Ann Lab Med.  2024 Nov;44(6):576-580. 10.3343/alm.2024.0086.

Association Between Clonal Hematopoiesis of Indeterminate Potential and Brain β-Amyloid Deposition in Korean Patients With Cognitive Impairment

• Yun J
• Youn YC
• Kim HR

• KMID: 2560805
• DOI: http://doi.org/10.3343/alm.2024.0086

Abstract

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and β-amyloid (Aβ) deposition in the brain, which causes Alzheimer’s disease. We aimed to investigate the potential role of CHIP in brain Aβ deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aβ positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aβ deposition, mutations in DNMT3A and the C:G > T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aβ deposition. As both CHIP and brain Aβ deposition are associated with aging, further research is required to elucidate their possible interplay.

Keyword

Alzheimer’s disease; β-Amyloid protein; Clonal hematopoiesis of indeterminate potential; Next-generation sequencing; Positron emission tomography

Figure

• 

  Fig. 1 Characteristics of CHIP variants in the Aβ-positive (N=43) and Aβ-negative (N=15) groups and forest plot of multivariate regression for the risk of brain Aβ deposition. (A) CHIP prevalence according to age. Bars indicate CHIP prevalence in different age groups. The line graph represents the cumulative prevalence of CHIP across the age groups. The absolute number of patients with CHIP and the total number of patients in each age group are displayed at the base of the graph. (B) CHIP prevalence according to gene. (C) Proportions of variant types in CHIP variants. (D) Percentages of different SNVs in CHIP variants. (E) VAFs of CHIP variants detected in the Aβ-positive and Aβ-negative groups. (F) Forest plot of multivariate logistic regression for the risk of brain Aβ deposition. Covariates included age, sex, presence of CHIP, and presence of the APOE ε4 allele. Abbreviations: Aβ, β-amyloid; CHIP, clonal hematopoiesis of indeterminate potential; CI, confidence interval; OR, odds ratio; SNV, single-nucleotide variant; VAF, variant allele frequency.

Reference

References

1. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. 2015; Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 126:9–16. DOI: 10.1182/blood-2015-03-631747. PMID: 25931582. PMCID: PMC4624443.

2. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. 2014; Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 371:2488–98. DOI: 10.1056/NEJMoa1408617. PMID: 25426837. PMCID: PMC4306669.

3. Jaiswal S, Libby P. 2020; Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol. 17:137–44. DOI: 10.1038/s41569-019-0247-5. PMID: 31406340. PMCID: PMC9448847.

4. Kim M, Kim JJ, Lee ST, Shim Y, Lee H, Bae S, et al. 2024; Association between aortic valve sclerosis and clonal hematopoiesis of indeterminate potential. Ann Lab Med. 44:279–88. DOI: 10.3343/alm.2023.0268. PMID: 38205526. PMCID: PMC10813825.

5. Mas-Peiro S, Hoffmann J, Fichtlscherer S, Dorsheimer L, Rieger MA, Dimmeler S, et al. 2020; Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur Heart J. 41:933–9. DOI: 10.1093/eurheartj/ehz591. PMID: 31504400. PMCID: PMC7033916.

6. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Ecke A, Abou-El-Ardat K, et al. 2019; Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4:25–33. DOI: 10.1001/jamacardio.2018.3965. PMID: 30566180. PMCID: PMC6439691.

7. Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lépine G, et al. 2017; DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 130:753–62. DOI: 10.1182/blood-2017-04-777029. PMID: 28655780.

8. Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. 2017; Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 130:742–52. DOI: 10.1182/blood-2017-02-769869. PMID: 28483762. PMCID: PMC5553576.

9. Savola P, Lundgren S, Keränen MAI, Almusa H, Ellonen P, Leirisalo-Repo M, et al. 2018; Clonal hematopoiesis in patients with rheumatoid arthritis. Blood Cancer J. 8:69. DOI: 10.1038/s41408-018-0107-2. PMID: 30061683. PMCID: PMC6066480.

10. Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, et al. 2023; Clonal hematopoiesis is associated with protection from Alzheimer's disease. Nat Med. 29:1662–70. DOI: 10.1038/s41591-023-02397-2. PMID: 37322115. PMCID: PMC10353941.

11. U.S. Food & Drug Administration. Drugs@FDA: FDA-approved drugs. Amyvid/labels for NDA202008. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf. Updated on April 2012.

12. U.S. Food & Drug Administration. Drugs@FDA: FDA-approved drugs. Neuraceq/labels for NDA204677. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf. Updated on March 2014.

13. U.S. Food & Drug Administration. Drugs@FDA: FDA-approved drugs. Vizamyl/labels for NDA203137. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203137s000lbl.pdf. Updated on October 2013.

14. Sabri O, Seibyl J, Rowe C, Barthel H. 2015; Beta-amyloid imaging with florbetaben. Clin Transl Imaging. 3:13–26. DOI: 10.1007/s40336-015-0102-6. PMID: 25741488. PMCID: PMC4339690.

15. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, et al. 2014; A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 10:844–52. DOI: 10.1016/j.jalz.2014.01.001. PMID: 24798886. PMCID: PMC4317324.

16. Petersen RC. 2011; Clinical practice. Mild cognitive impairment. N Engl J Med. 364:2227–34. DOI: 10.1056/NEJMcp0910237. PMID: 21651394.

17. American Psychiatric Association. 2022. Diagnostic and statistical manual of mental disorders. 5th ed., text revision. American Psychiatric Association;Washington, DC: DOI: 10.1176/appi.books.9780890425787.

18. Bolton KL, Koh Y, Foote MB, Im H, Jee J, Sun CH, et al. 2021; Clonal hematopoiesis is associated with risk of severe Covid-19. Nat Commun. 12:5975. DOI: 10.1038/s41467-021-26138-6. PMID: 34645798. PMCID: PMC8514469. PMID: 3cb397d07d014cc5b6487816e9888d83.

19. Moon I, Kong MG, Ji YS, Kim SH, Park SK, Suh J, et al. 2023; Clinical, mutational, and transcriptomic characteristics in elderly Korean individuals with clonal hematopoiesis driver mutations. Ann Lab Med. 43:145–52. DOI: 10.3343/alm.2023.43.2.145. PMID: 36281508. PMCID: PMC9618905.

20. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. 2013; Signatures of mutational processes in human cancer. Nature. 500:415–21. DOI: 10.1038/nature12477. PMID: 23945592. PMCID: PMC3776390.