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Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that...

While clonal hematopoiesis (CH) is associated with protection from Alzheimer's disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.¹ discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition.

Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before...

Senescence-associated secretory phenotype (SASP) in cancer refers to the bioactive secretome produced by senescence cells in the tumor microenvironment, which could be triggered by therapeutics or local stress conditions. Here, we provided a SASP Score in glioblastoma (GBM) with generating a SASP gene panel to identify the potential small molecular candidate targeting SASP in GBM. The effectiveness of this scoring method was firstly interrogated with our in-house GBM cohort and public datasets,...

In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3...

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Aging and cognitive impairment increase the risk for Alzheimer's disease (AD), and growing evidence suggests that transposable elements (TEs) in the genome play a role in aging and AD. The mechanisms of TE dysregulation in this context are unclear, but one possibility is that epigenetic changes, including DNA hypomethylation and/or reduced chromatin structure, underlie age- and AD-related TE activity. Therefore, the purpose of the present study was to generate a resource for studying TE...

The weight-adjusted waist index (WWI) is a novel anthropometric measure designed to better reflect central obesity than traditional indices such as body mass index and waist circumference (WC). This study examined the prospective association between WWI and cardiometabolic multimorbidity (CMM) and evaluated its predictive utility. We included 3,348 participants (mean age 63 years; 45.1% male) from the English Longitudinal Study of Ageing who were free from hypertension, coronary heart disease,...

People with dementia have complex medical, functional, and social needs and experience highly variable care quality and outcomes across the U.S. health care system. Community-based physicians, nurse practitioners, and physician assistants serve critical roles in diagnosing and managing dementia, yet little is known about this workforce and factors contributing to variability in care. The National Dementia Workforce Study (NDWS), sponsored by the National Institute on Aging, is conducting large...

Researchers worried by plan giving political appointees more control over where funding goes

CONCLUSION: Older adults who regularly play cards/mahjong have a lower risk of all-cause mortality, especially in the oldest groups. These leisure activities may promote longevity, but further research is needed to understand why.

Alzheimer's disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing (snRNA-seq) from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia, reconstructing circadian expression profiles across cell types. Although core clock rhythms were preserved in AD, many cell-type-specific circadian outputs were disrupted....