring: the Framingham Heart Study
    Galit Weinstein
    Boston University School of Medicine, Boston, MA 02118, USA
    Stroke 44:812-5. 2013
    ..This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke...
  8. pmc Ischemic stroke is associated with the ABO locus: the EuroCLOT study
    Frances M K Williams
    Department of Twin Research and Genetic Epidemiology, King s College London, United Kingdom
    Ann Neurol 73:16-31. 2013
    ..We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype...
  9. pmc APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline
    Katherine J Bangen
    Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, California Electronic address
    J Stroke Cerebrovasc Dis 22:1361-9. 2013
    ..We aimed to further elucidate these relationships and extend previous findings by examining data from a more comprehensive cognitive assessment than used in prior studies...
  10. pmc APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis
    Sabrina Schilling
    Department of Epidemiology, Raymond Poincare Hospital, University of Versailles St Quentin en Yvelines, Versailles, France
    Neurology 81:292-300. 2013
    ..We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds...
  11. pmc Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy
    Andrew J Westwood
    From the Department of Neurology A J W, A B, A P, R A, P A W, S S and Sections of Preventative Medicine and Cardiology, Department of Medicine R S V, Boston University School of Medicine Department of Biostatistics A B, Boston University School of Public Health, Boston Framingham Heart Study A B, A P, R A, P A W, R S V, S S, Framingham, MA University of California at Davis C D, Sacramento, CA National Institute on Aging T B H, Bethesda, MD Boston University Medical Center T C C, X m H, L E B, Section of Endocrinology, Diabetes, and Nutrition, Boston Novartis Institutes for Biomedical Research R R, Cambridge, MA
    Neurology 82:1613-9. 2014
    ..To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages...
  12. pmc Brain imaging and cognitive predictors of stroke and Alzheimer disease in the Framingham Heart Study
    Galit Weinstein
    From the Department of Neurology, Boston University School of Medicine, Boston, MA G W, A S B, R A, P A W, S S The Framingham Heart Study, Boston, MA G W, A S B, R A, P A W, S S Department of Biostatistics, Boston University School of Public Health, Boston, MA A S B and the Department of Neurology, University of California at Davis, Sacramento, CA C D
    Stroke 44:2787-94. 2013
    ..Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer disease (AD) risk...
  13. pmc Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study
    Aleksandra Pikula
    From the Boston University Schools of Medicine and Public Health, Boston, MA A P, A S B, T C C, S R P, D V, R A, M K H, C S K, P A W, R S V, S S Framingham Heart Study, Framingham, MA A P, A S B, S R P, C D, R A, M K H, C S K, P A W, R S V, S S and University of California at Davis, Sacramento C D
    Stroke 44:2768-75. 2013
    ..We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample...
  14. pmc Serum brain-derived neurotrophic factor and the risk for dementia: the Framingham Heart Study
    Galit Weinstein
    Department of Neurology, Boston University School of Medicine, Boston, Massachusetts2The Framingham Heart Study, Boston, Massachusetts
    JAMA Neurol 71:55-61. 2014
    ..Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset...
  15. pmc Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging
    Z S Tan
    Department of Medicine, Division of Geriatric Medicine, Easton Center for Alzheimer s Disease Research, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, USA
    Neurology 78:658-64. 2012
    ..We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort...
  16. pmc Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study
    Aleksandra Pikula
    Boston University Schools of Medicine and Public Health, MA, USA
    Circulation 125:2100-7. 2012
    ....
  17. pmc Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium
    Myriam Fornage
    Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
    Ann Neurol 69:928-39. 2011
    ..WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified...
  18. pmc Common variants at 6q22 and 17q21 are associated with intracranial volume
    M Arfan Ikram
    Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands
    Nat Genet 44:539-44. 2012
    ..5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size...
  19. pmc Common variants at 12q14 and 12q24 are associated with hippocampal volume
    Joshua C Bis
    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
    Nat Genet 44:545-51. 2012
    ....
  20. pmc Association of parental dementia with cognitive and brain MRI measures in middle-aged adults
    S Debette
    Department of Neurology, Boston University School of Medicine, B602, 72 East Concord Street, Boston, MA 02118, USA
    Neurology 73:2071-8. 2009
    ..We related prospectively verified parental dementia to brain MRI and cognitive testing in the offspring, within a 2-generational community-based cohort...
  21. pmc Incorporating biological information into association studies of sequencing data
    Gary K Chen
    Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
    Genet Epidemiol 35:S29-34. 2011
    ....
  22. pmc Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease
    Helena Schmidt
    Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria
    Brain 134:3384-97. 2011
    ..Additional investigations are required to explore the biological mechanisms underlying the observed association...
  23. pmc Genome-wide analysis of genetic loci associated with Alzheimer disease
    Sudha Seshadri
    Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
    JAMA 303:1832-40. 2010
    ..Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD)...
  24. pmc Parental occurrence of stroke and risk of stroke in their children: the Framingham study
    Sudha Seshadri
    Department of Neurology, Boston University School of Medicine, 72 E Concord St, B602, Boston, MA 02118, USA
    Circulation 121:1304-12. 2010
    ..Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status...
  25. pmc Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study
    Stephanie Debette
    Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
    Stroke 41:600-6. 2010
    ..We simultaneously assessed the relation of white matter hyperintensities and BI with incident stroke, mild cognitive impairment, dementia, and mortality in a middle-aged community-based cohort...
  26. pmc Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    JAMA 302:2565-72. 2009
    ..The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD)...
  27. pmc Bivariate heritability of total and regional brain volumes: the Framingham Study
    Anita L Destefano
    Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, USA
    Alzheimer Dis Assoc Disord 23:218-23. 2009
    ..These data extend current knowledge by showing that these 2 different types of magnetic resonance imaging measures do not share underlying genetic or environmental influences...
  28. pmc Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study
    Aleksandra Pikula
    Boston University School of Medicine, Boston, MA, USA
    Stroke 40:2959-64. 2009
    ..The relation of plasma ADMA to subclinical vascular brain injury has not been previously studied in a middle-aged, community-based sample...
  29. pmc Association of the endogenous nitric oxide synthase inhibitor ADMA with carotid artery intimal media thickness in the Framingham Heart Study offspring cohort
    Renke Maas
    Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
    Stroke 40:2715-9. 2009
    ..We hypothesized that plasma ADMA concentrations are positively related to common carotid artery intimal-media thickness (CCA-IMT) and to internal carotid (ICA)/bulb IMT...
  30. pmc Depressive symptoms and risk of dementia: the Framingham Heart Study
    J S Saczynski
    Department of Medicine and Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA, USA
    Neurology 75:35-41. 2010
    ..We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period...
  31. pmc Cardiac index is associated with brain aging: the Framingham Heart Study
    Angela L Jefferson
    Department of Neurology, Alzheimer s Disease Center, Boston University School of Medicine, 72 E Concord St, B 7800, Boston, MA 02118, USA
    Circulation 122:690-7. 2010
    ..We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community...
  32. pmc Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study)
    Angela L Jefferson
    Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
    Am J Cardiol 108:1346-51. 2011
    ..In conclusion, although these observational cross-sectional data cannot establish causality, they suggest a nonlinear association between LVEF and measures of accelerated cognitive aging...
  33. pmc Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project
    Renate B Schnabel
    National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, MA, USA
    Circ Cardiovasc Genet 4:557-64. 2011
    ..The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated...
  34. pmc Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline
    S Debette
    Department of Neurology, Boston University School of Medicine, Boston, MA, USA
    Neurology 77:461-8. 2011
    ..Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline...
  35. pmc Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels
    Stephanie Debette
    Department of Neurology, Boston University School of Medicine, B602, 72 East Concord St, Boston, MA 02118, USA
    Circ Res 109:554-63. 2011
    ..Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings...
  36. pmc Association of HSP70 and its co-chaperones with Alzheimer's disease
    Linda Broer
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
    J Alzheimers Dis 25:93-102. 2011
    ..However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD...
  37. pmc Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment-Part 2
    Sudha Seshadri
    Department of Neurology, Boston University School of Medicine, MA, USA
    Alzheimers Dement 7:35-52. 2011
    ..Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiological studies...
  38. pmc Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes
    Gyungah Jun
    Department of Medicine, Boston University, USA
    Arch Neurol 67:1473-84. 2010
    ..To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes...
  39. pmc Visceral fat is associated with lower brain volume in healthy middle-aged adults
    Stephanie Debette
    Department of Neurology, Boston University School of Medicine, MA, USA
    Ann Neurol 68:136-44. 2010
    ....
  40. pmc Association of matrix metalloproteinases with MRI indices of brain ischemia and aging
    Jose Rafael Romero
    Department of Neurology, School of Medicine at Boston University, Boston, MA 02118 2526, United States
    Neurobiol Aging 31:2128-35. 2010
    ..04). Neither biomarker was associated with SCI. Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging...