Abstract
Recent evidence suggests an association of beta-amyloid (Abeta) with vascular risk factors and the medications to treat them, which could potentially obfuscate the usefulness of Abeta for prediction of mild cognitive impairment (MCI) or Alzheimer disease (AD). In a subcohort from the Alzheimer's Disease Anti-inflammatory Prevention Trial (enriched for family history of AD), we investigated whether systolic blood pressure, total cholesterol, triglycerides, serum creatinine, apolipoprotein E, and use of statins and antihypertensives influenced the predictive value of serum Abeta for MCI/AD during a 2-year period. We collected blood samples to quantify serum Abeta from cognitively normal participants (n = 203) at baseline and ascertained the outcome of MCI/AD (n = 24) for a period of approximately 2 years. In an unadjusted model, the lowest quartile of Abeta(1-42) (hazard ratio [HR] = 2.93, 95% CI [1.02-8.32], P = 0.04) and of the Abeta(1-42)/Abeta(1-40) ratio (HR = 3.53, 95% CI [1.24-10.07], P = 0.02), compared with the highest quartile, predicted conversion to MCI/AD, but no impact of Abeta(1-40) was observed. No relationship between nonsteroidal antiinflammatory drug interventions and Abeta on MCI/AD risk was evident. Once data were adjusted for potential confounders (age, sex, and education), vascular risk factors, and the medications listed above, the lowest quartiles of Abeta(1-42) (HR = 4.47, 95% CI [1.39-14.39], P = 0.01), and of the Abeta(1-42/)Abeta(1-40) ratio (HR 4.87, 95% CI [1.50-15.87], P = 0.01) became strong predictors of conversion to MCI/AD. In this subcohort of individuals at risk for AD, the association of Abeta with vascular risk factors and medications to treat these conditions did not interfere with Abeta's predictive value for MCI/AD.
Highlights
Sequential processing of the amyloid precursor protein by the β- and γ-secretases results in production of β-amyloid (Aβ)1-40 and Aβ1-42 fragments
The origin of blood Aβ remains under investigation, accumulating literature suggests that changes in Aβ1-42 or Aβ1-40 may be indicative of disease onset and progression and that low Aβ1-42/Aβ1-40 ratios are useful in prediction of mild cognitive impairment (MCI) and/or Alzheimer disease (AD) [4,5,6]
42 and the Aβ1-42/Aβ1-40 ratio may be useful in predicting MCI/AD, results that are consistent with two previous longitudinal studies in showing that low Aβ1-42 and the ratios predict conversion to MCI/AD and support the work by Schupf et al showing that low Aβ1-42 and Aβ1-42/Aβ1-40 ratios predict conversion to AD during a 2-year period [5,6]
Summary
Sequential processing of the amyloid precursor protein by the β- and γ-secretases results in production of β-amyloid (Aβ) and Aβ1-42 fragments. Evaluation of peripheral Aβ levels for AD diagnosis/ prediction and as biomarkers of clinical end points in trials remains an active area of investigation. The origin of blood Aβ remains under investigation, accumulating literature suggests that changes in Aβ1-42 or Aβ1-40 may be indicative of disease onset and progression and that low Aβ1-42/Aβ1-40 ratios are useful in prediction of MCI and/or AD [4,5,6]. Differences among studies in the duration of follow-up prior to conversion have led to differing results pertaining to the predictive value of Aβ toward AD onset and may be attributable to the changes in Aβ levels with preclinical disease progression [6,7]. Schupf and coworkers demonstrated that during a 5-year pe-
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