Preclinical Alzheimer disease—the challenges ahead | Nature Reviews Neurology
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Preclinical Alzheimer disease—the challenges ahead

Nature Reviews Neurology volume 9, pages 54–58 (2013)Cite this article

Subjects

Abstract

There is growing recognition that the pathophysiological process of Alzheimer disease (AD) begins many years prior to clinically obvious symptoms, and the concept of a presymptomatic or preclinical stage of AD is becoming more widely accepted. Advances in biomarker studies have enabled detection of AD pathology in vivo in clinically normal older individuals. The predictive value of these biomarkers at the individual patient level, however, remains to be elucidated. The ultimate goal of identifying individuals in the preclinical stages of AD is to facilitate early intervention to delay and perhaps even prevent emergence of the clinical syndrome. A number of challenges remain to be overcome before this concept can be validated and translated into clinical practice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Desikan, R. S. et al. Amyloid-β-associated clinical decline occurs only in the presence of elevated P-tau. Arch. Neurol. 69, 709–713 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Knopman, D. S. et al. Short-term clinical outcomes for stages of NIA–AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jack, C. R. Jr et al. An operational approach to NIA–AA criteria for preclinical Alzheimer's disease. Ann. Neurol. 71, 765–775 (2011).

    Article  Google Scholar 

  6. Reiman, E. M. et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc. Natl Acad. Sci. USA 101, 284–289 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Quiroz, Y. T. et al. Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann. Neurol. 68, 865–875 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vlassenko, A. G. et al. Amyloid-beta plaque growth in cognitively normal adults: longitudinal [11C]-Pittsburgh compound B data. Ann. Neurol. 70, 857–861 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Holtzman, D. M. CSF biomarkers for Alzheimer's disease: current utility and potential future use. Neurobiol. Aging 32 (Suppl. 1), S4–S9 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee, H. G. et al. Challenging the amyloid cascade hypothesis: senile plaques and amyloid-β as protective adaptations to Alzheimer disease. Ann. NY Acad. Sci. 1019, 1–4 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. O'Brien, J. L. et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology 74, 1969–1976 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Machulda, M. M. et al. Effect of APOE ε4 status on intrinsic network connectivity in cognitively normal elderly subjects. Arch. Neurol. 68, 1131–1136 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Landau, S. M. et al. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol. Aging 32, 1207–1218 (2011).

    Article  PubMed  Google Scholar 

  14. Petrella, J. R., Sheldon, F. C., Prince, S. E., Calhoun, V. D. & Doraiswamy, P. M. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology 76, 511–517 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fox, N. C. et al. Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64, 1563–1572 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Kantarci, K. et al. APOE modifies the association between Aβ load and cognition in cognitively normal older adults. Neurology 78, 232–240 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rentz, D. M. et al. Cognition, reserve, and amyloid deposition in normal aging. Ann. Neurol. 67, 353–364 (2010).

    PubMed  Google Scholar 

  18. Roe, C. M. et al. Cerebrospinal fluid biomarkers, education, brain volume, and future cognition. Arch. Neurol. 68, 1145–1151 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Klunk, W. E. Amyloid imaging as a biomarker for cerebral beta-amyloidosis and risk prediction for Alzheimer dementia. Neurobiol. Aging 32 (Suppl. 1), S20–S36 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Morris, J. C. et al. Pittsburgh Compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch. Neurol. 66, 1469–1475 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rowe, C. C. et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol. Aging 31, 1275–1283 (2010).

    Article  PubMed  Google Scholar 

  22. Sperling, R. A., Jack, C. R. Jr & Aisen, P. S. Testing the right target and right drug at the right stage. Sci. Transl. Med. 3, 111cm33 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-Aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 69, 203–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Hyman, B. T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 68, 1062–1064 (2011).

    Article  PubMed  Google Scholar 

  26. Karlawish, J. Addressing the ethical, policy, and social challenges of preclinical Alzheimer disease. Neurology 77, 1487–1493 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Green, R. C. et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N. Engl. J. Med. 361, 245–254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Karlawish, J. Measuring decision-making capacity in cognitively impaired individuals. Neurosignals 16, 91–98 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Osterberg, L. & Blaschke, T. Adherence to medication. N. Engl. J. Med. 353, 487–497 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Kent, D. M. & Hayward, R. A. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA 298, 1209–1212 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. The Alzheimer's Association. Changing the trajectory of Alzheimer's disease: a national imperative. The Alzheimer's Association [online], (2010).

  33. Rosow, K. et al. Countrywide strategic plans on Alzheimer's disease: developing the framework for the international battle against Alzheimer's disease. Alzheimers Dement. 7, 615–621 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work of R. A. Sperling and K. A. Johnson is supported in part by the National Institute on Aging (P01 AG036694; P50 AG005134; R01 AG027435; R01 AG037497), the American Health Assistance Foundation, and the Alzheimer's Association. J. Karlawish's work is supported by a Robert Wood Johnson Investigator Award in Health Policy Research. The authors thank N. Arzoumanian for her assistance with preparation of this manuscript before submission.

Author information

Authors and Affiliations

  1. Departments of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, 02115, MA, USA

    Reisa A. Sperling

  2. Departments of Medicine and Medical Ethics and Health Policy, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, 19104, PA, USA

    Jason Karlawish

  3. Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, 33 Fruit Street, Boston, 02114, MA, USA

    Keith A. Johnson

Authors
  1. Reisa A. Sperling
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jason Karlawish
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Keith A. Johnson
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Reisa A. Sperling.

Ethics declarations

Competing interests

R. A. Sperling has served as a site investigator for: Pfizer, Janssen, Avid/Lilly, and Bristol-Myers Squibb. She has served as a consultant to Roche, Janssen, Pfizer, Bayer, Satori, Biogen/IDEC, Merck, and Eisai. J. Karlawish serves on the professional advisory board for SeniorBridge and also has shares in this company. He is a co-holder of a licence on the University of Pennsylvania Integrated Neurodegenerative Disease database. K. A. Johnson has served as a site investigator and/or consultant for: General Electric Health Care, Pfizer, Janssen, Bristol-Myers Squibb, Elan, Bayer, Avid/Lilly, Siemens, and Genzyme.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sperling, R., Karlawish, J. & Johnson, K. Preclinical Alzheimer disease—the challenges ahead. Nat Rev Neurol 9, 54–58 (2013). https://doi.org/10.1038/nrneurol.2012.241

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.241

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing