Gene specific effects on brain volume and cognition ofTMEM106Bin frontotemporal lobar degeneration
Authors: Vandebergh Marijne , Ramos Eliana Marisa , Corriveau-Lecavalier Nick , Ramanan Vijay K , Kornak John , Mester Carly , Kolander Tyler , Brushaber Danielle , Staffaroni Adam M , Geschwind Daniel , Wolf Amy , Kantarci Kejal , Gendron Tania F , Petrucelli Leonard , Van den Broeck Marleen , Wynants Sarah , Baker Matthew C , Borrego – Écija Sergi , Appleby Brian , Barmada Sami , Bozoki Andrea , Clark David , Darby R Ryan , Dickerson Bradford C , Domoto-Reilly Kimiko , Fields Julie A. , Galasko Douglas R. , Ghoshal Nupur , Graff-Radford Neill , Grant Ian M , Honig Lawrence S , Hsiung Ging-Yuek Robin , Huey Edward D , Irwin David , Knopman David S , Kwan Justin Y , Léger Gabriel C , Litvan Irene , Masdeu Joseph C , Mendez Mario F , Onyike Chiadi , Pascual Belen , Pressman Peter , Ritter Aaron , Roberson Erik D , Snyder Allison , Sullivan Anna Campbell , Tartaglia M Carmela , Wint Dylan , Heuer Hilary W , Forsberg Leah K , Boxer Adam L , Rosen Howard J , Boeve Bradley F , Rademakers Rosa 
Published: April 2024

Background and Objectives

TMEM106Bhas been proposed as a modifier of disease risk in FTLD-TDP, particularly inGRNmutation carriers. Furthermore,TMEM106Bhas 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 ofTMEM106Bon gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients.

Methods

Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation inC9orf72, GRN, MAPT, VCP, TBK1, TARDBP,symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for theTMEM106Brs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association betweenTMEM106Band genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations betweenTMEM106Band each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time byTMEM106Bpredictor interactions were fitted.

Results

The minor allele ofTMEM106Brs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume inGRNmutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomaticGRNmutation carriers only. The minor allele ofTMEM106Brs1990622 also associated with greater cognitive scores among allC9orf72mutation carriers and in presymptomaticC9orf72mutation carriers, under the recessive dosage model.

Discussion

We identified associations ofTMEM106Bwith gray matter volume and cognition in the presence ofGRNandC9orf72mutations. This further supportsTMEM106Bas modifier of TDP-43 pathology. The association ofTMEM106Bwith outcomes of interest in presymptomaticGRNandC9orf72mutation carriers could additionally reflect TMEM106B’s impact on divergent pathophysiological changes before the appearance of clinical symptoms.