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Related Concept Videos

Bone Disorders01:29

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Aging and its effect on bone remodeling is the most common cause of bone disorders. In young and healthy people, bone deposition and resorption happen at an equal rate to maintain optimal bone health.
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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
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Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
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Lethal Alleles02:41

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Agouti: A Lethal Allele
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Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone.

Charles A Schurman1, Gurcharan Kaur2, Serra Kaya2

  • 1Buck Institute for Research on Aging, Novato, California, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 13, 2026
PubMed
Summary

Alzheimer's disease (AD) is linked to bone fractures. This study found Apolipoprotein E4 (APOE4) impairs osteocyte function, causing bone fragility in females, suggesting a link between cognitive decline and skeletal health.

Keywords:
Alzheimer's diseaseagingapolipoprotein eboneosteocytes

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Area of Science:

  • Neuroscience and Skeletal Biology
  • Molecular and Genetic Mechanisms of Aging

Background:

  • Alzheimer's disease (AD) patients exhibit increased fracture risk, and osteoporosis predicts AD.
  • The molecular mechanisms connecting cognitive decline and skeletal deterioration are poorly understood.
  • Osteocytes, bone cells, are implicated in skeletal health and may link to neurodegeneration.

Purpose of the Study:

  • To investigate the role of apolipoprotein E (APOE) alleles in bone health and their connection to neurodegeneration.
  • To determine the sex-specific effects of different human APOE alleles on bone and brain health.
  • To identify molecular targets for early diagnosis and treatment of age-related cognitive and skeletal issues.

Main Methods:

  • Proteomic analysis of cortical bone from aged mice.
  • Utilized humanized APOE2, APOE3, and APOE4 knock-in mouse models.
  • Analyzed bone and hippocampus tissue from the same animals for transcriptomic and proteomic changes.

Main Results:

  • Cortical bone from aged mice showed enrichment of neurodegeneration-associated proteins, including APOE.
  • APOE4 significantly altered the bone transcriptome and proteome in a sex-specific manner, more pronounced in females.
  • APOE4 induced bone fragility in female mice by impairing osteocyte perilacunocanalicular remodeling, independent of structural changes.

Conclusions:

  • APOE4 is identified as a key molecular driver of early osteocyte dysfunction and reduced bone quality, particularly in females.
  • These findings suggest a direct link between APOE genotype, osteocyte health, and bone fragility.
  • Osteocytes represent a potential target for early diagnosis of cognitive impairment and therapeutic intervention for bone fragility in aging females.