Biological markers for early detection and pharmacological treatment of Alzheimer's disease

The introduction of biological markers in the clinical management of Alzheimer's disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.

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Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽

10.1093/genetics/165.3.1233 ◽

2003 ◽

Vol 165 (3) ◽

pp. 1233-1242

Author(s):

Joshua M Shulman ◽

Mel B Feany

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Genetic Modifier ◽

Genetic Modifiers ◽

Protein Tau ◽

Major Class ◽

Drosophila Model ◽

Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

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Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

International Journal of Alzheimer s Disease ◽

10.4061/2011/956104 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Katsumi Matsuzaki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Physicochemical Properties ◽

Lipid Rafts ◽

Molecular Mechanisms ◽

Amyloid Fibrils ◽

Protein A ◽

Pivotal Role ◽

Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

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Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms19123702 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3702 ◽

Cited By ~ 12

Author(s):

Grazia Femminella ◽

Tony Thayanandan ◽

Valeria Calsolaro ◽

Klara Komici ◽

Giuseppe Rengo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multimodal Imaging ◽

Molecular Mechanisms ◽

Imaging Techniques ◽

Structural Mri ◽

Imaging Biomarkers ◽

Significant Burden ◽

Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

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EUROPEAN CONGRESS ON THE EARLY DETECTION OF ALZHEIMER'S DISEASE: BIOLOGICAL MARKERS AND LONGITUDINAL RESEARCH

International Journal of Epidemiology ◽

10.1093/ije/18.4.1011 ◽

1989 ◽

Vol 18 (4) ◽

pp. 1011-1012

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Detection ◽

Biological Markers ◽

Longitudinal Research ◽

European Congress

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Amyloid imaging in Alzheimer’s disease: a potential new era of personalized medicine?

Translational Neuroscience ◽

10.2478/s13380-014-0205-y ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

Antoine Leuzy ◽

Eduardo Zimmer ◽

Serge Gauthier ◽

Pedro Rosa-Neto

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Personalized Medicine ◽

Amyloid Imaging ◽

Phase Iii ◽

Diagnostic Process ◽

European Medicines Agency ◽

Amyloid Pet ◽

Positron Emission

AbstractRecent advances along clinical and neuropathological lines, as well as in our ability to detect the deposition of β-amyloid (Aβ) in vivo using positron emission tomography (PET), have helped redefine Alzheimer’s disease (AD) as a dynamic clinicobiological entity. On the basis of these advances, AD is now conceptualized as a continuum comprising asymptomatic, minimally symptomatic, and dementia phases, with detection of brain Aβ — in particular, via PET amyloid imaging — central to the diagnostic process. In this respect, [18F]florbetapir (Amyvid™) and [18F]flutemetamol (Vizamyl™) have recently received approval for clinical use from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), with additional radiofluorinated tracers for detection of Aβ in phase III trials. Recent initiatives such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) suggest that Aβ production, oligomerization and aggregation begins many years, possibly decades, before detectable cognitive impairment, with Aβ shown to associate with cognitive decline and conversion to dementia. While personalized medicine has now emerged as a prospect for the field, the recent decision by the Centers for Medicare & Medicaid Services (CMS) — who declined to cover the cost of amyloid PET imaging citing insufficient evidence to support its clinical utility — highlights that such a move may be premature.

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Alzheimer's disease alters astrocytic functions related to neuronal support and transcellular internalization of mitochondria

10.1101/2021.09.15.460570 ◽

2021 ◽

Author(s):

Riikka Lampinen ◽

Irina Belaya ◽

Liudmila Saveleva ◽

Jeffrey R Liddell ◽

Dzhessi Rait ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Physiological Conditions ◽

Human Neurons ◽

Mitochondrial Transfer ◽

Starting Point ◽

First Time

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.

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Clinical and Neuropsychological Features of Alzheimer’s Disease

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0059 ◽

2013 ◽

pp. 791-804

Author(s):

Jason Hassenstab ◽

Jeffrey Burns ◽

John C. Morris

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Diagnostic Criteria ◽

Biological Markers ◽

Diagnostic Process ◽

Clinical Diagnostic ◽

Quantitative Basis ◽

Neuropsychological Characteristics ◽

Clinical Diagnostic Criteria

This chapter reviews the clinical and neuropsychological characteristics and course of dementia caused by AD with a focus on its earliest symptomatic stages, as the typical person affected by AD is not profoundly demented (48% of individuals affected by AD are mildly demented, 31% are moderately demented, and only 21% are severely demented (Hebert et al., 2003)). The chapter is written from the viewpoint of the clinician. It addresses the variability in current sets of clinical diagnostic criteria for AD, and provides the rationale for the use of biological markers (biomarkers) to aid in moving the diagnostic process from a syndromic to a quantitative basis.

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