The journal of nutrition, health & aging

, Volume 14, Issue 4, pp 299–302 | Cite as

Evolving early (pre-dementia) Alzheimer’s disease trials: Suit the outcomes to the population and study design

  • R. S. Doody
Article

Abstract

Assuming that some cases of Alzheimer’s disease (AD) could be prevented or delayed, prevention trials will be developed for this neurodegenerative condition. Initially, stakeholders will have to agree about the definition of prevention—true primary prevention, meaning the prevention of AD neuropathological changes; the prevention of clinical signs and symptoms that often augur AD; or preventing the progression of signs and symptoms to full-blown dementia. True primary prevention trials will have to rely completely upon neuroimaging or biomarker outcomes that reflect AD pathology. On the other hand, trials designed to prevent signs and symptoms of dementia will require researchers to agree on the phenomenology that would constitute an unequivocal endpoint: cognitive worsening on one or more measure compared to a normative group; development of Mild cognitive impairment (MCI); or development of Alzheimer’s dementia. Prevention trials utilizing any of these outcomes in the general public will be large, will have to utilize low risk public health interventions, and might therefore have only a small impact (treatment effect size), especially if the studies are too short or the study populations are too diverse. An alternative to interventions aimed at the general public would be any attempt to prevent signs and symptoms of dementia in individuals thought to be at an increased risk for clinical dementia. These trials could try to reduce the development of signs and symptoms of dementia in cognitively normal subjects, or they could try to prevent progression from some form of Mild Cognitive Impairment to AD, or they could have the more subtle goal of reducing the accumulation of subclinical deficits in MCI subjects. If the populations for these trials are limited to individuals who have abnormal laboratory and neuroimaging studies associated with AD neuropathology, the results will not generalize to biomarker-negative, at risk individuals, who are likely to constitute the majority of any clinically relevant study population. Outcome measures for each study design will depend upon the characteristics of the study.

Key words

Prevention cognitive aging mild cognitive impairment progression Alzheimer’s disease outcomes 

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References

  1. 1.
    Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–2117.CrossRefPubMedGoogle Scholar
  2. 2.
    Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 2007;69:1622–1634.CrossRefPubMedGoogle Scholar
  3. 3.
    Thal LJ, Carta A, Doody R, et al. Prevention protocols for Alzheimer disease. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11Suppl 3:46–49.PubMedGoogle Scholar
  4. 4.
    Salthouse TA. Memory aging from 18 to 80. Alzheimer Dis Assoc Disord 2003;17:162–167.CrossRefPubMedGoogle Scholar
  5. 5.
    Rountree SD, Waring SC, Chan WC, Lupo PJ, Darby EJ, Doody RS. Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment: prognosis and conversion to dementia. Dement Geriatr Cogn Disord 2007;24:476–482.CrossRefPubMedGoogle Scholar
  6. 6.
    Haroutunian V, Schnaider-Beeri M, Schmeidler J, et al. Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol 2008;65:1211–1217.CrossRefPubMedGoogle Scholar
  7. 7.
    Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306–319.CrossRefPubMedGoogle Scholar
  8. 8.
    Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355:2652–2663.CrossRefPubMedGoogle Scholar
  9. 9.
    Dubois B, Feldman HH, Jacova C et.al. Lancet 2007;6(8):734–746CrossRefGoogle Scholar
  10. 10.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–259.CrossRefPubMedGoogle Scholar
  11. 11.
    Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379–2388.CrossRefPubMedGoogle Scholar
  12. 12.
    Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of Rofecoxib in patients with Mild Cognitive Impairment Neuropsychopharmacology 2005;30:1204–1215Google Scholar
  13. 13.
    Feldman HH, Ferris S, Winblad B, et.al. Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study 2007;6:501–512Google Scholar
  14. 14.
    Winblad B, Gauthier S, Scinto L et. al. Safety and efficacy of galantamine in subjects with mild cognitive impairment Neurology 2008;70:2024–2035.Google Scholar
  15. 15.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303–308.CrossRefPubMedGoogle Scholar
  16. 16.
    Visser, PJ, Kester A, Jolles J, Verhey F. Ten-year risk of dementia in subjects with mild cognitive impairment Neurology 2006;67:1207.Google Scholar
  17. 17.
    Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology 2009;72:1555–1561.CrossRefPubMedGoogle Scholar
  18. 18.
    Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004;63:651–657.PubMedGoogle Scholar
  19. 19.
    Bouwman FH, Schoonenboom SNM, van der Flier WM, et al. CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment Neurobiology of Aging 2006;28(7):1070–1074CrossRefPubMedGoogle Scholar
  20. 20.
    Shaw L, Vanderstichele H, Knapik-Czajka M et. al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative Ann Neurol 2009;65:403–413.CrossRefPubMedGoogle Scholar
  21. 21.
    Hansson O, Zetterberg H, Buchhave P, et.al. Lancet Neurology 2006;5(3):228–234.CrossRefPubMedGoogle Scholar
  22. 22.
    Mattsson N, Zetterberg H, Hansson O etal. CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment JAMA 2009;302:385–393.CrossRefPubMedGoogle Scholar
  23. 23.
    Frisoni GB, Prestia A, Zanetti O et.al. Markers of Alzheimer’s disease in a population attending a memory clinic Alzheimer’s & Dementia 2009;5:307–317.CrossRefGoogle Scholar
  24. 24.
    Fleisher AS, Sowell BB, Taylor C etal. Clinical predictors of progresson to Alzheimer disease in amnestic mild cognitive impairment Neurology 2007;68:1588–1595.CrossRefPubMedGoogle Scholar

Copyright information

© Serdi and Springer Verlag France 2010

Authors and Affiliations

  • R. S. Doody
    • 1
  1. 1.Effie Marie Cain Chair in Alzheimer’s Disease Research, Baylor College of MedicineAlzheimer’s Disease and Memory Disorders CenterHoustonUSA

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