Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, and is typically characterized by memory loss. In addition, during the disease progression, most patients develop behavioural and psychiatric symptoms of dementia (BPSD). Frontotemporal Lobar Degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. It is characterized mainly by behavioural disturbances, whereas memory is conserved. The two major neuropathologic hallmarks of AD are extracellular Amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Conversely, in FTLD the deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include the Amyloid Precursor Protein (β−APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). The majority of mutations in these genes are often associated with a very early onset (40–50 years of age). Regarding FTLD, the first mutations described are located in the Microtubule Associated Protein Tau gene (MAPT). Tau is a component of microtubules, which represent the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Mutations in MAPT are associated with an early onset of the disease (40–50 years), and the clinical phenotype is consistent with Frontotemporal Dementia (FTD). Recently, mutations in a second gene, named progranulin (GRN), have been identified in some families with FTLD. The pathology associated with these mutations is most frequently characterized by the immunostaining of TAR DNA Binding Protein 43 (TDP-43), which is a transcription factor. The clinical phenotype associated with GRN mutations is highly heterogeneous, including FTD, Progressive Aphasia, Corticobasal Syndrome, and AD. Age at disease onset is variable, ranging from 45 to 85 years of age. The majority of cases of AD and FTLD are however sporadic, and likely several genetic and environmental factors contribute to their development. Concerning AD, it is known that the presence of the ε4 allele of the Apolipoprotein E gene is a susceptibility factor, increasing the risk of about 4 fold. A number of additional genetic factors, including cytokines, chemokines, Nitric Oxide Synthases, contribute to the susceptibility for the disease. Some of them also influence the risk to develop FTLD. Variability in serotonin transporter gene could influence the development of BPSD. In this chapter, current knowledge on molecular mechanisms at the basis of AD and FTLD, as well as the role of genetics, will be presented and discussed.
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References
Albani D, Prato F, Tettamanti M et al (2009) The serotonin transporter promoter polymorphic region is not a risk factor for Alzheimer’s disease related behavioral disturbances. J Alzheimers Dis 18(1):125–130
Angelucci F, Bernardini S, Gravina P et al (2009). Delusion symptoms and response to antipsychotic treatment are associated with the 5-HT2A receptor polymorphism (102T/C) in Alzheimer’s disease: a 3-year follow-up longitudinal study. J Alzheimers Dis 17(1):203–211
Assal F, Alarcón M, Solomon EC et al (2004) Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease. Arch Neurol 61(8):1249–1253
Baker M, Litvan I, Houlden H et al (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8(4):711–715
Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919
Baki L, Shioi J, Wen P et al (2004) PS1 activates PI3 K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23:2586–2596.
Bentahir M, Nyabi O, Verhamme J et al (2006) Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 96:732–742
Bernardi L, Maletta RG, Tomaino C et al (2006) The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol Aging 27(5):702–709
Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115(6):1449–1457
Blacker D, Wilcox MA, Laird NM et al (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19(4):357–360
Bruni AC, Bernardi L, Colao R et al (2010) Worldwide distribution of PSEN1 Met146Leu mutation. Neurology 74:798–806
Collins JS, Perry RT, Watson B Jr et al (2000) Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. Am J Med Genet 96(6):823–830
Combarros O, Infante J, Llorca J, Berciano J (2004a) No evidence for association of the monocyte chemoattractant protein-1 (–2518) gene polymorphism and Alzheimer’s disease. Neurosci Lett 360(1-2):25–28
Combarros O, Infante J, Llorca J et al (2004b) The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer’s disease. Neurosci Lett 366(3):312–314
Conrad C, Andreadis A, Trojanowski JQ et al (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol 41(2):277–281
Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923
Crawford F, Freeman M, Abdullah L et al (2000) No association between the NOS3 codon 298 polymorphism and Alzheimer’s disease in a sample from the United States. Ann Neurol 47(5):687
Cross AJ (1990) Serotonin in Alzheimer-type dementia and other dementing illnesses. Ann NY Acad Sci 600:405–415
Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924
Dahiyat M, Cumming A, Harrington C et al (1999) Association between Alzheimer’s disease and the NOS3 gene. Ann Neurol 46(4):664–667
Di Maria E, Tabaton M, Vigo T et al (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47(3):374–377
Du Y, Dodel RC, Eastwood BJ et al (2000) Association of an interleukin 1 alpha polymorphism with Alzheimer’s disease. Neurology 55(4):480–483
Engelborghs S, Dermaut B, Goeman J et al (2003) Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects. J Neurol Neurosurg Psychiatry 74: 1148–1151
Fabre SF, Forsell C, Viitanen M et al (2001) Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations. Exp Neurol 168:413–418
Farrer LA, Abraham CR, Volicer L et al (1995) Allele epsilon 4 of apolipoprotein E shows a dose effect on age at onset of Pick disease. Exp Neurol 136:162–170
Fenoglio C, Galimberti D, Lovati C et al (2004) MCP-1 in Alzheimer’s disease patients: A-2518G polymorphism and serum levels. Neurobiol Aging 25(9):1169–1173
Galimberti D, Fenoglio C, Cortini F et al (2010) GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis 19(1):171–177
Galimberti D, Fenoglio C, Lovati C et al (2004) CCR2-64I polymorphism and CCR5Delta32 deletion in patients with Alzheimer’s disease. J Neurol Sci 225(1–2):79–83
Galimberti D, Scarpini E, Venturelli E et al (2008) Association of a NOS1 promoter repeat with Alzheimer’s disease. Neurobiol Aging 29(9):1359–1365
Galimberti D, Venturelli E, Gatti A et al (2005) Association of neuronal nitric oxide synthase C276T polymorphism with Alzheimer’s disease. J Neurol 252:985–986
Galimberti D, Venturelli E, Villa C et al (2009) MCP-1 A-2518G polymorphism: effect on susceptibility for frontotemporal lobar degeneration and on cerebrospinal fluid MCP-1 levels. J Alzheimers Dis 17(1):125–133
Gass J, Cannon A, Mackenzie IR et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15(20):2988–3001
Geschwind D, Karrim J, Nelson SF, Miller B (1998) The apolipoprotein E epsilon4 allele is not a significant risk factor for frontotemporal dementia. Ann Neurol 44:134–138
Goate A, Chartier-Harlin MC, Mullan M et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706
Goedert M, Jakes R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739:240–250
Griffin WS (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 83(suppl):470S–474S
Grimaldi LM, Casadei VM, Ferri C et al (2000) Association of early-onset Alzheimer’s disease with an interleukin-1alpha gene polymorphism. Ann Neurol 47(3):361–365
Grupe A, Li Y, Rowland C, Nowotny P et al (2006) A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet 78(1):78–88
Guidi I, Galimberti D, Venturelli E et al (2005) Influence of the Glu298Asp polymorphism of NOS3 on age at onset and homocysteine levels in AD patients. Neurobiol Aging 26(6):789–794
Gustafson L, Abrahamson M, Grubb A et al (1997) Apolipoprotein-E genotyping in Alzheimer’s disease and frontotemporal dementia. Dement Geriatr Cogn Disord 8:240–243
Ha TM, Cho DM, Park SW, Joo MJ, Lee BJ, Kong BG, Kim JM, Yoon JS, Kim YH (2005) Evaluating associations between 5-HTTLPR polymorphism and Alzheimer’s disease for Korean patients. Dement Geriatr Cogn Disord 20(1):31–34
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356
Harold D, Abraham R, Hollingworth P et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093
He Z, Bateman A (2003) Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81:600–612
Helisalmi S, Linnaranta K, Lehtovirta M et al (1996) Apolipoprotein E polymorphism in patients with different neurodegenerative disorders. Neurosci Lett 205:61–64
Hosler BA, Siddique T, Sapp PC et al (2000) Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21−q22. JAMA 284:1664–1669
Hou CE, Carlin D, Miller BL (2004) Non-Alzheimer’s disease dementias: anatomic, clinical, and molecular correlates. Can J Psychiatry 49(3):164–171
Huerta C, Alvarez V, Mata IF et al (2004) Chemokines (RANTES and MCP-1) and chemokine-receptors (CCR2 and CCR5) gene polymorphisms in Alzheimer’s and Parkinson’s disease. Neurosci Lett 370(2–3):151–154
Huppert SS, Ilagan MX, De Strooper B, Kopan R (2005) Analysis of Notch function in presomitic mesoderm suggests a γ-secretase-independent role for presenilins in somite differentiation. Dev Cell 8:677–688
Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705
Lambert JC, Heath S, Even G et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099
Larner AJ, Doran M (2009) Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer’s disease: an update. J Alzheimers Dis 17(2):259–265
Le Ber I, Camuzat A, Berger E et al (2009) Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 72:1669–1676
Lendon CL, Lynch T, Norton J et al (1998) Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21–22. Neurology 50:1546–1555
Lesch KP, Balling U, Gross J et al (1994) Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 95(2):157–162
Levy-Lahad E, Wasco W, Poorkaj P et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269(5226):973–977
Li Y, Grupe A, Rowland C et al (2006) DAPK1 variants are associated with Alzheimer’s disease and allele-specific expression. Hum Mol Genet 15(17):2560–2568
Licastro F, Chiappelli M (2003) Brain immune responses cognitive decline and dementia: relationship with phenotype expression and genetic background. Mech Ageing Dev 124:539–548
Liou YJ, Hong CJ, Liu HC et al (2002) No association between the neuronal nitric oxide synthase gene polymorphism and Alzheimer’s disease. Am J Med Gen 114:687–688
Lotrich FE, Pollock BG, Ferrell RE (2001) Polymorphism of the serotonin transporter: implications for the use of selective serotonin reuptake inhibitors. Am J Pharmacogenomics 1(3):153–164
Mackenzie IR, Baker M, West G et al (2006) A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129:853–867
Monastero R, Cefalu AB, Camarda C et al (2003) No association between Glu298Asp endothelial nitric oxide synthase polymorphism and Italian sporadic Alzheimer’s disease. Neurosci Lett 341:229–232
Morita M, Al-Chalabi A, Andersen PM et al (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66(6):839–844
Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554
Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
Nicoll JA, Mrak RE, Graham DI et al (2000) Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann Neurol 47(3):365–368
Palmer AM (1996) Neurochemical studies of Alzheimer’s disease. Neurodegeneration 5:381–391
Papassotiropoulos A, Bagli M, Jessen F et al (1999) A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer’s disease. Ann Neurol 45(5):666-668
Pericak-Vance MA, Bebout JL, Gaskell PC Jr et al (1991) Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 48(6):1034–1050
Pesiridis G, Lee VMY, Trojanowski JQ (2009) Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Gen 18(2):R156–162
Poorkaj P, Bird TD, Wijsman E et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825
Raber J, Huang Y, Ashford JW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 25(5):641–650
Rademakers R, Cruts M, Dermaut B et al (2002) Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 7:1064–1074
Rademakers R, Cruts M, van Broeckhoven C (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24(4):277–295
Reif A, Herterich S, Strobel A et al (2006) A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11(3):286–300
Reinikainen KJ, Soininen H, Riekkinen PJ (1990) Neurotransmitter changes in Alzheimer’s disease: implications to diagnostics and therapy. J Neurosci Res 27(4):576–586
Riemenschneider M, Diehl J, Muller U et al (2002) Apolipoprotein E polymorphism in German patients with frontotemporal degeneration. J Neurol Neurosurg Psychiatry 72:639–641
Rocchi A, Micheli D, Ceravolo R et al (2003) Serotoninergic polymorphisms (5-HTTLPR and 5-HT2A): association studies with psychosis in Alzheimer disease. Genet Test 7(4):309–314
Rosen HJ, Hartikainen KM, Jagust W et al (2002) Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD. Neurology 58:1608–1615
Rosso SM, Kamphorst W, de Graaf B et al (2001) Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21–22. Brain 124:1948–1957
Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26
Sánchez-Guerra M, Combarros O, Alvarez-Arcaya A et al (2001) The Glu298Asp polymorphism in the NOS3 gene is not associated with sporadic Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70:566–567
Sato N, Ueki A, Ueno H et al (2009) Dopamine D3 receptor gene polymorphism influences on behavioral and psychological symptoms of dementia (BPSD) in mild dementia of Alzheimer’s type. J Alzheimers Dis 17(2):441–448
Saur D, Vanderwinden JM, Seidler B et al (2004) Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis. Proc Natl Acad Sci 101(6):1662–1667
Scarpini E, Galimberti D, Guidi I et al (2006) Progressive, isolated language disturbance: its significance in a 65-year-old-man. A case report with implications for treatment and review of literature. J Neurol Sci 240(1–2):45–51
Seshadri S, Beiser A, Selhub J et al (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New Engl J Med 346:476-483
Sherrington R, Rogaev EI, Liang Y et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760
Short RA, Graff-Radford NR, Adamson J et al (2002) Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes. Arch Neurol 59:611–615
Skibinski G, Parkinson NJ, Brown JM et al (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37:806–808
Snowden JS, Neary D, Mann DM (2002) Frontotemporal dementia. Br J Psychiatry 180:140–143
Snowden JS, Pickering-Brown SM, Mackenzie IR et al (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129:3091–3102
Spillantini MG, Murrell JR, Goedert M et al (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95:7737–7741
Srinivasan R, Davidson Y, Gibbons L et al (2006) The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males. J Neurol Neurosurg Psychiatry 77:154–158
Steiner H, Romig H, Grim MG et al (1999) The biological and pathological function of the presenilin-1 dExon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 274:7615–7618
Stevens M, van Duijn CM, de Knijff P et al (1997) Apolipoprotein E gene and sporadic frontal lobe dementia. Neurology 48:1526–1529
Sukonick DL, Pollock BG, Sweet RA et al (2001) The 5-HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer disease. Arch Neurol 58(9):1425–1428
Sweet RA, Pollock BG, Sukonick DL et al (2001) The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. Int Psychogeriatr 13(4):401–409
Tanzi RE, Gusella JF et al (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235(4791):880–884
Tedde A, Nacmias B, Cellini E et al (2002) Lack of association between NOS3 polymorphism and Italian sporadic and familial Alzheimer’s disease. J Neurol 249:110–111
Ueki A, Ueno H, Sato N, Shinjo H, Morita Y (2007) Serotonin transporter gene polymorphism and BPSD in mild Alzheimer’s disease. J Alzheimers Dis 12(3):245–253
van der Zee J, Rademakers R, Engelborghs S et al (2006) A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129:841–852
Vance C, Al-Chalabi A, Ruddy D et al (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 129:868–876
Venturelli E, Galimberti D, Fenoglio C et al (2006) Candidate gene analysis of IP-10 gene in patients with Alzheimer’s disease. Neurosci Lett 404(1–2):217–221
Venturelli E, Galimberti D, Lovati C et al (2005) The T-786C NOS3 polymorphism in Alzheimer’s disease: association and influence on gene expression. Neurosci Lett 382(3):300–303
Venturelli E, Villa C, Fenoglio C et al (2009) The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration. Eur J Neurol 16(1):37–42
Venturelli E, Villa C, Scarpini E et al (2008) Neuronal nitric oxide synthase C276T polymorphism increases the risk for frontotemporal lobar degeneration. Eur J Neurol 15(1):77–81
Verpillat P, Camuzat A, Hannequin D et al (2002) Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis. Eur J Hum Genet 10:399–405
Wang Y, Newton DC, Robb GB et al (1999) RNA diversity has profound effects on the translation of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 96(21):121505–12155
Wilhelmsen KC, Lynch T, Pavlou E et al (1994) Localization of disinhibition–dementia–parkinsonism–amyotrophy complex to 17q21–22. Am J Hum Genet 55:1159–1165
Yu CE, Bird TD, Bekris LM et al (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67(2):161–170
Zhu J, Nathan C, Jin W et al (2002) Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defence and wound repair. Cell 111:867–878
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Galimberti, D., Scarpini, E. (2011). Behavioral Genetics of Neurodegenerative Disorders. In: Cryan, J., Reif, A. (eds) Behavioral Neurogenetics. Current Topics in Behavioral Neurosciences, vol 12. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2011_181
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