In a recent study published in Nature Medicine, researchers tested whether clonal hematopoiesis of indeterminate potential (CHIP) status was associated with Alzheimer's disease (AD)-related pathological changes, e.g., clinical dementia.
Study: Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Image Credit: SewCreamStudio/Shutterstock.com
Around 10 to 30% of people older than 70 show an age-related expansion of hematopoietic stem cells (HSCs) called CHIP, as detected by deoxyribonucleic acid (DNA) sequencing from peripheral blood or bone marrow cells.
Studies in mice have also shown a potential causal link between CHIP and increased risk of atherosclerotic cardiovascular disease (CVD) and death, as well as hematological neoplasms such as acute myeloid leukemia.
The functional alterations in macrophage-like hematopoietic brain cells called microglia (MG) are a primary driver of AD risk, as assessed by genome-wide association studies (GWAS).
Because CHIP-associated truncating or loss-of-function mutations influence the function of myeloid cells, the researchers tested whether CHIP was associated with the risk of AD.
About the study
In the present study, researchers used blood-derived whole-genome sequencing (WGS) data from two cohorts of the Trans-omics for Precision Medicine (TOPMed) project, the Framingham Heart Study (FHS) and the Cardiovascular Health Study (CHS), to identify CHIP variants.
The discovery set comprised blood DNA sequencing data from 1,362 and 4,368 individuals with and without AD, respectively. Since FHS and CHS were prospective studies with data on incident AD diagnosis, in this study, the researchers used time-to-event competing risks regression (CRR) models used to derive the CHIP/AD association.
Also, the team knew the age of all blood donors at the time of the blood draw, their sex, and the apolipoprotein E (APOE) genotype as covariates for the study model.
Notably, all individuals diagnosed with AD met the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) criteria for definite, probable, or possible AD.
In most cases, they made an AD diagnosis before the blood draw; however, even for prevalent and incident AD cases, the diagnosis was made within five years of blood sample collection. An association between CHIP and APOE genotype could have confounded the study results; hence, the researchers also determined the prevalence of APOE genotypes stratified by CHIP status in TOPMed, which used lower-depth WGS.
The strongest genetic risk factor for AD is the APOE genotype, with APOE ε4 conferring higher risk than the APOE ε3 allele, while APOE ε2 provides protection.
Next, the researchers replicated the finding using the AD Sequencing Project (ADSP) data to maximize the power to detect CHIP associations. To this end, they also sequenced 1,776 samples from the DNA derived from the brain.
The prevalence of incident AD dementia among FHS and CHS participants was 92/2,437 and 166/743. Compared to FHS, CHS had more female participants with, on average, more age, which led to a higher rate of AD dementia in CHS vs. FHS (22.3% vs. 3.8%) in the follow-up period.
Mendelian randomization (MR) analyses helped the researchers draw causal inferences between inherited genetic polymorphisms influencing the risk of a trait and its association with a disease (in this case, CHIP and AD).
The team performed a one- and two-sample and a two-sample MR using 24 and 36 CHIP-associated polymorphisms for the risk of AD as the instruments and the CHIP as an outcome.
In the former, they found that a higher genetic risk of CHIP was associated with reduced odds of AD and no evidence of a causal effect in this direction in the latter, with respective ORs of 0.90 and 0.97 per 1 log-odds increase in the risk of CHIP, P=3.3 × 10−4, 0.26 using the weighted median estimator.
In CHS and FHS cohorts, the CHIP-associated decrement in risk for AD dementia was of a similar magnitude among people with the APOE ε3ε3 genotype or with an APOE ε4 allele but not in those with APOE ε2ε2 or APOE ε2ε3 genotypes.
The researchers presented evidence favoring the role of mutant, bone marrow-derived cells in protecting against the risk of progression to AD. First, they showed that CHIP carriers had a lower risk of AD dementia (odds ratio (OR) = 0.64) in multiple cohorts, an effect not attributable to survival bias.
Accordingly, seven of eight CHIP carriers had mutations in blood and a microglia-enriched fraction of the brain.
Likewise, six CHIP carriers had mutated cells that comprised a large proportion of the microglial pool in the examined samples, i.e., the first preliminary evidence of brain infiltration by bone marrow-derived mutant cells, which had a microglial-like phenotype.
Second, MR analyses supported a surprising inverse causal association between CHIP and AD dementia.
A higher score on neuritic plaque density and neurofibrillary tangle distribution indicates a more extensive accumulation of pathologic features during brain autopsy.
In this study, thirdly, the researchers demonstrated that CHIP modulated the pathophysiology of AD. For instance, it lowered the levels of neuritic plaques and neurofibrillary tangles in those with no AD-related dementia.
Thus, in ADSP participants, AD neuropathologic change (ADNC) was lower in CHIP than non-CHIP carriers with the APOE ε3ε3 genotype or an APOE ε4 allele; however, the same did not happen in those with APOE ε2ε2\ε2ε3 genotypes.
The degree of protection from AD dementia in CHIP carriers was comparable to those carrying an APOE ε2 allele, the inherited allele conferring the highest protection against AD.
Surprisingly, CHIP carriers had a high proportion of mutant microglia-like cells in their brains, as assessed via amplicon sequencing of nuclei from samples with sorted and unsorted brain fractions.
Therapies to effectively slow down or halt AD progression are lacking. Based on the study findings, the authors predicted that a more extensive characterization of phenotypic variations between mutant and wild-type microglial cells might provide much-needed insights into how to halt AD progression.