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Background: Emerging findings indicate that the hypothalamus, the body's principal homeostatic centre, plays a crucial role in modulating cognition, but comprehensive population-based studies are lacking., Methods: We used cross-sectional data from the Rhineland Study (N = 5812, 55.2 ± 13.6 years, 58% women) and the UK Biobank Imaging Study (UKB) (N = 45,076, 64.2 ± 7.7 years, 53% women), two large-scale population-based cohort studies. Volumes of hypothalamic structures were obtained from 3T structural magnetic resonance images through an automatic parcellation procedure (FastSurfer-HypVINN). The standardised cognitive domain scores were derived from extensive neuropsychological test batteries. We employed multivariable linear regression to assess associations of hypothalamic volumes with age, sex and cognitive performance., Findings: In older individuals, volumes of total, anterior and posterior hypothalamus, and mammillary bodies were smaller, while those of medial hypothalamus and tuberal region were larger. Larger medial hypothalamus volume was related to higher cortisol levels in older individuals, providing functional validation. Volumes of all hypothalamic structures were larger in men compared to women. In both sexes, larger volumes of total, anterior and posterior hypothalamus, and mammillary bodies were associated with better domain-specific cognitive performance, whereas larger volumes of medial hypothalamus and tuberal region were associated with worse domain-specific cognitive performance., Interpretation: We found strong age and sex effects on hypothalamic structures, as well as robust associations between these structures and domain-specific cognitive functions. Overall, these findings thus implicate specific hypothalamic subregions as potential therapeutic targets against age-associated cognitive decline., Funding: Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association., Competing Interests: Declaration of interests MMBB reports the following declarations of interests: Co-PI of the project: Cluster of Excellence, “ImmunoSensation2—the immune sensory system” from German Research Funding Foundation (DFG); Grant number: EXC 2151–390873048. Co-PI of the project: Collaborative Research Center 1454 “Metaflammation & Cellular Programming”, German Research Funding Foundation (DFG); Grant number: 43232535. Co-PI of the project: Competence Cluster in Nutrition Research, “Diet—Body—Brain (DietBB2)”, German Ministry for Science and Education (BMBF); Grant number: 01EA1809C. PI of the project: “PreBeDem–Mit Prävention und Behandlung gegen Demenz”, German Ministry for Science and Education (BMBF); Grant number: 01KX2230. Collaborator of the project: “Perceived Stress, inflammation, and the risk of neurodegeneration”, Alzheimer Forschung Initiative (AFI); Grant number: #22017. Member of the Scientific Advisory Board, Central Institute of Mental Health, Mannheim, Germany. Member of the Advisory Board, Leibniz Institute on Aging–Fritz Lipmann Institute. Member of the Executive Board of the Cluster of Excellence ImmunoSensation2. NAA reports the following declarations of interests: European Research Council Grant (Number: 101041677) from the European Union. Profilbildung Grant for the project “InVirtuo 4.0” from Ministry of Culture and Science of the State of North Rhine-Westphalia, Germany. Chair of the Scientific and Bioethics Advisory Committee (2022–2024) and Executive Committee member (2024-present) of the European Huntington's Disease Network. Advisory Board member of the International Society for Neurodegenerative Diseases. Other co-authors report no relevant declarations of interests for this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Reports linking proton pump inhibitors (PPIs) with cognition and dementia show conflicting results, with limited evidence on underlying biological mechanisms. However, existing studies did not investigate brain microstructure, which could provide valuable insights into early structural changes indicative of cognitive decline. Analyses were based on cross-sectional baseline data from the Rhineland Study (n = 7,465; mean age 55.3 ± 13.7 years, range 30-95 years, 56.5% women). Using multivariate linear regression, we investigated associations between PPI use and cognition and brain macro- and microstructural measures (fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter integrity). Analyses were stratified by short-term (< 3 years) and long-term (≥ 3 years) PPI use, with additional age stratification (< 65 years; ≥65 years) for cognitive outcomes. PPI users, especially younger individuals, showed poorer global cognition and working memory. Notably, younger long-term users had worse total memory. PPI use was not associated with brain volume or FA, but both short-term and long-term users showed higher MD in cognitive-related brain regions. Our findings indicate that prolonged PPI use, particularly in younger long-term users, is associated with poorer cognitive performance. Moreover, PPI users showed higher MD, indicating potential white matter integrity disruptions. Further research is needed to ascertain causality and underlying mechanisms behind PPI-related cognitive decline., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Blood-derived microRNAs (miRNAs) are potential candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel miRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking., Methods: We examined blood-derived miRNAs and miRNA co-expression clusters in relation to cognitive domains, structural magnetic resonance imaging measures, target gene expression, and genetic variants in 2869 participants of a population-based cohort., Results: Five previously identified and 14 novel miRNAs were associated with cognitive domains. Eleven of these were also associated with cortical thickness and two with hippocampal volume. Multi-omics analysis showed that certain identified miRNAs were genetically influenced and regulated genes in pathways like neurogenesis and synapse assembly., Discussion: We identified miRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood-based biomarkers or therapeutic targets of subclinical cognitive dysfunction., Highlights: We investigated the association of blood-derived microRNAs with cognitive domains. Five previously identified and 14 novel microRNAs were associated with cognition. Eleven cognition-related microRNAs were also associated with cortical thickness. Identified microRNAs were linked to genes associated with neuronal functions. Results provide putative biomarkers or therapeutic targets of cognitive aging., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)