Abstract
Cerebrospinal fluid and positron emission tomography biomarkers accurately predict an underlying Alzheimer's disease (AD) pathology; however, they represent either invasive or expensive diagnostic tools. Therefore, a blood-based biomarker like plasma amyloid beta (Aβ) that could correlate with the underlying AD pathology and serve as a prognostic biomarker or an AD screening strategy is urgently needed as a cost-effective and non-invasive diagnostic tool. In this paper we review the demographic, biologic, genetic and technical aspects that affect plasma Aβ levels. Findings of cross-sectional and longitudinal studies of plasma Aβ, including autosomal dominant AD cases, sporadic AD cases, Down syndrome cases and population studies, are also discussed. Finally, we review the association between cerebrovascular disease and Aβ plasma levels and the responses observed in clinical trials. Based on our review of the current literature on plasma Aβ, we conclude that further clinical research and assay development are needed before measures of plasma Aβ can be interpreted so they can be applied as trait, risk or state biomarkers for AD.
Highlights
Alzheimer’s disease (AD) is the most common underlying cause of dementia globally, and the leading cause of years lost to disability in high-income countries as well as the second greatest cause of this worldwide according to the World Health Organization
amyloid beta (Aβ) production and correlation between plasma, cerebrospinal fluid (CSF) and parenchymal Aβ measurements Aβ is a byproduct of Aβ precursor protein (APP) metabolism that is generated by most cells, and amyloid plaques are the result of the deposition of mainly Aβ1-40 and Aβ1-42 in the brain, other species of Aβ are present [6]
A more complex association was found for plasma Aβ1-40 and Aβ1-42 levels in the AD Neuroimaging Initiative (ADNI) cohort, showing an interaction between age and diagnostic groups defined by an AD-like CSF tau and Aβ profile [10]
Summary
Alzheimer’s disease (AD) is the most common underlying cause of dementia globally, and the leading cause of years lost to disability in high-income countries as well as the second greatest cause of this worldwide according to the World Health Organization. A more complex association was found for plasma Aβ1-40 and Aβ1-42 levels in the AD Neuroimaging Initiative (ADNI) cohort, showing an interaction between age and diagnostic groups defined by an AD-like CSF tau and Aβ profile [10] Based on these results, only younger MCI and AD subjects with an ADlike CSF signature showed lower Aβ1-40 and Aβ1-42 values than older MCI and AD subjects with an AD-like CSF signature or subjects with a normal CSF signature. Most of these studies do not report sensitivity, specificity or area under the curve (AUC) measures for plasma Aβ levels, it is clear from these publications that determination of plasma Aβ levels is not useful as a diagnostic classifier. Longitudinal results in the CN population and MCI and sporadic AD cases Different measures of plasma Aβ have been associated with progression to dementia (Table 4): high baseline Aβ1-42 [30,57], low baseline Aβ1-42/Aβ1-40 [58,59], low baseline Aβ1-40 or Aβ1-42 [60], high baseline Aβ1-40 [29], high Aβ1-40 or low Aβ1-42/Aβ1-40 [61] and low Aβ1-40 in older
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