Use of an Alzheimer’s disease polygenic risk score to identify mild cognitive impairment in adults in their 50s

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Early identification of younger, non-demented adults at elevated risk for Alzheimer’s disease (AD) is crucial because the pathological process begins decades before dementia onset. Toward that end, we showed that an AD polygenic risk score (PRS) could identify mild cognitive impairment (MCI) in adults who were only in their 50s. Participants were 1176 white, non-Hispanic community-dwelling men of European ancestry in the Vietnam Era Twin Study of Aging (VETSA): 7% with amnestic MCI (aMCI); 4% with non-amnestic MCI (naMCI). Mean age was 56 years, with 89% <60 years old. Diagnosis was based on the Jak-Bondi actuarial/neuropsychological approach. We tested six P-value thresholds (0.05–0.50) for single nucleotide polymorphisms included in the ADPRS. After controlling for non-independence of twins and non-MCI factors that can affect cognition, higher PRSs were associated with significantly greater odds of having aMCI than being cognitively normal (odds ratios (ORs) = 1.36–1.43 for thresholds P < 0.20–0.50). The highest OR for the upper vs. lower quartile of the ADPRS distribution was 3.22. ORs remained significant after accounting for APOE-related SNPs from the ADPRS or directly genotyped APOE. Diabetes was associated with significantly increased odds of having naMCI (ORs = 3.10–3.41 for thresholds P < 0.05–0.50), consistent with naMCI having more vascular/inflammation components than aMCI. Analysis of sensitivity, specificity, and negative and positive predictive values supported some potential of ADPRSs for selecting participants in clinical trials aimed at early intervention. With participants 15+ years younger than most MCI samples, these findings are promising with regard to efforts to more effectively treat or slow AD progression.

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This work was supported by National Institute on Aging R01 AG018386, AG022381, AG022982, AG050595 (W.S.K.), R01 AG018384 (M.J.L.), R03 AG046413 (C.E.F), and K08 AG047903 (M.S.P), and the VA San Diego Center of Excellence for Stress and Mental Health. The content is the responsibility of the authors and does not necessarily represent official views of the NIA, NIH, or VA. The Cooperative Studies Program of the U.S. Department of Veterans Affairs provided financial support for development and maintenance of the Vietnam Era Twin Registry. We would also like to acknowledge the continued cooperation and participation of the members of the VET Registry and their families.

Author information

Author notes

  1. These authors contributed equally: Mark W. Logue, Matthew S. Panizzon, William S. Kremen.


  1. Research Service, VA Boston Healthcare System, Boston, MA, USA

    • Mark W. Logue
  2. Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA

    • Mark W. Logue
  3. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • Mark W. Logue
  4. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    • Matthew S. Panizzon
    • , Jeremy A. Elman
    • , Sean N. Hatton
    • , Daniel E. Gustavson
    • , Anders M. Dale
    • , Carol E. Franz
    •  & William S. Kremen
  5. Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA

    • Matthew S. Panizzon
    • , Jeremy A. Elman
    • , Sean N. Hatton
    • , Daniel E. Gustavson
    • , Anders M. Dale
    • , Carol E. Franz
    •  & William S. Kremen
  6. Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Nathan A. Gillespie
    •  & Michael C. Neale
  7. NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Ole A. Andreassen
  8. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Ole A. Andreassen
  9. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
  10. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
  11. Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA

    • Michael J. Lyons
  12. Department of Psychology, University of California, Riverside, Riverside, CA, USA

    • Chandra A. Reynolds
  13. Department of Family Medicine and Public Health, VA San Diego Healthcare System, La Jolla, CA, USA

    • Xin Tu
  14. Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA

    • William S. Kremen


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Conflict of interest

Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to William S. Kremen.

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