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      Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker

      review-article
      1 , 1 , 1 ,
      Alzheimer's Research & Therapy
      BioMed Central

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          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.

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          Most cited references60

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          National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.

          We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
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            Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

            To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.
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              Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.

              We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers. Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Alzheimers Res Ther
                Alzheimers Res Ther
                Alzheimer's Research & Therapy
                BioMed Central
                1758-9193
                2013
                8 March 2013
                8 September 2013
                : 5
                : 2
                : 8
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
                Article
                alzrt162
                10.1186/alzrt162
                3706955
                23470128
                4896ad3e-21c2-408b-87e0-501d81b049bf
                Copyright ©2013 BioMed Central Ltd
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                Neurology
                Neurology

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