Work

The shared genetic architecture of the TDP‐43 spectrum: Bridging clinical FTLD and neuropathological endophenotypes

Year: 2026

Type: review

Abstract: INTRODUCTION TAR DNA‐binding protein 43 (TDP‐43) proteinopathies encompass a spectrum of conditions including frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP), limbic‐predominant age‐related TDP‐43 encephalopathy (LATE‐NC), and hippocampal sclerosis (HS). FTLD‐TDP is further classified into several pathological subtypes (A, B, C, D, and E), which differ in the distribution and morphology of TDP‐43 inclusions. Clinical and neuropathological variability across FTLD, FTLD‐TDP, LATE‐NC, and HS has hindered the translatability of genetic discoveries between clinical and pathological disease categories. By leveraging their genetic convergence, we aimed to refine effect size estimates and uncover variants that influence the TDP‐43 spectrum. METHODS We conducted an inverse variance weighted fixed‐effects meta‐analysis using METAL, combining neuropathological datasets (FTLD‐TDP subtypes: A [ N cases = 193], B [ N cases = 288], C [ N cases = 467], and controls [ N controls = 3153]), HS ( N cases = 751; N controls = 6413), or LATE‐NC ( N cases = 1325; N controls = 1787). Additionally, we performed a random‐effects meta‐analysis that included clinically diagnosed FTLD ( N cases = 4685; N controls = 15,308) and neuropathological datasets. Moreover, we performed colocalization, fine‐mapping, and functional annotation analyses. RESULTS Three loci reached genome‐wide significance. The GRN (rs5848) and TMEM106B (rs3807865) loci were associated with FTLD‐TDP (A and B), LATE‐NC, and HS. Colocalization and fine‐mapping analyses supported genetic signals at GRN and TMEM106B loci, while functional annotation suggested that rs3807865 and rs3807866 influence regulatory activity and TMEM106B expression in glial cells. MAPT demonstrated association across all combinations of TDP‐43 proteinopathies (except FTLD‐TDP B and C) and clinical FTLD, specifically the H1c haplotype. DISCUSSION Our results extend the known role of GRN and TMEM106B beyond FTLD‐TDP subtype A, while MAPT involvement suggests a role beyond traditional tauopathies.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.71943