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S5‐01–03: Biomarkers for prevention trials
Author(s) -
Holtzman David M.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.560
Subject(s) - clinical dementia rating , dementia , medicine , clinical trial , cohort , disease , alzheimer's disease , oncology , pathogenesis , pathology
Background: Evidence suggests that the pathology of Alzheimer disease (AD), including the accumulation of amyloid(A ), tau, and neuronal and synaptic loss, are present by the time the earliest clinical manifestations of AD are evident. A accumulation likely drives disease pathogenesis and begins years prior to clinical manifestations. It is likely that the most effective treatments for AD will need to begin in individuals who are clinically normal to delay the onset and prevent the disease. To efficiently test treatments within these samples, it is critical to develop biomarkers that predict the clinical onset of disease with high likelihood so that prevention trials can be designed that utilize many fewer patients than is currently required. Methods: A group of longitudinally followed cognitively normal elderly controls (clinical dementia rating CDR 0) and individuals with very mild dementia (CDR 0.5) were studied. CSF was obtained and analyzed for A 42, tau, ptau181, and other biomarkers. Brain MRI scans as well as PET scans utilizing Pittsburgh compound B were also obtained from the same individuals. Results: In CDR 0 individuals, CSF tau/A 42 strongly predicts conversion to CDR 0 over 3-4 years. CSF A 42 is significantly correlated with whole brain volume in this non-demented cohort. In CDR 0.5 individuals clinically diagnosed with dementia of the Alzheimer type, CSF A 42, tau, and p-tau181 all strongly predict clinical progression. Further, tau levels inversely correlate with brain volume in this very mildly demented group. Regardless of clinical status, CSF A 42 is highly sensitive and specific for the presence of cortical amyloid as assessed by PIB. Conclusions: CSF biomarkers A 42 and tau strongly predict clinical outcome in both clinically normal as well as in very mildly demented individuals. A decrease in CSF A 42 likely occurs before increases in CSF tau during the pathogenesis of AD. Use of these and other candidate biomarkers could greatly decrease sample size required for prevention trials by identifying individuals who have AD pathology in the asymptomatic as well as in the mildly symptomatic stages of AD and who have a high likelihood for clinical worsening over a several year period.