Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, Walton RL, Ahmed S, Viollet C, Ding J, Makarious MB, Diez-Fairen M, Portley MK, Shah Z, Abramzon Y, Hernandez DG, Blauwendraat C, Stone DJ, Eicher J, Parkkinen L, Ansorge O, Clark L, Honig LS, Marder K, Lemstra A, St George-Hyslop P, Londos E, Morgan K, Lashley T, Warner TT, Jaunmuktane Z, Galasko D, Santana I, Tienari PJ, Myllykangas L, Oinas M, Cairns NJ, Morris JC, Halliday GM, Van Deerlin VM, Trojanowski JQ, Grassano M, Calvo A, Mora G, Canosa A, Floris G, Bohannan RC, Brett F, Gan-Or Z, Geiger JT, Moore A, May P, Krüger R, Goldstein DS, Lopez G, Tayebi N, Sidransky E, American Genome Center, Norcliffe-Kaufmann L, Palma JA, Kaufmann H, Shakkottai VG, Perkins M, Newell KL, Gasser T, Schulte C, Landi F, Salvi E, Cusi D, Masliah E, Kim RC, Caraway CA, Monuki ES, Brunetti M, Dawson TM, Rosenthal LS, Albert MS, Pletnikova O, Troncoso JC, Flanagan ME, Mao Q, Bigio EH, Rodríguez-Rodríguez E, Infante J, Lage C, González-Aramburu I, Sanchez-Juan P, Ghetti B, Keith J, Black SE, Masellis M, Rogaeva E, Duyckaerts C, Brice A, Lesage S, Xiromerisiou G, Barrett MJ, Tilley BS, Gentleman S, Logroscino G, Serrano GE, Beach TG, McKeith IG, Thomas AJ, Attems J, Morris CM, Palmer L, Love S, Troakes C, Al-Sarraj S, Hodges AK, Aarsland D, Klein G, Kaiser SM, Woltjer R, Pastor P, Bekris LM, Leverenz JB, Besser LM, Kuzma A, Renton AE, Goate A, Bennett DA, Scherzer CR, Morris HR, Ferrari R, Albani D, Pickering-Brown S, Faber K, Kukull WA, Morenas-Rodriguez E, Lleó A, Fortea J, Alcolea D, Clarimon J, Nalls MA, Ferrucci L, Resnick SM, Tanaka T, Foroud TM, Graff-Radford NR, Wszolek ZK, Ferman T, Boeve BF, Hardy JA, Topol EJ, Torkamani A, Singleton AB, Ryten M, Dickson DW, Chiò A, Ross OA, Gibbs JR, Dalgard CL, Traynor BJ, Scholz SW. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021 Mar;53(3):294-303. Epub 2021 Feb 15 PubMed.

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  1. In this paper, Chia et al. described the analysis of an impressive volume of whole-genome-sequencing (WGS) data with the main objective to characterize genetic determinants of Lewy body dementia. They report five genome-wide significant signals, three already known (GBA, SNCA and APOE) and two new to LBD (BIN1 and TMEM175).

    This paper is based on classical approaches, particularly well-performed without unnecessary analyses as we can sometimes see in such genetic papers. The results are very solid, with replication in independent populations and sensitivity analyses in pathologically defined LBD. This latter point is particularly relevant since the two new loci are already known to be associated with the risk of other neurodegenerative diseases.

    In a way, it's as if the authors had a Ferrari, i.e., WGS, but decided to bridle it to a Ford to do reasonable analyses at first, genome-wide association (GWAS) and whole-exome sequencing (WES). This is definitely not a criticism. There is no doubt that these data will be particularly valuable to decipher more deeply the genetics of LBD, especially structural variants as mentioned by the authors and will be a remarkable resource for all researchers working on neurodegenerative diseases.

    These genetic data seem to support that LBD lies on the continuum of Parkinson’s disease and Alzheimer’s disease. Beyond APOE, SNCA, and GBA, TMEM175 is a genetic risk factor for PD, and BIN1 is for AD. In particular, BIN1 is the second genetic factor of Alzheimer's disease after APOE in terms of association level (Seshadri et al., 2010) and Chia et al. also report that the sentinel variant associated with LBD (the same as the one associated with AD), is also associated with neurofibrillary tangle pathology in the brains of LBD cases. This latter observation is of particular interest since this association was also reported in the brains of AD cases (Chapuis et al., 2013). This seems to reinforce the role of the BIN1-tau interaction in pathophysiological processes (Sottejeau et al ., 2015; Sartori et al, 2019). 

    References:

    Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM, . Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010 May 12;303(18):1832-40. PubMed.

    Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, Geller F, Sottejeau Y, Harold D, Dourlen P, Grenier-Boley B, Kamatani Y, Delepine B, Demiautte F, Zelenika D, Zommer N, Hamdane M, Bellenguez C, Dartigues JF, Hauw JJ, Letronne F, Ayral AM, Sleegers K, Schellens A, Broeck LV, Engelborghs S, De Deyn PP, Vandenberghe R, O'Donovan M, Owen M, Epelbaum J, Mercken M, Karran E, Bantscheff M, Drewes G, Joberty G, Campion D, Octave JN, Berr C, Lathrop M, Callaerts P, Mann D, Williams J, Buée L, Dewachter I, Van Broeckhoven C, Amouyel P, Moechars D, Dermaut B, Lambert JC, GERAD consortium. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013 Nov;18(11):1225-34. Epub 2013 Feb 12 PubMed.

    Sottejeau Y, Bretteville A, Cantrelle FX, Malmanche N, Demiaute F, Mendes T, Delay C, Alves Dos Alves H, Flaig A, Davies P, Dourlen P, Dermaut B, Laporte J, Amouyel P, Lippens G, Chapuis J, Landrieu I, Lambert JC. Tau phosphorylation regulates the interaction between BIN1's SH3 domain and Tau's proline-rich domain. Acta Neuropathol Commun. 2015 Sep 23;3:58. PubMed.

    Sartori M, Mendes T, Desai S, Lasorsa A, Herledan A, Malmanche N, Mäkinen P, Marttinen M, Malki I, Chapuis J, Flaig A, Vreulx AC, Ciancia M, Amouyel P, Leroux F, Déprez B, Cantrelle FX, Maréchal D, Pradier L, Hiltunen M, Landrieu I, Kilinc D, Herault Y, Laporte J, Lambert JC. BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation. Acta Neuropathol. 2019 Oct;138(4):631-652. Epub 2019 May 7 PubMed.

    View all comments by Jean-Charles Lambert

  2. This is important work which explains the connections of dementia with Lewy bodies with Alzheimer’s and Parkinson’s diseases, as indeed indicated by the coexistence of Lewy bodies, amyloid plaques, and neurofibrillary tangles in dementia with Lewy bodies.

    The results of this GWAS study will contribute to understanding the mechanism behind the origin of dementia with Lewy bodies and could in the end lead to mechanism-based therapies.

    View all comments by Maria Grazia Spillantini

  3. Among dementia, Lewy body disease (LBD) is the second most common type of progressive dementia after Alzheimer's disease. As in most dementias, LBD causes a progressive decline in cognitive function. However, compared to AD, several symptoms are more specific of LBD: visual hallucinations, Parkinson's disease (PD)-like signs, and a younger age at onset.

    The main feature of LBD is the abnormal accumulation of α-synuclein protein into specific masses, the Lewy bodies. Interestingly, α-synuclein is also associated with Parkinson's disease and patients with Lewy bodies in their brains also have plaques and tangles associated with AD. More generally, the necropsy of aged people finds accumulations of neuropathologies that account for the association between age and dementia. Thus, among the 1,362 autopsied participants of three community-based clinico-pathologic cohorts, 44 percent had a clinical dementia diagnosis (Power et al., 2018). In this study, the pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of Aβ plaques. Age-related increases in dementia risk could be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk.

    Several questions remained: Does the co-existence of neuropathological features of different dementias in one individual occur by chance, or does the clinical expression of dementia vary according to the predominance of one of these neuropathological features over others? One way to try to answer these questions can be approached by genetics. Here, Chia et al. have performed a whole-genome sequencing on 2,981 LBD cases and 2,173 neurologically healthy controls. A replication study for the GWAS analyses was also performed in 970 LBD cases and 8,928 controls. This GWAS identified five independent genome-wide-significant loci that influence risk for developing LBD. Among these, three were already known as LBD genes, the GBA (Glucocerebrosidase) already associated with PD, the famous AD APOE gene encoding apolipoprotein E, and the famous PD gene SNCA encoding α-synuclein. They added two new genes to this list: another famous AD gene, BIN1 (bridging integrator 1) and the TMEM175 gene on chromosome 4p16.3, a known PD risk locus.

    The risk scores for AD and PD of the subjects included in the population sample of this study, derived from the very rich collection of GWAS already published in the literature, were associated with LBD disease status, and with age at death, age at onset, and the duration of illness observed among LBD cases. Individuals diagnosed with LBD had a 66 percent increased genetic risk for developing AD and a 20 percent increased genetic risk for developing PD. The AD genetic risk score was also found to be significantly associated with an earlier age of death in LBD and shorter disease duration. Conversely, the PD genetic risk score was associated with an earlier age at onset among patients diagnosed with LBD. No evidence of interaction between the genetic risk scores of AD and PD in the LBD cohort was detected, implying that AD and PD risk variants were independently associated with LBD risk.

    These results suggest that the co-existence of neuropathological features of dementias in one individual does not occur by chance. Dementia syndrome may be explained by a combination of various pathological processes (vascular, amyloid, tau, α-synuclein) mixed in a subtle dosage offering a wide range of clinical features for LBD patients. This discovery will have also an implication on the treatment strategy, as more and more drugs will be available for these different dementia pathways. Indeed, it would be now interesting to include subgroups of LBD patients in AD and PD drug trials to test if they can also benefit of these new treatments.

    References:

    Power MC, Mormino E, Soldan A, James BD, Yu L, Armstrong NM, Bangen KJ, Delano-Wood L, Lamar M, Lim YY, Nudelman K, Zahodne L, Gross AL, Mungas D, Widaman KF, Schneider J. Combined neuropathological pathways account for age-related risk of dementia. Ann Neurol. 2018 Jul;84(1):10-22. Epub 2018 Jun 26 PubMed.

    View all comments by Philippe Amouyel

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News

  1. Lewy Body Dementia Shares Risk Genes with Alzheimer’s, Parkinson’s

Mutations

  1. APOE c.43+78G>A (rs769449)