Singular cases of Alzheimer's disease disclose new and old genetic "acquaintances".
Alzheimer’s disease
Amyloid
Biomarkers
Dementia
Genetics
Mutation
Journal
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
ISSN: 1590-3478
Titre abrégé: Neurol Sci
Pays: Italy
ID NLM: 100959175
Informations de publication
Date de publication:
May 2021
May 2021
Historique:
received:
18
06
2020
accepted:
25
09
2020
pubmed:
3
10
2020
medline:
15
5
2021
entrez:
2
10
2020
Statut:
ppublish
Résumé
Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age. To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants. Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS). We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases. This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.
Sections du résumé
BACKGROUND
BACKGROUND
Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age.
OBJECTIVES
OBJECTIVE
To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants.
METHODS
METHODS
Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS).
RESULTS
RESULTS
We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases.
CONCLUSIONS
CONCLUSIONS
This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.
Identifiants
pubmed: 33006056
doi: 10.1007/s10072-020-04774-y
pii: 10.1007/s10072-020-04774-y
pmc: PMC8043869
doi:
Substances chimiques
Presenilin-1
0
Presenilin-2
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2021-2029Références
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert M-O, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13:614–629
doi: 10.1016/S1474-4422(14)70090-0
Duits FH, Teunissen CE, Bouwman FH, Visser P-J, Mattsson N, Zetterberg H, Blennow K, Hansson O, Minthon L, Andreasen N, Marcusson J, Wallin A, Rikkert MO, Tsolaki M, Parnetti L, Herukka S-K, Hampel H, De Leon MJ, Schröder J, Aarsland D, Blankenstein MA, Scheltens P, van der Flier WM (2014) The cerebrospinal fluid “Alzheimer profile”: easily said, but what does it mean? Alzheimers Dement 10:713–723.e2
doi: 10.1016/j.jalz.2013.12.023
Wu L, Rosa-Neto P, Hsiung G-YR, Sadovnick AD, Masellis M, Black SE, Jia J, Gauthier S (2012) Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci 39:436–445
doi: 10.1017/S0317167100013949
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23
doi: 10.1038/ng1934
Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN (2017) The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 136:665–677
doi: 10.1007/s00439-017-1779-6
Sjögren M, Vanderstichele H, Agren H, Zachrisson O, Edsbagge M, Wikkelsø C, Skoog I, Wallin A, Wahlund LO, Marcusson J, Nägga K, Andreasen N, Davidsson P, Vanmechelen E, Blennow K (2001) Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values. Clin Chem 47:1776–1781
doi: 10.1093/clinchem/47.10.1776
Vanderstichele H, De Vreese K, Blennow K, Andreasen N, Sindic C, Ivanoiu A, Hampel H, Bürger K, Parnetti L, Lanari A, Padovani A, DiLuca M, Bläser M, Olsson AO, Pottel H, Hulstaert F, Vanmechelen E (2006) Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU(181P) assay for discrimination between Alzheimer’s disease and dementia with Lewy bodies. Clin Chem Lab Med 44:1472–1480
doi: 10.1515/CCLM.2006.258
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1:345–347
doi: 10.1038/ng0892-345
Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C (1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7:43–51
doi: 10.1093/hmg/7.1.43
Wenham PR, Price WH, Blandell G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337:1158–1159
doi: 10.1016/0140-6736(91)92823-K
Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, Dickson DW (2011) Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 122:137–153
doi: 10.1007/s00401-011-0839-6
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, Boxer AL, Dickson DW, Grossman M, Hallett M, Josephs KA, Kertesz A, Lee SE, Miller BL, Reich SG, Riley DE, Tolosa E, Troster AI, Vidailhet M, Weiner WJ (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 80:496–503
doi: 10.1212/WNL.0b013e31827f0fd1
Pardini M, Huey ED, Spina S, Kreisl WC, Morbelli S, Wassermann EM, Nobili F, Ghetti B, Grafman J (2019) FDG-PET patterns associated with underlying pathology in corticobasal syndrome. Neurology 92:e1121–e1135
doi: 10.1212/WNL.0000000000007038
Sandbrink R, Zhang D, Beyreuther K, Schaeffer S, Bauer J, Masters CL, Förstl H (1996) Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer’s disease patients. Ann Neurol 40:265–266
doi: 10.1002/ana.410400225
Dermaut B, Cruts M, Slooter AJC, Van Gestel S, De Jonghe C, Vanderstichele H, Vanmechelen E, Breteler MM, Hofman A, van Duijn CM, Van Broeckhoven C (1999) The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet 64:290–292
doi: 10.1086/302200
Albani D, Roiter I, Artuso V, Batelli S, Prato F, Pesaresi M, Galimberti D, Scarpini E, Bruni A, Franceschi M, Piras MR, Confaloni A, Forloni G (2007) Presenilin-1 mutation E318G and familial Alzheimer’s disease in the Italian population. Neurobiol Aging 28:1682–1688
doi: 10.1016/j.neurobiolaging.2006.07.003
Jin S, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, Ibero-American Alzheimer Disease Genetics Group Researchers, Cruchaga C (2012) Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease Ibero-American cohort. Alzheimers Res Ther 4:34
doi: 10.1186/alzrt137
To MD, Gokgoz N, Doyle TG, Donoviel DB, Knight JA, Hyslop PS, Bernstein A, Andrulis IL (2006) Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene 25:3557–3564
doi: 10.1038/sj.onc.1209397
Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard A-C, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier J-G, Olaso R, Boland A, Meyer V, Deleuze J-F, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D (2016) Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet 24:710–716
doi: 10.1038/ejhg.2015.173
Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J (2015) Rare variants in β-amyloid precursor protein (APP) and Parkinson’s disease. Eur J Hum Genet 23:1328–1333
doi: 10.1038/ejhg.2014.300
Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle M-B, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D (2012) The French series of autosomal dominant early onset Alzheimer’s disease cases: mutation Spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis 30:847–856
doi: 10.3233/JAD-2012-120172
Cruchaga C, Chakraverty S, Mayo K, FLM V, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St. Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM, for the NIA-LOAD/NCRAD Family Study Consortium (2012) Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One 7:e31039
doi: 10.1371/journal.pone.0031039
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608
doi: 10.15252/emmm.201606210
Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues J-F, Tzourio C, Frebourg T, Lathrop M, Deleuze J-F, Hannequin D, Genin E, Amouyel P, Debette S, Lambert J-C, Campion D, Hannequin D, Campion D, Wallon D, Martinaud O, Zarea A, Nicolas G, Rollin-Sillaire A, Bombois S, Mackowiak M-A, Deramecourt V, Pasquier F, Michon A, Le Ber I, Dubois B, Godefroy O, Etcharry-Bouyx F, Chauviré V, Chamard L, Berger E, Magnin E, Dartigues J-F, Auriacombe S, Tison F, de la Sayette V, Castan D, Dionet E, Sellal F, Rouaud O, Thauvin C, Moreaud O, Sauvée M, Formaglio M, Mollion H, Roullet-Solignac I, Vighetto A, Croisile B, Didic M, Félician O, Koric L, Ceccaldi M, Gabelle A, Marelli C, Labauge P, Jonveaux T, Vercelletto M, Boutoleau-Bretonnière C, Castelnovo G, Paquet C, Dumurgier J, Hugon J, De Boisgueheneuc F, Belliard S, Bakchine S, Sarazin M, Barrellon M-O, Laurent B, Blanc F, Pariente J, Jurici S (2017) Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59:220.e1–220.e9
doi: 10.1016/j.neurobiolaging.2017.07.001
Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK, Cheng D, Karl T, Garner B (2013) Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33:4387–4394
doi: 10.1523/JNEUROSCI.4165-12.2013
Apostolova LG, Risacher SL, Duran T, Stage EC, Goukasian N, West JD, Do TM, Grotts J, Wilhalme H, Nho K, Phillips M, Elashoff D, Saykin AJ (2018) Associations of the top 20 Alzheimer disease risk variants with brain amyloidosis. JAMA Neurol 75:328–341
doi: 10.1001/jamaneurol.2017.4198
Willnow TE, Andersen OM (2013) Sorting receptor SORLA - a trafficking path to avoid Alzheimer disease. J Cell Sci 126:2751–2760
doi: 10.1242/jcs.125393
Andersen OM, Rudolph I-M, Willnow TE (2016) Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol 132:653–665
doi: 10.1007/s00401-016-1615-4
Svetoni F, Frisone P, Paronetto MP (2016) Role of FET proteins in neurodegenerative disorders. RNA Biol 13:1089–1102
doi: 10.1080/15476286.2016.1211225
Münch C, Rosenbohm A, Sperfeld A-D, Uttner I, Reske S, Krause BJ, Sedlmeier R, Meyer T, Hanemann CO, Stumm G, Ludolph AC (2005) Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD. Ann Neurol 58:777–780
doi: 10.1002/ana.20631
Wider C, Dachsel JC, Farrer MJ, Dickson DW, Tsuboi Y, Wszolek ZK (2010) Elucidating the genetics and pathology of Perry syndrome. J Neurol Sci 289:149–154
doi: 10.1016/j.jns.2009.08.044
Stockmann M, Meyer-Ohlendorf M, Achberger K, Putz S, Demestre M, Yin H, Hendrich C, Linta L, Heinrich J, Brunner C, Proepper C, Kuh GF, Baumann B, Langer T, Schwalenstöcker B, Braunstein KE, von Arnim C, Schneuwly S, Meyer T, Wong PC, Boeckers TM, Ludolph AC, Liebau S (2013) The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian syndromes. J Neural Transm 120:785–798
doi: 10.1007/s00702-012-0910-z
Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P (2017) Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy. Eur J Hum Genet 25:973–981
doi: 10.1038/ejhg.2017.87
Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K (2016) A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol 132:213–224
doi: 10.1007/s00401-016-1566-9
Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch NC, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Gerpen V, Jan A, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK (2012) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:8
doi: 10.1038/ng.1027
Sassi C, Nalls MA, Ridge PG, Gibbs JR, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Bras J, Blumenau S, Thielke M, Josties C, Freyer D, Dietrich A, Hammer M, Baier M, Dirnagl U, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Goate AM, Singleton AB, Guerreiro R, Hodges A, Hardy J, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kölsch H, Kehoe PG, Vardy ERLC, Hooper NM, Mann DM, Pickering-Brown S, Brown K, Lowe J, Morgan K, Smith AD, Wilcock G, Warden D, Holmes C (2018) Mendelian adult-onset leukodystrophy genes in Alzheimer’s disease: critical influence of CSF1R and NOTCH3. Neurobiol Aging 66:179.e17–179.e29
doi: 10.1016/j.neurobiolaging.2018.01.015
Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, Dursun B, Bilgic B, Santana I, Hanagasi H, Gurvit H, Gibbs JR, Oliveira C, Emre M, Singleton A (2012) Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer’s disease. Neurobiol Aging 33:1008.e17–1008.e23
doi: 10.1016/j.neurobiolaging.2011.10.009
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JSK, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert J-C, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St. George-Hyslop P, Singleton A, Hardy J (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127
doi: 10.1056/NEJMoa1211851
Belorgey D, Crowther DC, Mahadeva R, Lomas DA (2002) Mutant Neuroserpin (S49P) that causes familial encephalopathy with Neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. J Biol Chem 277:17367–17373
doi: 10.1074/jbc.M200680200
Roussel BD, Lomas DA, Crowther DC (2016) Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis). Epileptic Disord 18:103–110
doi: 10.1684/epd.2016.0847