bioRxiv Science⌕ Search

Biology subjects

Bali, D.

Publications and source records attributed to Bali, D..

2 recordsLinked to original sources

Stable episodic memory and high education do not influence the rate of Alzheimer's disease pathology as measured by plasma p-tau217

Alzheimers disease (AD) neuropathological changes can be detected with blood-based biomarkers during the long preclinical phase that precedes clinical diagnosis. Tau phosphorylated at threonine 217 (p-tau217) has been found to closely correlate with brain A{beta} burden. A recent large-scale cross-sectional study showed elevated p-tau217 concentrations in older individuals (Aarsland et al., 2025). This increase was higher in those with AD dementia and mild cognitive impairment (MCI), and lower in those with intact cognition and higher educational attainment. Thus, intact cognition and higher education may be associated with lower levels of AD neuropathological changes. Here we tested this hypothesis using longitudinal data from the population-based Betula study (n=1005; 1531 samples). The results revealed increases with increasing age over 10 years in p-tau217, where individuals with accelerated episodic-memory decline had the strongest increase. There were no differences in p-tau217 trajectories between individuals with lower or higher education or with well-maintained or age-typical decline in episodic memory. The lack of association with education was further replicated in the independent BioFINDER-2 cohort. These findings underscore the value of plasma p-tau217 for detecting early pathological changes in population-based settings but provide no support that individuals with well-maintained episodic memory or high educational attainment are spared from neuropathological changes.

neuroscience↗

Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood

Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studied in vitro and in animal models, but less is known about the mechanisms in vivo in humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to the PPM1H gene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, and PPM1H shRNA- knockdown increased CD34+ and CD34+90+ cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulation in vivo in humans, and identifying PPM1H as a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.

genomics↗