Short tandem repeat expansions in patients with neurodegenerative dementia

Due to the overlapping clinical features of neurodegenerative dementia (NDD)-including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), accurate diagnosis remains challenging in early stages. Multiple dementias can be caused by short tandem repeat (STR) expansions. However, systematic investigation of known pathogenic STRs in large dementia cohorts remains lacking.

We used ExpansionHunter (EH) to assess 22 neurodegenerative disease-associated STRs in whole-genome sequencing (WGS) data from 950 patients with AD, 222 patients with FTD, 165 patients with DLB, 231 patients with PSP, and 1522 cognitively normal controls. Repeat primed-polymerase chain reaction (RP-PCR) was performed to validate EH calls that exceeded the intermediate thresholds of STR. We also attempted to use ExpansionHunter Denovo (EHDn) to detect C9orf72 expansions missed by EH.

EHDn improved the detection rate of C9orf72 expansions. After sample quality control, 33 PCR-validated pathogenic expansions were identified in nine genes (C9orf72, ATXN8OS, NOTCH2NLC, HTT, FMR1, DMPK, AR, CACNA1A, and PPP2R2B) among 1559 patients with NDD, accounting for 2.12% of cases. Burden-based logistic regression analyses demonstrated that the presence of pathogenic STR expansions was significantly associated with NDD status (OR = 3.57, p = 4.70 × 10^-2). Additionally, intermediate-length TBP alleles showed a nominal enrichment in PSP compared with controls (2.61% vs 0.54%; OR = 6.25, p = 2.00 × 10^-2).

Our findings provide evidence for the clinical pleiotropy of STRs in NDD and their involvement in NDD pathogenesis.

This study was supported by the National Natural Science Foundation of China(U22A20300, 82502244, 823714434, 82071216), the National Key R&D Program of China(2023YFC3603700), STI2030-Major Projects(2021ZD0201803), Outstanding Youth Fund of Hunan Provincial Natural Science Foundation(2024JJ2097), Youth Fund of Hunan Provincial Natural Science Foundation(2025JJ60696), Hunan Health Commission Grant(20232460), Postdoctoral Fellowship Program of CPSF(GZC20233185), China Postdoctoral Science Foundation (2025M772318), and the Scientific Research Program of FuRong Laboratory (2024PT5108).