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To the editor: With great interest we read the study of Cochran et al. in which they report significantly higher frequencies of rare loss-of-function variants in TET2 in individuals with Alzheimer disease (AD) or frontotemporal dementia (FTD) as compared to healthy individuals.1 As genotyping was performed by sequencing blood-derived DNA obtained from predominantly elderly individuals, we would like to discuss these results in view of recent developments in age-related clonal hematopoiesis (ARCH) research,2,3 which is also known as clonal hematopoiesis of indeterminate potential (CHIP).
Hematopoietic stem cells (HSCs) continuously accumulate somatic mutations during aging.4 ARCH arises when an HSC acquires a somatic mutation that confers a competitive survival advantage leading to its gradual expansion. With this competitive advantage, the mutated HSC will progressively increase its contribution to peripheral blood production. When the HSC “clone” contributes to a high enough fraction of peripheral blood cells, the somatic mutations it has acquired over time become detectable by conventional protocols for next-generation sequencing. We previously reported that at extreme ages (111 and 115 years), up to ∼70%–75% of all peripheral blood cells were generated by one HSC clone and its subclones.5,6
ARCH is typically instigated by somatic mutations in genes previously linked with myeloid neoplasms, most notably in genes encoding the epigenetic regulators TET2, DNMT3A, and ASXL1.7, 8, 9, 10 In particular for somatic mutations in TET2, a strong correlation between chronological age and detectable carriership has been reported, of which a considerable part can be characterized as rare loss-of-function mutations.7,8 Hence, given the nature of the study sample used by Cochran et al.,1 i.e., blood tissue obtained from elderly individuals, it is reassuring, though not surprising, that the authors identified considerable numbers of rare loss-of-function mutations in TET2.
In light of the potential somatic origin of TET2 mutations, our concern was raised when we noted the disparity in age between the cohorts contrasted by Cochran et al.1 for the discovery phase of their study. The authors compared relatively old individuals with AD and FTD (median age 59 and 65 years) with younger healthy individuals (median age 40 years) and find that mutations in TET2 associate with a 29-fold increased risk of AD/FTD (OR: 28.9, 95%CI 4.5–1,200, p = 4.9 × 10−7; AD subjects: n = 227; FTD subjects: n = 208; healthy control subjects n = 671). In comparison, a previous large-scale sequencing study conducted by Jaiswal et al.7 reported that detectable somatic mutations in TET2, DNMT3A, and ASXL1 were extremely rare in the blood of individuals aged <40 years, while nearly 10% of the individuals aged between 60 and 69 years were reported to carry detectable somatic mutations in these genes. In accordance, in the replication analysis conducted by Cochran et al.,1 in which the age of the individuals with AD and FTD (median age 79 and 76 years) more closely resembled the age of healthy control subjects (median age 74 years), the authors reported only a 1.7-fold increased AD/FTD risk (OR = 1.7, 95%CI 1.2–2.6, p = 6.1 × 10−3; AD subjects n = 2,530; FTD subjects n = 319; healthy control subjects n = 2,457). Hence, the previously reported age-associated increase of carriers with somatic mutations in TET2 could imply that the reported AD association in the discovery phase reported by Cochran et al.1 was confounded by the differences in age between the AD/FTD subjects and the healthy individuals.
To conclude, we advocate utmost caution when interpreting the results of sequencing data assayed on the blood of elderly individuals, especially when considering rare mutations in genes previously linked to myeloid clonal expansions, such as TET2, DNMT3A, and ASXL1. In such events, it would be prudent to provide additional evidence supporting either the somatic or germline nature of these variants, to substantiate any observed association with age or disease.
References
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