Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease

Doecke, James D.; Laws, Simon M.; Faux, Noel; Wilson, William J.; Burnham, Samantha; Lam, Chiou Peng; Mondal, Alinda; Bedő, Justin; Bush, Ashley I.; Brown, Belinda M.; Ruyck, Karl De; Ellis, Kathryn A.; Fowler, Christopher; Gupta, Veer; Head, Richard; Macaulay, S. Lance; Pertile, Kelly K.; Rowe, Christopher C.; Rembach, Alan; Rodrigues, Mark; Rumble, Rebecca; Szoeke, Cassandra; Taddei, Kevin; Taddei, Tania; Trounson, Brett; Ames, David; Masters, Colin L.; Martins, Ralph N.

doi:10.1001/archneurol.2012.1282

Cited by 363 publications

(260 citation statements)

References 30 publications

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“…Increased expression of APP, altered APP isoform ratios and processing patterns, and enhanced β-secretase activity are observed in platelets from patients with AD [60][61][62] , and these changes could result in overproduction of Aβ in the periphery. Blood levels of albumin, an Aβ carrier, are reduced in patients with AD 63 . The quantity and function of erythrocytes (another Aβ carrier) are also altered in such patients, and their erythrocytes show compromised binding of Aβ 64,65 .…”

Section: Blood Abnormalitiesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Blood Abnormalitiesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…Moreover, both Doecke et al (2012) [134] and O'Bryant et al (2011) [135] have found diagnostic accuracy across cohorts employing biomarker algorithms/profiles. These encouraging results provide additional support for the blood-based profiles/ signatures.…”

Section: Blood Prospective Candidate Biomarkersmentioning

confidence: 97%

“…However, two analyses, utilizing large and well-characterized clinical cohorts, have discovered that a set of inflammatory molecules display modified expression as a function of AD [130,134]. Moreover, both Doecke et al (2012) [134] and O'Bryant et al (2011) [135] have found diagnostic accuracy across cohorts employing biomarker algorithms/profiles.…”

Section: Blood Prospective Candidate Biomarkersmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…For example, thanks to ADNI, it is currently known that AD starts to develop many years before symptoms are manifested [305,306], as well as the order in which biomarkers become abnormal [307,308] or the order in which atrophy of the brain occurs [309,310]. Identification of new biomarkers (in blood [311], ˛-Synuclein [312],. .…”

Section: Publicly Available Ad Datasetsmentioning

confidence: 99%