Study unlocks genetic secrets in APOEε4 carriers that could defend against Alzheimer's

NewsGuard 100/100 Score

In a recent study published in the journal Acta Neuropathologica, researchers identified protective genetic variations in APOEε4 carriers against Alzheimer's disease (AD) using whole-genome sequencing  (WGS) and pathway analysis.

Schematic abstract for the protective effect of FN1 variants. Study: Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s diseaseSchematic abstract for the protective effect of FN1 variants. Study: Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease

Background 

AD is characterized by progressive memory loss and cognitive decline, often without symptoms for an extended period. At autopsy, AD brains typically reveal β-amyloid plaques and neurofibrillary tangles of tau protein. Despite advances in understanding, AD remains largely untreatable, with existing drugs providing minimal relief, primarily due to incomplete knowledge of its pathological mechanisms. Genetic factors, notably the APOEε4 allele, significantly influence the disease's variability across individuals and ethnic groups. This allele's effects vary, with some carriers experiencing milder or delayed symptoms, underscoring the need for further research to explain these complex genetic interactions and develop better treatments and diagnostics.

About the study 

All human samples in the study were de-identified, ensuring that researchers could not infer or obtain personal information from the donors. Prior to generating clinical data, approvals were secured from the Institutional Review Board at both Columbia University Irving Medical Center and Mayo Clinic. The study also included animal experiments, which adhered to the Institutional Animal Care and Use Committee (IACUC) guidelines at Columbia University under the approved protocol ACAABN3554. This program follows AAALAC International accredited standards and maintains an Animal Welfare Assurance with the Public Health Service.

For the zebrafish studies, both wild-type AB strains and fn1b−/− homozygous knockout fish lines, ranging from 8 to 10 months old and of both genders, were utilized. Animals were randomly assigned to experimental conditions from the same clutch to ensure consistency.

Human cohorts featured in this study included the NIA-AD Family Based Study (NIA-AD FBS), which involved multiplex families across the USA. Families were selected based on the presence of at least one member diagnosed with definite or probable AD post-age 60 and a sibling with a similar onset. Detailed demographic and clinical data were available for these participants. The Washington Heights/Inwood Columbia Aging Project (WHICAP) recruited individuals aged 65 years and older from northern Manhattan to study clinical and genetic risk factors for dementia. The Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) targeted a different ethnic group, including families from Puerto Rico, the Dominican Republic, and New York, to identify protective alleles in APOEε4 healthy carriers.

All procedures, from the care and use of animals to the handling of S samples, were carried out under ethical standards and protocols approved by relevant authorities, ensuring a high level of scientific integrity and respect for both human and animal subjects involved in the research.

Study results 

The present study accessed WGS data from 3,578 individuals across over 700 families of non-Hispanic White and Caribbean Hispanic descent, all affected by AD. Through harmonization and quality control of the WGS data, researchers identified rare coding variants in APOEε4 carriers who were cognitively unaffected and elderly. These carriers, both homozygous and heterozygous, had rare variants not present in non-carriers. The research prioritized variants potentially damaging to protein products, discovering 510 variants in 476 genes, particularly noted in the fibronectin 1 (FN1) gene, among others. 

Gene ontology analysis further revealed a strong enrichment for extracellular matrix (ECM)-related processes in the identified variants. This indicated that functional alterations in ECM composition could offer protective mechanisms in APOEε4 carriers, suggesting that APOEε4-related increases in ECM components could be counteracted by loss-of-function variants in these genes. Two significant genes, collagen type VI alpha 2 chain (COL6A2) and FN1, were examined for variants that might influence ECM stability through changes in charged residues, hypothesized to impact protein function.

Further analyses involved an independent cohort from databases such as the Alzheimer's Disease Genetic Consortium (ADGC) and the United Kingdom Biobank (UKB), focusing on non-Hispanic White individuals to test the replication of findings. The variant rs140926439 in FN1 showed a significantly reduced risk of AD in APOEε4 homozygous carriers, corroborating the protective effect of this variant against AD. Additionally, sensitivity analyses confirmed these findings, reinforcing the variant's potential as a protective factor in AD progression.

The study also explored the correlation between APOEε4 dosage and FN1 deposition at the blood-brain barrier. Immunostaining analyses in brain tissues of individuals with different APOE genotypes showed that FN1 levels increased with APOEε4 dosage, particularly in homozygous carriers. 

Lastly, the potential role of FN1 in modulating responses to amyloid toxicity was examined using a zebrafish model. The loss of FN1 function in zebrafish led to reduced gliovascular interactions and a decreased gliotic response after amyloid treatment, suggesting that fibronectin could play a crucial role in the regulation of amyloid beta clearance. This aligns with the hypothesis that FN loss-of-function variants could be protective against AD pathology by enhancing the clearance of toxic protein aggregates and modulating immune system activity.

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Kumar Malesu, Vijay. (2024, April 15). Study unlocks genetic secrets in APOEε4 carriers that could defend against Alzheimer's. News-Medical. Retrieved on May 22, 2024 from https://www.news-medical.net/news/20240415/Study-unlocks-genetic-secrets-in-APOEceb54-carriers-that-could-defend-against-Alzheimers.aspx.

  • MLA

    Kumar Malesu, Vijay. "Study unlocks genetic secrets in APOEε4 carriers that could defend against Alzheimer's". News-Medical. 22 May 2024. <https://www.news-medical.net/news/20240415/Study-unlocks-genetic-secrets-in-APOEceb54-carriers-that-could-defend-against-Alzheimers.aspx>.

  • Chicago

    Kumar Malesu, Vijay. "Study unlocks genetic secrets in APOEε4 carriers that could defend against Alzheimer's". News-Medical. https://www.news-medical.net/news/20240415/Study-unlocks-genetic-secrets-in-APOEceb54-carriers-that-could-defend-against-Alzheimers.aspx. (accessed May 22, 2024).

  • Harvard

    Kumar Malesu, Vijay. 2024. Study unlocks genetic secrets in APOEε4 carriers that could defend against Alzheimer's. News-Medical, viewed 22 May 2024, https://www.news-medical.net/news/20240415/Study-unlocks-genetic-secrets-in-APOEceb54-carriers-that-could-defend-against-Alzheimers.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Exploring how intense ultrasound can release biological indicators of disease