Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors

  1. Joshua S Talboom
  2. Asta K Håberg
  3. Matthew D De Both
  4. Marcus A Naymik
  5. Isabelle Schrauwen
  6. Candace R Lewis
  7. Stacy F Bertinelli
  8. Callie Hammersland
  9. Mason A Fritz
  10. Amanda J Myers
  11. Meredith Hay
  12. Carol A Barnes
  13. Elizabeth Glisky
  14. Lee Ryan
  15. Matthew J Huentelman  Is a corresponding author
  1. The Translational Genomics Research Institute, United States
  2. Norwegian University of Science and Technology, Norway
  3. University of Miami, United States
  4. Arizona Alzheimer's Consortium, United States

Abstract

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.

Data availability

The data that support the findings of this study are freely available at Dryad (https://datadryad.org) doi:10.5061/dryad.2867k2m.

The following data sets were generated

Article and author information

Author details

  1. Joshua S Talboom

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4327-4103
  2. Asta K Håberg

    Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew D De Both

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Marcus A Naymik

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Isabelle Schrauwen

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Candace R Lewis

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Stacy F Bertinelli

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Callie Hammersland

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mason A Fritz

    The Translational Genomics Research Institute, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Amanda J Myers

    Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Meredith Hay

    Arizona Alzheimer's Consortium, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Carol A Barnes

    Arizona Alzheimer's Consortium, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Elizabeth Glisky

    Arizona Alzheimer's Consortium, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Lee Ryan

    Arizona Alzheimer's Consortium, Phoenix, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Matthew J Huentelman

    The Translational Genomics Research Institute, Phoenix, United States
    For correspondence
    mhuentelman@tgen.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7390-9918

Funding

Mueller Family Charitable Trust

  • Matthew J Huentelman

Arizona DHS in support of the Arizona Alzheimer's Consortium

  • Matthew J Huentelman

Flinn Foundation

  • Matthew J Huentelman

National Institutes of Health (R01- AG041232)

  • Amanda J Myers

National Institutes of Health (R01-AG049465-05)

  • Carol A Barnes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: For all participants, informed consent, and consent to publish was obtained before study participation. This protocol and consent were approved by the Western Institutional Review Board (WIRB, protocol #20111988).

Copyright

© 2019, Talboom et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,091
    views
  • 646
    downloads
  • 32
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Joshua S Talboom
  2. Asta K Håberg
  3. Matthew D De Both
  4. Marcus A Naymik
  5. Isabelle Schrauwen
  6. Candace R Lewis
  7. Stacy F Bertinelli
  8. Callie Hammersland
  9. Mason A Fritz
  10. Amanda J Myers
  11. Meredith Hay
  12. Carol A Barnes
  13. Elizabeth Glisky
  14. Lee Ryan
  15. Matthew J Huentelman
(2019)
Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors
eLife 8:e46179.
https://doi.org/10.7554/eLife.46179

Share this article

https://doi.org/10.7554/eLife.46179

Further reading

    1. Medicine
    2. Neuroscience
    Tomohiro Umeda, Ayumi Sakai ... Takami Tomiyama
    Research Article

    Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer’s disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson’s disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.

    1. Medicine
    2. Neuroscience
    Joanna Kosinska, Julian C Assmann ... Markus Schwaninger
    Research Article

    Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid-rich (LA) diet. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. DMF lacked efficacy in the LA diet-fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCAR2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hcar2 in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.