{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:45:50Z","timestamp":1768567550407,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,5]]},"group-title":"Neurology","reference-count":60,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    has been proposed as a modifier of disease risk in FTLD-TDP, particularly in\n                    <jats:italic>GRN<\/jats:italic>\n                    mutation carriers. Furthermore,\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Participants were enrolled through the ARTFL\/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in\n                    <jats:italic>C9orf72, GRN, MAPT, VCP, TBK1, TARDBP,<\/jats:italic>\n                    symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR\u00ae+NACC-FTLD sum of boxes. Subsequently, associations between\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    predictor interactions were fitted.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The minor allele of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in\n                    <jats:italic>GRN<\/jats:italic>\n                    mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic\n                    <jats:italic>GRN<\/jats:italic>\n                    mutation carriers only. The minor allele of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    rs1990622 also associated with greater cognitive scores among all\n                    <jats:italic>C9orf72<\/jats:italic>\n                    mutation carriers and in presymptomatic\n                    <jats:italic>C9orf72<\/jats:italic>\n                    mutation carriers, under the recessive dosage model.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>\n                    We identified associations of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    with gray matter volume and cognition in the presence of\n                    <jats:italic>GRN<\/jats:italic>\n                    and\n                    <jats:italic>C9orf72<\/jats:italic>\n                    mutations. This further supports\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    as modifier of TDP-43 pathology. The association of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    with outcomes of interest in presymptomatic\n                    <jats:italic>GRN<\/jats:italic>\n                    and\n                    <jats:italic>C9orf72<\/jats:italic>\n                    mutation carriers could additionally reflect TMEM106B\u2019s impact on divergent pathophysiological changes before the appearance of clinical symptoms.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.04.05.24305253","type":"posted-content","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T19:25:18Z","timestamp":1712345118000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene specific effects on brain volume and cognition of\n                  <i>TMEM106B<\/i>\n                  in frontotemporal lobar 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