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000283071 0247_ $$2doi$$a10.1002/alz70856_103532
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000283071 0247_ $$2ISSN$$a1552-5260
000283071 0247_ $$2ISSN$$a1552-5279
000283071 037__ $$aDZNE-2025-01478
000283071 041__ $$aEnglish
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000283071 1001_ $$aPasternak, Maurice$$b0
000283071 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283071 245__ $$aTMEM106B modulates disease severity in genetic frontotemporal dementia phenoconverters
000283071 260__ $$c2025
000283071 3367_ $$0PUB:(DE-HGF)1$$2PUB:(DE-HGF)$$aAbstract$$babstract$$mabstract$$s1767011723_31206
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000283071 520__ $$aA common variant within TMEM106B is associated with risk for Frontotemporal Lobar Degeneration-Tar DNA binding Protein-43 (FTLD-TDP). A recent study has shown that the minor allele G of TMEM106B-rs1990622 confers protection against FTLD-TDP in symptomatic mutation carriers through reductions in NfL serum levels, brain atrophy, and cognitive decline. It is unknown whether this protective effect is present in phenoconverters of the disease.We included 518 participants from the GENetic Frontotemporal dementia Initiative (GENFI), which recruits genetic FTD cases and their family members, both carriers and non-carriers of FTD mutations. Of these, 21 were phenoconverters, 209 were non-carrier controls, 70 were presymptomatic and 45 symptomatic C9orf72 carriers, 92 presymptomatic and 29 symptomatic GRN carriers, and 39 presymptomatic and 13 symptomatic MAPT carriers. Effects of interaction between TMEM106B-rs1990622 and phenoconverter status were examined using mixed effects models, with a random effects structure featuring subjects nested within families and fixed effects for age at baseline and sex. Serum neurofilament light chain (NfL) was measured using the Simoa platform. Cognitive assessment included the Mini-Mental State Examination (MMSE), tests of attention, processing speed, executive function, and language, as well as the Cambridge Behavioural Inventory (CBI), with mixed effects also including years of education as a covariate. Brain volumetry was assessed using T1-weighted MRI and these mixed effect models also included additional covariates of total intracranial volume and scanner site.In phenoconverters, each copy of the protective allele G was associated with a significant reduction in the rate of serum NfL accumulation (-5.33 pg/mL/year; p = 7.79 × 10-9). Structural imaging analyses revealed decreased rates of atrophy in fronto-orbital regions and the insular cortex among protective allele carriers. Cognitive trajectories showed significantly slower decline across multiple domains including general cognition (MMSE; p = 0.003), attention and processing speed (p = 2.2 × 10-4), executive function (p = 2.6 × 10-7), language (p = 2.9 × 10-3), and behavioural symptoms as measured by CBI (p = 9.5 × 10-3).The TMEM106B-rs1990622 protective variant significantly modulates disease progression in genetic FTD phenoconverters across multiple markers, suggesting its potential as a therapeutic target.
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000283071 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000283071 650_7 $$2NLM Chemicals$$aBiomarkers
000283071 650_7 $$2NLM Chemicals$$aTMEM106B protein, human
000283071 650_7 $$2NLM Chemicals$$aMembrane Proteins
000283071 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000283071 650_7 $$2NLM Chemicals$$atau Proteins
000283071 650_7 $$2NLM Chemicals$$aProgranulins
000283071 650_7 $$2NLM Chemicals$$aNeurofilament Proteins
000283071 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000283071 650_7 $$2NLM Chemicals$$aMAPT protein, human
000283071 650_7 $$2NLM Chemicals$$aneurofilament protein L
000283071 650_2 $$2MeSH$$aHumans
000283071 650_2 $$2MeSH$$aMale
000283071 650_2 $$2MeSH$$aFemale
000283071 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000283071 650_2 $$2MeSH$$aMiddle Aged
000283071 650_2 $$2MeSH$$aBiomarkers: blood
000283071 650_2 $$2MeSH$$aMembrane Proteins: genetics
000283071 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000283071 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000283071 650_2 $$2MeSH$$aAged
000283071 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000283071 650_2 $$2MeSH$$aBrain: pathology
000283071 650_2 $$2MeSH$$aBrain: diagnostic imaging
000283071 650_2 $$2MeSH$$atau Proteins: genetics
000283071 650_2 $$2MeSH$$aProgranulins: genetics
000283071 650_2 $$2MeSH$$aNeurofilament Proteins: blood
000283071 650_2 $$2MeSH$$aMutation: genetics
000283071 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000283071 650_2 $$2MeSH$$aAtrophy
000283071 7001_ $$aMirza, Saira S$$b1
000283071 7001_ $$aPaterson, Andrew D$$b2
000283071 7001_ $$aTartaglia, Carmela$$b3
000283071 7001_ $$aMitchell, Sara$$b4
000283071 7001_ $$aBlack, Sandra E$$b5
000283071 7001_ $$aFreedman, Morris$$b6
000283071 7001_ $$aTang-Wai, David F$$b7
000283071 7001_ $$aRogaeva, Ekaterina$$b8
000283071 7001_ $$aCash, David M$$b9
000283071 7001_ $$aBocchetta, Martina$$b10
000283071 7001_ $$avan Swieten, John$$b11
000283071 7001_ $$aLaforce, Robert$$b12
000283071 7001_ $$aTagliavini, Fabrizio$$b13
000283071 7001_ $$aBorroni, Barbara$$b14
000283071 7001_ $$aGalimberti, Daniela$$b15
000283071 7001_ $$aRowe, James B$$b16
000283071 7001_ $$aGraff, Caroline$$b17
000283071 7001_ $$aFinger, Elizabeth$$b18
000283071 7001_ $$aSorbi, Sandro$$b19
000283071 7001_ $$ade Mendonça, Alexandre$$b20
000283071 7001_ $$aButler, Christopher$$b21
000283071 7001_ $$aGerhard, Alexander$$b22
000283071 7001_ $$aSánchez-Valle, Raquel$$b23
000283071 7001_ $$aMoreno, Fermin$$b24
000283071 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b25$$udzne
000283071 7001_ $$aVandenberghe, Rik$$b26
000283071 7001_ $$aDucharme, Simon$$b27
000283071 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b28$$udzne
000283071 7001_ $$aOtto, Markus$$b29
000283071 7001_ $$aSantana, Isabel$$b30
000283071 7001_ $$aRohrer, Jonathan D$$b31
000283071 7001_ $$aMasellis, Mario$$b32
000283071 7001_ $$aGENFI$$b33$$eCollaboration Author
000283071 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70856_103532$$gVol. 21 Suppl 2, no. Suppl 2, p. e103532$$nSuppl 2$$pe103532$$tAlzheimer's and dementia$$v21 Suppl 2$$x1552-5260$$y2025
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