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Hidden confounding biases hinder identifying causal protein biomarkers for Alzheimer's disease in non-randomized studies. While Mendelian randomization (MR) can mitigate these biases using protein quantitative trait loci (pQTLs) as instrumental variables, some pQTLs violate core assumptions, leading to biased conclusions. To address this, we propose MR-SPI, a novel MR method that selects valid pQTL instruments using Leo Tolstoy's Anna Karenina principle and performs robust post-selection...

Alzheimer's disease, a progressive neurodegenerative pathology, is characterized by the accumulation of Amyloid-β plaques in the brain. Lecanemab (BAN2401), a humanized IgG1 monoclonal antibody, binds with high affinity to Amyloid-β protofibrils. It is the first monoclonal antibody for Alzheimer's disease to receive full FDA approval. This systematic review, conducted meticulously, examines the current use and safety of Lecanemab in treating Alzheimer's disease. We screened literature from...

DLG3, also known as Synapse-associated protein 102 (SAP102), is essential for the organization and plasticity of excitatory synapses within the central nervous system (CNS). It plays a critical role in clustering and moving key components necessary for learning and memory processes. Mutations in the DLG3 gene, which result in truncated SAP102 proteins, have been associated with a range of neurological disorders, including X-linked intellectual disability (XLID), autism spectrum disorders (ASD),...

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The role of microglia in the amyloid cascade of Alzheimer's disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay...

Connectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity...

The locus coeruleus (LC) is among the first brain structures impacted by Alzheimer's disease (AD), and noradrenergic denervation may contribute to early neurovascular dysfunction in AD. Mechanistic links between the LC and cerebral perfusion have been demonstrated in rodents, but there have been no similar studies in aging humans. Community-dwelling older adults with no history of stroke or dementia (N=66) underwent structural (T1-MPRAGE; T1-FSE) and perfusion (resting pCASL) MRI. Plasma AD...

Carling et al. report that late-onset Alzheimer's disease (LOAD) risk alleles drive cellular senescence, a hallmark of aging, in a tau- and sex-dependent manner. Mechanistic insights into interactions among genetic risk, biological aging, and sex differences in LOAD are presented.

During the last few decades, life expectancy has increased worldwide along with the prevalence of several age-related diseases. Among aging pathways, cellular senescence and chronic inflammation (or "inflammaging") appear to be connected to gut homeostasis and dysbiosis of the microbiome. Cellular senescence is a state of essentially irreversible cell cycle arrest that occurs in response to stress. Although senescent cells (SC) remain metabolically active, they do not proliferate and can secrete...

CONCLUSIONS AND IMPLICATIONS: The results of this study revealed that better indoor environments in terms of cooling, heating, acoustics, odor, and lighting could potentially delay nursing home admission. Integrating the assessments of these indoor environmental factors into policy frameworks may enhance the effectiveness of long-term care strategies and promote aging.

Global average life expectancy has steadily increased over the last several decades and is projected to reach ~ 77 years by 2050. As it stands, the number of people > 60 years currently outnumbers children younger than 5 years, and by 2050, it is anticipated that the global population of people aged > 60 years will double, surpassing 2.1 billion. This demographic shift in our population is expected to have substantial consequences on health services globally due to the disease burden associated...

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation...

Plasma membrane protein degradation and recycling are regulated by the endolysosomal system, wherein endocytic vesicles bud from the plasma membrane into the cytoplasm and mature into endosomes and then degradative lysosomes. As such, the endolysosomal system plays a critical role in determining the abundance of proteins on the cell surface and influencing cellular identity and function. Highly polarized cells, like neurons, rely on the endolysosomal system for axonal and dendritic...

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models in vivo and in vitro. ISG15 overexpression in cells...

Amyloid β (Aβ) forms aggregates in the Alzheimer's disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of...

Stroke risk increases with chronological age, but the relationship with biological age (BA) acceleration is poorly understood. We aimed to examine the association between BA acceleration and incident stroke and its subtypes, explore the modifying effects on genetic susceptibility, and assess how BA acceleration mediates the effect of behavior score. We studied 253,932 UK Biobank participants and computed two BA measures (Klemera-Doubal Method [KDM], Phenotypic Age [PhenoAge]), with BA...

Ageing is associated with a decline in the number and fitness of adult stem cells^(1,2). Ageing-associated loss of stemness is posited to suppress tumorigenesis^(3,4), but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered^(5,6) mouse models and primary cells^(5,6) to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by...

Dry mouth results from decreased saliva secretion due to aging or drug side effects. Decreased saliva secretion causes dryness in the oral cavity that makes swallowing difficult and increases the risk of aspiration pneumonia. There are few fundamental treatments for dry mouth. Here we investigated whether treatment of old mice with nicotinamide mononucleotide (NMN) improved factors associated with dry mouth. Young (16-week-old) and old (113-week-old) male mice were treated subcutaneously with...

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