Loss of Y chromosome in Alzheimer’s patients co-occurs with somatic mutations beyond CHIP drivers
Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events with implications for aging and Alzheimer disease (AD). LOY is linked to increased AD risk, whereas CHIP may be protective, and their co-occurrence remains unclear. We conducted whole-exome sequencing of CD4<sup>+</sup> T cells, NK cells, and myeloid cells from AD patients and controls exhibiting LOY or retention of Y chromosome. We identified 39 variants in known myeloid and lymphoid driver genes, with up to 35% co-occurring with LOY in the same clone. In addition, we detected 192 unknown drivers of clonal hematopoiesis, enriched in AD-LOY individuals (odds ratio 4.8, <i>P</i> = 0.041). In myeloid cells, total driver burden correlated with LOY (ρ = 0.52, <i>P</i> = 0.00041). These results indicate that LOY is a primary driver of clonal hematopoiesis in AD, seeding myeloid clones that accumulate unknown driver variants, whereas most canonical CHIP mutations arise independently. Our study reveals distinct, partially overlapping clonal architectures for LOY and CHIP and highlights LOY-driven myeloid expansion as a contributor to AD pathogenesis.
Authors
- Maciej Siedlar (ORCID: https://orcid.org/0000-0002-3904-5412)
- Martin Ingelsson (ORCID: https://orcid.org/0000-0001-5466-8370)
- Monika Horbacz (ORCID: https://orcid.org/0000-0003-1644-2957)
- Ulana Juhas (ORCID: https://orcid.org/0000-0001-8393-5845)
- Edyta Rychlicka-Buniowska (ORCID: https://orcid.org/0000-0001-8050-2489)
- Natalia H. Filipowicz (ORCID: https://orcid.org/0000-0002-9673-2649)
- Karolina Bukowska-Straková (ORCID: https://orcid.org/0000-0001-9181-439X)
- Lena Kilander (ORCID: https://orcid.org/0000-0001-6600-9110)
- Bożena Bruhn‐Olszewska (ORCID: https://orcid.org/0000-0003-2141-0247)
- Arkadiusz Piotrowski (ORCID: https://orcid.org/0000-0002-0823-0607)
- Hanna Davies (ORCID: https://orcid.org/0000-0002-6289-3815)
- Jarosław Baran (ORCID: https://orcid.org/0000-0003-1787-1972)
- Jan Piotr Dumanski (ORCID: https://orcid.org/0000-0002-1489-1452)
- Alicja Klich‐Rączka (ORCID: https://orcid.org/0000-0002-9311-0078)
- Kazimierz Węglarczyk (ORCID: https://orcid.org/0000-0001-5255-5436)
- Daniil Sarkisyan (ORCID: https://orcid.org/0000-0002-2451-4386)
- Kinga Drężek-Chyła
- Magdalena Wójcik-Zalewska
- Mikołaj Koszyński
- Janusz Ryś
Institutions
- Uppsala University (SE)
- Jagiellonian University (PL)
- University Health Network (CA)
- Science for Life Laboratory (SE)
- Occupational Cancer Research Centre (CA)
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- Ontario Brain Institute (CA)
- Gdańsk Medical University (PL)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2025-11-19
- DOI
- https://doi.org/10.26508/lsa.202503533
- Citations
- 2
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.33