Download PDF
Semin Neurol 2011; 31(5): 449-460
DOI: 10.1055/s-0031-1299784
© Thieme Medical Publishers

Genetics of Dementia

Henry L. Paulson1 , 2 , Indu Igo1
  • 1Department of Neurology, University of Michigan, Ann Arbor, Michigan
  • 2University of Michigan, Alzheimers Disease Center, Ann Arbor, Michigan
Further Information

Publication History

Publication Date:
21 January 2012 (online)

    Permissions and Reprints

ABSTRACT

Genetic factors are now recognized to play an important role in most age-related dementias. Although other factors, including aging itself, contribute to dementia, in this review the authors focus on the role of specific disease-causing genes and genetic factors in the most common age-related dementias. They review each dementia within the context of a genes/environment continuum, with varying levels of genetic versus environmental influence. All major classes of dementia will be discussed but greatest attention will be given to the most common dementia, Alzheimer's disease, for which several new genetic factors were recently identified.

KEYWORDS

Amyloid - frontotemporal dementia - dementia with Lewy bodies - neurodegeneration - genetic risk factors

REFERENCES

  • 1 Bertram L, Lill C M, Tanzi R E. The genetics of Alzheimer disease: back to the future.  Neuron. 2010;  68 (2) 270-281
    Google Scholar
  • 2 Van Broeckhoven C. The future of genetic research on neurodegeneration.  Nat Med. 2010;  16 (11) 1215-1217
    Google Scholar
  • 3 Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer's disease.  Hum Mol Genet. 2010;  19 (R1) R12-R20
    Google Scholar
  • 4 Kim J, Basak J M, Holtzman D M. The role of apolipoprotein E in Alzheimer's disease.  Neuron. 2009;  63 (3) 287-303
    Google Scholar
  • 5 Green R C, Roberts J S, Cupples L A REVEAL Study Group et al. Disclosure of APOE genotype for risk of Alzheimer's disease.  N Engl J Med. 2009;  361 (3) 245-254
    Google Scholar
  • 6 Ashe K H, Zahs K R. Probing the biology of Alzheimer's disease in mice.  Neuron. 2010;  66 (5) 631-645
    Google Scholar
  • 7 Kim D, Tsai L H. Bridging physiology and pathology in AD.  Cell. 2009;  137 (6) 997-1000
    Google Scholar
  • 8 Thinakaran G, Koo E H. Amyloid precursor protein trafficking, processing, and function.  J Biol Chem. 2008;  283 (44) 29615-29619
    Google Scholar
  • 9 LaFerla F M. Pathways linking Abeta and tau pathologies.  Biochem Soc Trans. 2010;  38 (4) 993-995
    Google Scholar
  • 10 Ittner L M, Ke Y D, Delerue F et al.. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.  Cell. 2010;  142 (3) 387-397
    Google Scholar
  • 11 Cruchaga C, Kauwe J S, Mayo K et al.. SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease.  PLoS Genet. 2010;  6 (9) pii: e1001101
    Google Scholar
  • 12 Fagan A M, Head D, Shah A R et al.. Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.  Ann Neurol. 2009;  65 (2) 176-183
    Google Scholar
  • 13 Holtzman D M. Cerebrospinal fluid beta-amyloid 42, tau, and P-tau: confirmation now realization.  Arch Neurol. 2009;  66 (12) 1552-1553
    Google Scholar
  • 14 Hu W T, Chen-Plotkin A, Arnold S E et al.. Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment.  Acta Neuropathol. 2010;  119 (6) 669-678
    Google Scholar
  • 15 Jack Jr C R, Knopman D S, Jagust W J et al.. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.  Lancet Neurol. 2010;  9 (1) 119-128
    Google Scholar
  • 16 Jagust W J, Landau S M, Shaw L M Alzheimer's Disease Neuroimaging Initiative et al. Relationships between biomarkers in aging and dementia.  Neurology. 2009;  73 (15) 1193-1199
    Google Scholar
  • 17 Morris J C, Roe C M, Grant E A et al.. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease.  Arch Neurol. 2009;  66 (12) 1469-1475
    Google Scholar
  • 18 Vemuri P, Wiste H J, Weigand S D Alzheimer's Disease Neuroimaging Initiative et al. Serial MRI and CSF biomarkers in normal aging, MCI, and AD.  Neurology. 2010;  75 (2) 143-151
    Google Scholar
  • 19 Sperling R A, Aisen P S, Beckett L A et al.. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.  Alzheimers Dement. 2011;  7 (3) 280-292
    Google Scholar
  • 20 Bertram L, McQueen M B, Mullin K, Blacker D, Tanzi R E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.  Nat Genet. 2007;  39 (1) 17-23
    Google Scholar
  • 21 Colhoun H M, McKeigue P M, Davey Smith G. Problems of reporting genetic associations with complex outcomes.  Lancet. 2003;  361 (9360) 865-872
    Google Scholar
  • 22 Harold D, Abraham R, Hollingworth P et al.. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.  Nat Genet. 2009;  41 (10) 1088-1093
    Google Scholar
  • 23 Lambert J C, Heath S, Even G European Alzheimer's Disease Initiative Investigators et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.  Nat Genet. 2009;  41 (10) 1094-1099
    Google Scholar
  • 24 Seshadri S, Fitzpatrick A L, Ikram M A CHARGE Consortium et al. Genome-wide analysis of genetic loci associated with Alzheimer disease.  JAMA. 2010;  303 (18) 1832-1840
    Google Scholar
  • 25 Hollingworth P, Harold D, Sims R Alzheimer's Disease Neuroimaging Initiative et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.  Nat Genet. 2011;  43 (5) 429-435 10.1038/ng.803
    Google Scholar
  • 26 Bettens K, Sleegers K, Van Broeckhoven C. Current status on Alzheimer disease molecular genetics: from past, to present, to future.  Hum Mol Genet. 2010;  19 (R1) R4-R11
    Google Scholar
  • 27 Yerbury J J, Poon S, Meehan S et al.. The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures.  FASEB J. 2007;  21 (10) 2312-2322
    Google Scholar
  • 28 Kirszbaum L, Bozas S E, Walker I D. SP-40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges.  FEBS Lett. 1992;  297 (1–2) 70-76
    Google Scholar
  • 29 Thambisetty M, Simmons A, Velayudhan L et al.. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.  Arch Gen Psychiatry. 2010;  67 (7) 739-748
    Google Scholar
  • 30 Calero M, Rostagno A, Frangione B, Ghiso J. Clusterin and Alzheimer's disease.  Subcell Biochem. 2005;  38 273-298
    Google Scholar
  • 31 Braskie M N, Jahanshad N, Stein J L et al.. Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.  J Neurosci. 2011;  31 (18) 6764-6770
    Google Scholar
  • 32 Krych-Goldberg M, Atkinson J P. Structure-function relationships of complement receptor type 1.  Immunol Rev. 2001;  180 112-122
    Google Scholar
  • 33 Zanjani H, Finch C E, Kemper C et al.. Complement activation in very early Alzheimer disease.  Alzheimer Dis Assoc Disord. 2005;  19 (2) 55-66
    Google Scholar
  • 34 Eikelenboom P, Veerhuis R, Scheper W, Rozemuller A J, van Gool W A, Hoozemans J J. The significance of neuroinflammation in understanding Alzheimer's disease.  J Neural Transm. 2006;  113 (11) 1685-1695
    Google Scholar
  • 35 Rogers J, Li R, Mastroeni D et al.. Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes.  Neurobiol Aging. 2006;  27 (12) 1733-1739
    Google Scholar
  • 36 Brouwers N, Van Cauwenberghe C, Engelborghs S et al.. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.  Mol Psychiatry. 2011;  ; March 15 [Epub ahead of print]
    Google Scholar
  • 37 Tebar F, Bohlander S K, Sorkin A. Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.  Mol Biol Cell. 1999;  10 (8) 2687-2702
    Google Scholar
  • 38 Koo E H, Squazzo S L. Evidence that production and release of amyloid beta-protein involves the endocytic pathway.  J Biol Chem. 1994;  269 (26) 17386-17389
    Google Scholar
  • 39 Carey R M, Balcz B A, Lopez-Coviella I, Slack B E. Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid beta protein.  BMC Cell Biol. 2005;  6 30
    Google Scholar
  • 40 Harel A, Wu F, Mattson M P, Morris C M, Yao P J. Evidence for CALM in directing VAMP2 trafficking.  Traffic. 2008;  9 (3) 417-429
    Google Scholar
  • 41 Sakamuro D, Elliott K J, Wechsler-Reya R, Prendergast G C. BIN1 is a novel MYC-interacting protein with features of a tumour suppressor.  Nat Genet. 1996;  14 (1) 69-77
    Google Scholar
  • 42 Wigge P, McMahon H T. The amphiphysin family of proteins and their role in endocytosis at the synapse.  Trends Neurosci. 1998;  21 (8) 339-344
    Google Scholar
  • 43 Meunier B, Quaranta M, Daviet L, Hatzoglou A, Leprince C. The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170).  Eur J Cell Biol. 2009;  88 (2) 91-102
    Google Scholar
  • 44 Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system.  J Atheroscler Thromb. 2011;  18 (4) 274-281
    Google Scholar
  • 45 Ikeda Y, Abe-Dohmae S, Munehira Y et al.. Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release.  Biochem Biophys Res Commun. 2003;  311 (2) 313-318
    Google Scholar
  • 46 Langmann T, Mauerer R, Zahn A et al.. Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues.  Clin Chem. 2003;  49 (2) 230-238
    Google Scholar
  • 47 Jehle A W, Gardai S J, Li S et al.. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages.  J Cell Biol. 2006;  174 (4) 547-556
    Google Scholar
  • 48 Liang Y, Buckley T R, Tu L, Langdon S D, Tedder T F. Structural organization of the human MS4A gene cluster on chromosome 11q12.  Immunogenetics. 2001;  53 (5) 357-368
    Google Scholar
  • 49 Tateno H, Li H, Schur M J et al.. Distinct endocytic mechanisms of CD22 (Siglec-2) and Siglec-F reflect roles in cell signaling and innate immunity.  Mol Cell Biol. 2007;  27 (16) 5699-5710
    Google Scholar
  • 50 Crocker P R, Paulson J C, Varki A. Siglecs and their roles in the immune system.  Nat Rev Immunol. 2007;  7 (4) 255-266
    Google Scholar
  • 51 Dustin M L, Olszowy M W, Holdorf A D et al.. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts.  Cell. 1998;  94 (5) 667-677
    Google Scholar
  • 52 Lynch D K, Winata S C, Lyons R J et al.. A cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton.  J Biol Chem. 2003;  278 (24) 21805-21813
    Google Scholar
  • 53 Pimplikar S W, Nixon R A, Robakis N K, Shen J, Tsai L H. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.  J Neurosci. 2010;  30 (45) 14946-14954
    Google Scholar
  • 54 McGeer E G, McGeer P L. Innate immunity in Alzheimer's disease: a model for local inflammatory reactions.  Mol Interv. 2001;  1 (1) 22-29
    Google Scholar
  • 55 Bates K A, Verdile G, Li Q X et al.. Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests.  Mol Psychiatry. 2009;  14 (5) 469-486
    Google Scholar
  • 56 Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes.  Aging Cell. 2004;  3 (4) 169-176
    Google Scholar
  • 57 Rowe J A, Moulds J M, Newbold C I, Miller LHP. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1.  Nature. 1997;  388 (6639) 292-295
    Google Scholar
  • 58 Dietschy J M, Turley S D. Cholesterol metabolism in the brain.  Curr Opin Lipidol. 2001;  12 (2) 105-112
    Google Scholar
  • 59 Puglielli L, Tanzi R E, Kovacs D M. Alzheimer's disease: the cholesterol connection.  Nat Neurosci. 2003;  6 (4) 345-351
    Google Scholar
  • 60 Miwa Y, Takiuchi S, Kamide K et al.. Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females.  Biochem Biophys Res Commun. 2005;  331 (4) 1587-1593
    Google Scholar
  • 61 Ishikawa Y, Akasaka Y, Ishii T et al.. Distribution and synthesis of apolipoprotein J in the atherosclerotic aorta.  Arterioscler Thromb Vasc Biol. 1998;  18 (4) 665-672
    Google Scholar
  • 62 Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system.  J Atheroscler Thromb. 2011;  18 (4) 274-281
    Google Scholar
  • 63 Mack J T, Townsend D M, Beljanski V, Tew K D. The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds.  Curr Drug Metab. 2007;  8 (1) 47-57
    Google Scholar
  • 64 Brody D L, Magnoni S, Schwetye K E et al.. Amyloid-beta dynamics correlate with neurological status in the injured human brain.  Science. 2008;  321 (5893) 1221-1224
    Google Scholar
  • 65 Shankar G M, Li S, Mehta T H et al.. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.  Nat Med. 2008;  14 (8) 837-842
    Google Scholar
  • 66 Selkoe D J. Alzheimer's disease.  Cold Spring Harb Perspect Biol. 2011;  3 (7) pii: a004457
    Google Scholar
  • 67 Bartl M M, Luckenbach T, Bergner O, Ullrich O, Koch-Brandt C. Multiple receptors mediate apoJ-dependent clearance of cellular debris into nonprofessional phagocytes.  Exp Cell Res. 2001;  271 (1) 130-141
    Google Scholar
  • 68 Bell R D, Sagare A P, Friedman A E et al.. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.  J Cereb Blood Flow Metab. 2007;  27 (5) 909-918
    Google Scholar
  • 69 Stevens B, Allen N J, Vazquez L E et al.. The classical complement cascade mediates CNS synapse elimination.  Cell. 2007;  131 (6) 1164-1178
    Google Scholar
  • 70 Rademakers R, Rovelet-Lecrux A. Recent insights into the molecular genetics of dementia.  Trends Neurosci. 2009;  32 (8) 451-461
    Google Scholar
  • 71 Rohrer J D, Guerreiro R, Vandrovcova J et al.. The heritability and genetics of frontotemporal lobar degeneration.  Neurology. 2009;  73 (18) 1451-1456
    Google Scholar
  • 72 van der Zee J, Sleegers K, Van Broeckhoven C. Invited article: the Alzheimer disease-frontotemporal lobar degeneration spectrum.  Neurology. 2008;  71 (15) 1191-1197
    Google Scholar
  • 73 Renton A E, Majounie E, Waite A et al.. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.  Neuron. 2011;  72 (2) 257-268
    Google Scholar
  • 74 DeJesus-Hernandez M, Mackenzie I R, Boeve B F et al.. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.  Neuron. 2011;  72 (2) 245-256
    Google Scholar
  • 75 Ballatore C, Lee V M, Trojanowski J Q. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.  Nat Rev Neurosci. 2007;  8 (9) 663-672
    Google Scholar
  • 76 Chen-Plotkin A S, Lee V M, Trojanowski J Q. TAR DNA-binding protein 43 in neurodegenerative disease.  Nat Rev Neurol. 2010;  6 (4) 211-220
    Google Scholar
  • 77 Mackenzie I R, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia.  Lancet Neurol. 2010;  9 (10) 995-1007
    Google Scholar
  • 78 Urwin H, Josephs K A, Rohrer J D FReJA Consortium et al. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.  Acta Neuropathol. 2010;  120 (1) 33-41
    Google Scholar
  • 79 Coppola G, Karydas A, Rademakers R et al.. Gene expression study on peripheral blood identifies progranulin mutations.  Ann Neurol. 2008;  64 (1) 92-96
    Google Scholar
  • 80 Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration.  Neurology. 2008;  71 (16) 1235-1239
    Google Scholar
  • 81 Sleegers K, Brouwers N, Van Damme P et al.. Serum biomarker for progranulin-associated frontotemporal lobar degeneration.  Ann Neurol. 2009;  65 (5) 603-609
    Google Scholar
  • 82 Geser F, Martinez-Lage M, Robinson J et al.. Clinical and pathological continuum of multisystem TDP-43 proteinopathies.  Arch Neurol. 2009;  66 (2) 180-189
    Google Scholar
  • 83 Barmada S J, Skibinski G, Korb E, Rao E J, Wu J Y, Finkbeiner S. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis.  J Neurosci. 2010;  30 (2) 639-649
    Google Scholar
  • 84 Weihl C C. Valosin containing protein associated fronto-temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis.  Curr Alzheimer Res. 2011;  8 (3) 252-260
    Google Scholar
  • 85 Urwin H, Ghazi-Noori S, Collinge J, Isaacs A. The role of CHMP2B in frontotemporal dementia.  Biochem Soc Trans. 2009;  37 (Pt 1) 208-212
    Google Scholar
  • 86 Lee J A, Liu L, Gao F B. Autophagy defects contribute to neurodegeneration induced by dysfunctional ESCRT-III.  Autophagy. 2009;  5 (7) 1070-1072
    Google Scholar
  • 87 Deng H X, Chen W, Hong S T et al.. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.  Nature. 2011;  477 (7363) 211-215
    Google Scholar
  • 88 Van Deerlin V M, Sleiman P M, Martinez-Lage M et al.. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.  Nat Genet. 2010;  42 (3) 234-239
    Google Scholar
  • 89 Finch N, Carrasquillo M M, Baker M et al.. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.  Neurology. 2011;  76 (5) 467-474
    Google Scholar
  • 90 Bonifati V. Recent advances in the genetics of dementia with Lewy bodies.  Curr Neurol Neurosci Rep. 2008;  8 (3) 187-189
    Google Scholar
  • 91 Clark L N, Kartsaklis L A, Wolf Gilbert R et al.. Association of glucocerebrosidase mutations with dementia with Lewy bodies.  Arch Neurol. 2009;  66 (5) 578-583
    Google Scholar
  • 92 Brown K, Mastrianni J A. The prion diseases.  J Geriatr Psychiatry Neurol. 2010;  23 (4) 277-298
    Google Scholar
  • 93 Mead S, Poulter M, Uphill J et al.. Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.  Lancet Neurol. 2009;  8 (1) 57-66
    Google Scholar
  • 94 Angot E, Steiner J A, Hansen C, Li J Y, Brundin P. Are synucleinopathies prion-like disorders?.  Lancet Neurol. 2010;  9 (11) 1128-1138
    Google Scholar
  • 95 Kim J, Holtzman D M. Medicine. Prion-like behavior of amyloid-beta.  Science. 2010;  330 (6006) 918-919
    Google Scholar
  • 96 Frost B, Diamond M I. Prion-like mechanisms in neurodegenerative diseases.  Nat Rev Neurosci. 2010;  11 (3) 155-159
    Google Scholar
  • 97 Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M G. CADASIL.  Lancet Neurol. 2009;  8 (7) 643-653
    Google Scholar
  • 98 Ross C A, Tabrizi S J. Huntington's disease: from molecular pathogenesis to clinical treatment.  Lancet Neurol. 2011;  10 (1) 83-98
    Google Scholar
  • 99 Wild E J, Mudanohwo E E, Sweeney M G et al.. Huntington's disease phenocopies are clinically and genetically heterogeneous.  Mov Disord. 2008;  23 (5) 716-720
    Google Scholar
  • 100 Stevanin G, Brice A. Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4).  Cerebellum. 2008;  7 (2) 170-178
    Google Scholar
  • 101 Garcia-Arocena D, Hagerman P J. Advances in understanding the molecular basis of FXTAS.  Hum Mol Genet. 2010;  19 (R1) R83-R89
    Google Scholar
  • 102 Leehey M A. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment.  J Investig Med. 2009;  57 (8) 830-836
    Google Scholar

Henry L. PaulsonM.D. Ph.D. 

Professor of Neurology, Department of Neurology, University of Michigan

4001 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109

Email: henryp@umich.edu

      >