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  • Review Article
  • Published:

Ushering in the study and treatment of preclinical Alzheimer disease

Nature Reviews Neurology volume 9, pages 371–381 (2013)Cite this article

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A Correction to this article was published on 16 July 2013

This article has been updated

Abstract

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

Key Points

  • The pathogenic cascade of Alzheimer disease (AD) is thought to begin at least one to two decades prior to cognitive impairment

  • Disappointing results of several AD drugs in late-stage trials have suggested the need for early therapeutic intervention, calling for development of biomarkers and sensitive cognitive measures of preclinical disease

  • The best established measurements for detection and tracking of preclinical and clinical AD include MRI, fluorodeoxyglucose PET, amyloid PET, and cerebrospinal fluid measures of amyloid-β42, total tau, and phospho-tau

  • Studies of individuals with inherited AD can provide insights into cognitive and biomarker changes that precede clinical manifestation of AD, and are suitable candidates for ongoing monitoring and early-intervention strategies

  • We are entering an era of AD prevention research, with a number of preclinical AD treatment trials in the planning stages or under way for several at-risk, cognitively unimpaired populations

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Figure 1: Stages of Alzheimer disease.
Figure 2: Selected brain imaging approaches for detection of AD.
Figure 3: Dynamic biomarkers of the AD pathological cascade over time.
Figure 4: Temporal link between amyloid deposition and onset of AD dementia.

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Change history

  • 16 July 2013

    In the version of this article initially published, the appropriate references to support the following sentence were omitted, and incorrect references were cited:"By contrast, possession of one copy of the ε4 allele, which is found in about 25% of the population and about 60% of patients with AD dementia, is associated with higher risk of late-onset AD and younger age at dementia onset, and individuals with two copies of this allele have an especially high risk of AD."The references that should have been cited are:Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923 (1993).Saunders, A. M. et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467-1472 (1993).The error has been corrected for the HTML and PDF versions of the article.

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Acknowledgements

This article was supported by grants from the National Institute on Aging (R01AG031581 and P30AG19610 to E. M. Reiman, and RF1AG041705 to E. M. Reiman, P. N. Tariot and F. Lopera), the National Institute of Neurological Disorders and Stroke (F31-NS078786 to Y. T. Quiroz), Colciencias (1115-493-26133, 1115-545-31651 and 1115-519-29028 to F. Lopera), the Banner Alzheimer's Foundation, and the state of Arizona. The authors acknowledge research support from the Geoffrey Benne Gives Back Alzheimer's Initiative (to J. B. Langbaum), the Anonymous Foundation (to E. M. Reiman) and the Nomis Foundations (to P. N. Tariot, F. Lopera and E. M. Reiman). We thank H. Protas for her assistance in creating the figures prior to submission, and N. Fox, C. Rowe, M. Weiner and their colleagues for permission to use their images in Figure 2. We thank our valued research participants for their invaluable dedication and inspiration.

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Authors and Affiliations

  1. Banner Alzheimer's Institute, 901 East Willetta Street, Phoenix, 85006, AZ, USA

    Jessica B. Langbaum, Adam S. Fleisher, Kewei Chen, Napatkamon Ayutyanont, Pierre N. Tariot & Eric M. Reiman

  2. Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Calle 62 No. 5–59, Medellín, Colombia

    Francisco Lopera

  3. Department of Psychiatry, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    Yakeel T. Quiroz

  4. Department of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, 85259, AZ, USA

    Richard J. Caselli

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Contributions

J. B. Langbaum, K. Chen, N. Ayutyanont, F. Lopera, Y. T. Quiroz, R. J. Caselli and E. M. Reiman researched data for the article. A. S. Fleisher, P. N. Tariot and E. M. Reiman made substantial contributions to discussion of the content. J. B. Langbaum, P. N. Tariot and E. M. Reiman wrote the article. J. B. Langbaum, A. S. Fleisher, P. N. Tariot and E. M. Reiman contributed to review and/or editing of the manuscript before submission.

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Correspondence to Eric M. Reiman.

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Competing interests

J. B. Langbaum has received consulting fees from Janssen Alzheimer Immunotherapy. A. S. Fleisher has received consulting fees from Eli Lilly, Avid, Merck, Grifols, Quintiles; has been an invited speaker for Siemens, Quintiles, Avid; has Data and Safety Monitoring Board membership with Merck, Pfizer; has received grant funding from Lilly; has been involved in studies sponsored by Merck, Roche, Genentech, Pfizer, Avanir, Takeda, Lilly, BMS, Baxter, Neuroptix, Wyeth. Y. T. Quiroz serves as a consultant to Medavante. P. N. Tariot has received consulting fees from Abbott Laboratories, AC Immune, Adamas, Boehringer-Ingelheim, California Pacific Medical Center, Chase Pharmaceuticals, Chiesi, CME, Eisai, Elan, Medavante, Merz, Otsuka, Sanofi-Aventis; has received consulting fees and research support from AstraZeneca, Avanir, Avid, Bristol Myers Squibb, Cognoptix, Genentech, GlaxoSmithKline, Janssen, Eli Lilly, Medivation, Merck and Company, Pfizer, Roche; has received research support only from Baxter Healthcare Corp., Functional Neuromodulation, GE Healthcare, Medavante, Targacept, Toyama; has stock options in Adamas; and is listed as a contributor to a patent owned by the University of Rochester, 'Biomarkers of Alzheimer's Disease.' E. M. Reiman has been a Scientific Advisor for AstraZeneca, Baxter, Bayer, Eisai, Elan, Eli Lilly, GlaxoSmithKline, Intellect, Novartis, Siemens, Takeda; has research contracts with Avid/Eli Lilly and Genentech Research Grants; and has a patent pending for a biomarker strategy for the evaluation of presymptomatic AD treatments (through Banner Health). All other authors declare no competing interests.

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Langbaum, J., Fleisher, A., Chen, K. et al. Ushering in the study and treatment of preclinical Alzheimer disease. Nat Rev Neurol 9, 371–381 (2013). https://doi.org/10.1038/nrneurol.2013.107

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