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Novel Biomarkers in Alzheimer’s Disease
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Novel Biomarkers in Alzheimer’s Disease

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Omics/Informatics".

Deadline for manuscript submissions: closed (5 July 2020) | Viewed by 129614

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Chiara Villa

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Interests: genetics; Alzheimer’s disease; non-coding RNAs; neurodegeneration; epilepsy; brain; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most common form of dementia in the elderly, affecting about 46 million people worldwide. It is clinically characterized by the progressive deterioration of memory and other cognitive functions that results in the loss of autonomy and which ultimately requires full-time medical care. The diagnosis of AD currently relies on clinical criteria, including mental status assessment, neurological examination, and brain imaging tests. However, these imaging methods are conclusive only in the advanced stages of disease, whereas AD physiopathology begins several decades before onset of the first symptoms. It is therefore particularly important to identify potential biomarkers that can be used in the early detection of AD, i.e., before clinical signs appear, as well as to evaluate the efficiency of therapeutic agents under testing and to thus accelerate the therapeutic discovery process. In this Special Issue, the current knowledge as well as future perspectives on the role of biomarkers in screening, diagnosis, treatment and follow-up of Alzheimer’s disease will be discussed.

Dr. Chiara Villa
Guest Editor

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Keywords

  • biomarkers
  • Alzheimer’s disease
  • dementia
  • neurodegeneration
  • brain
  • genetics

Published Papers (22 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 601 KiB  
Editorial
Biomarkers for Alzheimer’s Disease: Where Do We Stand and Where Are We Going?
by Chiara Villa
J. Pers. Med. 2020, 10(4), 238; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040238 - 20 Nov 2020
Cited by 5 | Viewed by 2834
Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative and progressive disorder representing the most common form of dementia in older adults [...] Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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Research

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16 pages, 742 KiB  
Article
Behavioral and Psychological Symptoms of Dementia (BPSD): Clinical Characterization and Genetic Correlates in an Italian Alzheimer’s Disease Cohort
by Catia Scassellati, Miriam Ciani, Carlo Maj, Cristina Geroldi, Orazio Zanetti, Massimo Gennarelli and Cristian Bonvicini
J. Pers. Med. 2020, 10(3), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030090 - 14 Aug 2020
Cited by 15 | Viewed by 3916
Abstract
Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer’s Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically [...] Read more.
Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer’s Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. Purpose. To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. Methods. AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. Results. APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, “Psychosis” and “Hyperactivity” resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and “genexgene” interactions. Conclusions. We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the “genexgene” interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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12 pages, 602 KiB  
Article
Semantic Priming in Mild Cognitive Impairment and Healthy Subjects: Effect of Different Time of Presentation of Word-Pairs
by Valeria Guglielmi, Davide Quaranta, Ilaria Mega, Emanuele Maria Costantini, Claudia Carrarini, Alice Innocenti and Camillo Marra
J. Pers. Med. 2020, 10(3), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030057 - 29 Jun 2020
Cited by 4 | Viewed by 3126
Abstract
Introduction: Semantic memory is impaired in mild cognitive impairment (MCI). Two main hypotheses about this finding are debated and refer to the degradation of stored knowledge versus the impairment of semantic access mechanisms. The aim of our study is to evaluate semantic [...] Read more.
Introduction: Semantic memory is impaired in mild cognitive impairment (MCI). Two main hypotheses about this finding are debated and refer to the degradation of stored knowledge versus the impairment of semantic access mechanisms. The aim of our study is to evaluate semantic impairment in MCI versus healthy subjects (HS) by an experiment evaluating semantic priming. Methods: We enrolled 27 MCI and 20 HS. MCI group were divided, according to follow up, into converters-MCI and non converters-MCI. The semantic task consisted of 108 pairs of words, 54 of which were semantically associated. Stimuli were presented 250 or 900 ms later the appearance of the target in a randomized manner. Data were analyzed using factorial ANOVA. Results: Both HS and MCI answered more quickly for word than for non-word at both stimulus onset asynchrony (SOA) intervals. At 250 ms, both MCI and HS experienced a shorter time of response for related-word than for unrelated words (priming effect), while only the converters-MCI subgroup lost the priming effect. Further, we observed a rather larger Cohen’s d effect size in non converters-MCI than in converters-MCI. Conclusion: Our data, and in particular the absence of a semantic priming effect in converters-MCI, could reflect the impairment of semantic knowledge rather than the accessibility of semantic stores in MCI individuals that progress to dementia. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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14 pages, 1147 KiB  
Article
Influence of ApoE Genotype and Clock T3111C Interaction with Cardiovascular Risk Factors on the Progression to Alzheimer’s Disease in Subjective Cognitive Decline and Mild Cognitive Impairment Patients
by Valentina Bessi, Juri Balestrini, Silvia Bagnoli, Salvatore Mazzeo, Giulia Giacomucci, Sonia Padiglioni, Irene Piaceri, Marco Carraro, Camilla Ferrari, Laura Bracco, Sandro Sorbi and Benedetta Nacmias
J. Pers. Med. 2020, 10(2), 45; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020045 - 29 May 2020
Cited by 15 | Viewed by 3772
Abstract
Background: Some genes could interact with cardiovascular risk factors in the development of Alzheimer’s disease. We aimed to evaluate the interaction between ApoE ε4 status, Clock T3111C and Per2 C111G polymorphisms with cardiovascular profile in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment [...] Read more.
Background: Some genes could interact with cardiovascular risk factors in the development of Alzheimer’s disease. We aimed to evaluate the interaction between ApoE ε4 status, Clock T3111C and Per2 C111G polymorphisms with cardiovascular profile in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI). Methods: We included 68 patients who underwent clinical evaluation; neuropsychological assessment; ApoE, Clock and Per2 genotyping at baseline; and neuropsychological follow-up every 12–24 months for a mean of 13 years. We considered subjects who developed AD and non-converters. Results: Clock T3111C was detected in 47% of cases, Per2 C111G in 19% of cases. ApoE ε4 carriers presented higher risk of heart disease; Clock C-carriers were more frequently smokers than non C-carriers. During the follow-up, 17 patients progressed to AD. Age at baseline, ApoE ε 4 and dyslipidemia increased the risk of conversion to AD. ApoE ε4 carriers with history of dyslipidemia showed higher risk to convert to AD compared to ApoE ε4− groups and ApoE ε4+ without dyslipidemia patients. Clock C-carriers with history of blood hypertension had a higher risk of conversion to AD. Conclusions: ApoE and Clock T3111C seem to interact with cardiovascular risk factors in SCD and MCI patients influencing the progression to AD. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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29 pages, 957 KiB  
Article
Targeted Nutritional Intervention for Patients with Mild Cognitive Impairment: The Cognitive impAiRmEnt Study (CARES) Trial 1
by Rebecca Power, John M. Nolan, Alfonso Prado-Cabrero, Robert Coen, Warren Roche, Tommy Power, Alan N. Howard and Ríona Mulcahy
J. Pers. Med. 2020, 10(2), 43; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020043 - 25 May 2020
Cited by 15 | Viewed by 6875
Abstract
Omega-3 fatty acids (ω-3FAs), carotenoids, and vitamin E are important constituents of a healthy diet. While they are present in brain tissue, studies have shown that these key nutrients are depleted in individuals with mild cognitive impairment (MCI) in comparison to cognitively healthy [...] Read more.
Omega-3 fatty acids (ω-3FAs), carotenoids, and vitamin E are important constituents of a healthy diet. While they are present in brain tissue, studies have shown that these key nutrients are depleted in individuals with mild cognitive impairment (MCI) in comparison to cognitively healthy individuals. Therefore, it is likely that these individuals will benefit from targeted nutritional intervention, given that poor nutrition is one of the many modifiable risk factors for MCI. Evidence to date suggests that these nutritional compounds can work independently to optimize the neurocognitive environment, primarily due to their antioxidant and anti-inflammatory properties. To date, however, no interventional studies have examined the potential synergistic effects of a combination of ω-3FAs, carotenoids and vitamin E on the cognitive function of patients with MCI. Individuals with clinically confirmed MCI consumed an ω-3FA plus carotenoid plus vitamin E formulation or placebo for 12 months. Cognitive performance was determined from tasks that assessed global cognition and episodic memory. Ω-3FAs, carotenoids, and vitamin E were measured in blood. Carotenoid concentrations were also measured in tissue (skin and retina). Individuals consuming the active intervention (n = 6; median [IQR] age 73.5 [69.5–80.5] years; 50% female) exhibited statistically significant improvements (p < 0.05, for all) in tissue carotenoid concentrations, and carotenoid and ω-3FA concentrations in blood. Trends in improvements in episodic memory and global cognition were also observed in this group. In contrast, the placebo group (n = 7; median [IQR] 72 (69.5–75.5) years; 89% female) remained unchanged or worsened for all measurements (p > 0.05). Despite a small sample size, this exploratory study is the first of its kind to identify trends in improved cognitive performance in individuals with MCI following supplementation with ω-3FAs, carotenoids, and vitamin E. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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16 pages, 1137 KiB  
Article
Deficits in Mitochondrial Spare Respiratory Capacity Contribute to the Neuropsychological Changes of Alzheimer’s Disease
by Simon M. Bell, Matteo De Marco, Katy Barnes, Pamela J. Shaw, Laura Ferraiuolo, Daniel J. Blackburn, Heather Mortiboys and Annalena Venneri
J. Pers. Med. 2020, 10(2), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020032 - 29 Apr 2020
Cited by 19 | Viewed by 6099
Abstract
Alzheimer’s disease (AD) is diagnosed using neuropsychological testing, supported by amyloid and tau biomarkers and neuroimaging abnormalities. The cause of neuropsychological changes is not clear since they do not correlate with biomarkers. This study investigated if changes in cellular metabolism in AD correlate [...] Read more.
Alzheimer’s disease (AD) is diagnosed using neuropsychological testing, supported by amyloid and tau biomarkers and neuroimaging abnormalities. The cause of neuropsychological changes is not clear since they do not correlate with biomarkers. This study investigated if changes in cellular metabolism in AD correlate with neuropsychological changes. Fibroblasts were taken from 10 AD patients and 10 controls. Metabolic assessment included measuring total cellular ATP, extracellular lactate, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolytic function. All participants were assessed with neuropsychological testing and brain structural MRI. AD patients had significantly lower scores in delayed and immediate recall, semantic memory, phonemic fluency and Mini Mental State Examination (MMSE). AD patients also had significantly smaller left hippocampal, left parietal, right parietal and anterior medial prefrontal cortical grey matter volumes. Fibroblast MMP, mitochondrial spare respiratory capacity (MSRC), glycolytic reserve, and extracellular lactate were found to be lower in AD patients. MSRC/MMP correlated significantly with semantic memory, immediate and delayed episodic recall. Correlations between MSRC and delayed episodic recall remained significant after controlling for age, education and brain reserve. Grey matter volumes did not correlate with MRSC/MMP. AD fibroblast metabolic assessment may represent an emergent disease biomarker of AD. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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9 pages, 733 KiB  
Article
The Brain Metabolic Correlates of the Main Indices of Neuropsychological Assessment in Alzheimer’s Disease
by Agostino Chiaravalloti, Maria Ricci, Daniele Di Biagio, Luca Filippi, Alessandro Martorana and Orazio Schillaci
J. Pers. Med. 2020, 10(2), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020025 - 18 Apr 2020
Cited by 6 | Viewed by 4141
Abstract
Background: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer’s disease (AD). Methods: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid [...] Read more.
Background: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer’s disease (AD). Methods: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid (CSF) assay, mini-mental state examination (MMSE) and further neuropsychological tests: Rey auditory verbal learning test, immediate recall (RAVLT immediate); Rey auditory verbal learning test, delayed recall (RAVLT, delayed); Rey complex figure test, copy (RCFT, copy); Rey complex figure test, delayed recall (RCFT, delayed); Raven’s colored progressive matrices (RCPM); phonological word fluency test (PWF) and Stroop test. We performed the statistical analysis by using statistical parametric mapping (SPM12; Wellcome Department of Cognitive Neurology, London, UK). Results: A significant relationship has been reported between (18F)FDG uptake and RAVLT immediate test in Brodmann area (BA)37 and BA22 and with RCFT, copy in BA40, and BA7. We did not find any significant relationships with other tests. Conclusion: In the AD population, brain (18F)FDG uptake is moderately related to the neuropsychological assessment, suggesting a limited impact on statistical data analysis of glucose brain metabolism. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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Review

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34 pages, 1045 KiB  
Review
Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach
by Eleonora Del Prete, Maria Francesca Beatino, Nicole Campese, Linda Giampietri, Gabriele Siciliano, Roberto Ceravolo and Filippo Baldacci
J. Pers. Med. 2020, 10(4), 221; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040221 - 11 Nov 2020
Cited by 20 | Viewed by 5008
Abstract
A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, [...] Read more.
A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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39 pages, 421 KiB  
Review
Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use
by Cristina d’Abramo, Luciano D’Adamio and Luca Giliberto
J. Pers. Med. 2020, 10(3), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030116 - 08 Sep 2020
Cited by 25 | Viewed by 6927
Abstract
Alzheimer’s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease [...] Read more.
Alzheimer’s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease is still obscure. The current theories are based on pathological findings of amyloid plaques and tau neurofibrillary tangles that accumulate in the brain parenchyma of affected patients. These findings have defined, together with the extensive neurodegeneration, the diagnostic criteria of the disease. The ability to detect changes in the levels of amyloid and tau in cerebrospinal fluid (CSF) first, and more recently in blood, has allowed us to use these biomarkers for the specific in-vivo diagnosis of AD in humans. Furthermore, other pathological elements of AD, such as the loss of neurons, inflammation and metabolic derangement, have translated to the definition of other CSF and blood biomarkers, which are not specific of the disease but, when combined with amyloid and tau, correlate with the progression from mild cognitive impairment to AD dementia, or identify patients who will develop AD pathology. In this review, we discuss the role of current and hypothetical biomarkers of Alzheimer’s disease, their specificity, and the caveats of current high-sensitivity platforms for their peripheral detection. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
36 pages, 4530 KiB  
Review
The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers
by Chiara Argentati, Ilaria Tortorella, Martina Bazzucchi, Carla Emiliani, Francesco Morena and Sabata Martino
J. Pers. Med. 2020, 10(3), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030115 - 06 Sep 2020
Cited by 8 | Viewed by 4392
Abstract
Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of [...] Read more.
Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of SAD is still unclear, but several studies have shed light on the involvement of environmental factors and multiple susceptibility genes, such as Apolipoprotein E and other genetic risk factors, which are key mediators in different metabolic pathways (e.g., glucose metabolism, lipid metabolism, energetic metabolism, and inflammation). Furthermore, growing clinical evidence in AD patients highlighted the presence of affected systemic organs and blood similarly to the brain. Collectively, these findings revise the canonical understating of AD pathogenesis and suggest that AD has metabolic disorder features. This review will focus on AD as a metabolic disorder and highlight the contribution of this novel understanding on the identification of new biomarkers for improving an early AD diagnosis. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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27 pages, 1042 KiB  
Review
Biomarkers for Alzheimer’s Disease Early Diagnosis
by Eva Ausó, Violeta Gómez-Vicente and Gema Esquiva
J. Pers. Med. 2020, 10(3), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030114 - 04 Sep 2020
Cited by 56 | Viewed by 12630
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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15 pages, 403 KiB  
Review
Current Biomarkers for Alzheimer’s Disease: From CSF to Blood
by Kun Zou, Mohammad Abdullah and Makoto Michikawa
J. Pers. Med. 2020, 10(3), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030085 - 12 Aug 2020
Cited by 42 | Viewed by 6332
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, a diagnosis of AD depends on the clinical symptoms of dementia, magnetic resonance imaging to determine brain volume, and positron emission tomography [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, a diagnosis of AD depends on the clinical symptoms of dementia, magnetic resonance imaging to determine brain volume, and positron emission tomography imaging to detect brain amyloid or tau deposition. The best characterized biological fluid markers for AD are decreased levels of amyloid β-protein (Aβ) 42 and increased levels of phosphorylated tau and total tau in cerebrospinal fluid (CSF). However, less invasive and easily detectable biomarkers for the diagnosis of AD, especially at the early stage, are still under development. Here, we provide an overview of various biomarkers identified in CSF and blood for the diagnostics of AD over the last 25 years. CSF biomarkers that reflect the three hallmarks of AD, amyloid deposition, neurofibrillary tangles, and neurodegeneration, are well established. Based on the need to start treatment in asymptomatic people with AD and to screen for AD risk in large numbers of young, healthy individuals, the development of biomarkers for AD is shifting from CSF to blood. Elements of the core pathogenesis of AD in blood, including Aβ42, tau proteins, plasma proteins, or lipids have shown their usefulness and capabilities in AD diagnosis. We also highlight some novel identified blood biomarkers (including Aβ42/Aβ43, p-tau 181, Aβ42/APP669-711, structure of Aβ in blood, and flotillin) for AD. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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12 pages, 1339 KiB  
Review
The Viral Hypothesis in Alzheimer’s Disease: Novel Insights and Pathogen-Based Biomarkers
by Sean X Naughton, Urdhva Raval and Giulio M. Pasinetti
J. Pers. Med. 2020, 10(3), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030074 - 29 Jul 2020
Cited by 12 | Viewed by 9019
Abstract
Early diagnosis of Alzheimer’s disease (AD) and the identification of significant risk factors are necessary to better understand disease progression, and to develop intervention-based therapies prior to significant neurodegeneration. There is thus a critical need to establish biomarkers which can predict the risk [...] Read more.
Early diagnosis of Alzheimer’s disease (AD) and the identification of significant risk factors are necessary to better understand disease progression, and to develop intervention-based therapies prior to significant neurodegeneration. There is thus a critical need to establish biomarkers which can predict the risk of developing AD before the onset of cognitive decline. A number of studies have indicated that exposure to various microbial pathogens can accelerate AD pathology. Additionally, several studies have indicated that amyloid-β possess antimicrobial properties and may act in response to infection as a part of the innate immune system. These findings have led some to speculate that certain types of infections may play a significant role in AD pathogenesis. In this review, we will provide an overview of studies which suggest pathogen involvement in AD. Additionally, we will discuss a number of pathogen-associated biomarkers which may be effective in establishing AD risk. Infections that increase the risk of AD represent a modifiable risk factor which can be treated with therapeutic intervention. Pathogen-based biomarkers may thus be a valuable tool for evaluating and decreasing AD risk across the population. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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11 pages, 894 KiB  
Review
Use of Biomarkers in Ongoing Research Protocols on Alzheimer’s Disease
by Marco Canevelli, Giulia Remoli, Ilaria Bacigalupo, Martina Valletta, Marco Toccaceli Blasi, Francesco Sciancalepore, Giuseppe Bruno, Matteo Cesari and Nicola Vanacore
J. Pers. Med. 2020, 10(3), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030068 - 24 Jul 2020
Cited by 9 | Viewed by 2805
Abstract
The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer’s disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the [...] Read more.
The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer’s disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the “real world” remain to be clarified. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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20 pages, 1039 KiB  
Review
Advantages and Pitfalls in Fluid Biomarkers for Diagnosis of Alzheimer’s Disease
by Syed Haris Omar and John Preddy
J. Pers. Med. 2020, 10(3), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030063 - 17 Jul 2020
Cited by 12 | Viewed by 4887
Abstract
Alzheimer’s disease (AD) is a commonly occurring neurodegenerative disease in the advanced-age population, with a doubling of prevalence for each 5 years of age above 60 years. In the past two decades, there has been a sustained effort to find suitable biomarkers that [...] Read more.
Alzheimer’s disease (AD) is a commonly occurring neurodegenerative disease in the advanced-age population, with a doubling of prevalence for each 5 years of age above 60 years. In the past two decades, there has been a sustained effort to find suitable biomarkers that may not only aide with the diagnosis of AD early in the disease process but also predict the onset of the disease in asymptomatic individuals. Current diagnostic evidence is supportive of some biomarker candidates isolated from cerebrospinal fluid (CSF), including amyloid beta peptide (Aβ), total tau (t-tau), and phosphorylated tau (p-tau) as being involved in the pathophysiology of AD. However, there are a few biomarkers that have been shown to be helpful, such as proteomic, inflammatory, oral, ocular and olfactory in the early detection of AD, especially in the individuals with mild cognitive impairment (MCI). To date, biomarkers are collected through invasive techniques, especially CSF from lumbar puncture; however, non-invasive (radio imaging) methods are used in practice to diagnose AD. In order to reduce invasive testing on the patients, present literature has highlighted the potential importance of biomarkers in blood to assist with diagnosing AD. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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32 pages, 1771 KiB  
Review
Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights
by Chiara Villa, Marialuisa Lavitrano, Elena Salvatore and Romina Combi
J. Pers. Med. 2020, 10(3), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030061 - 10 Jul 2020
Cited by 32 | Viewed by 8814
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and [...] Read more.
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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20 pages, 656 KiB  
Review
Obesity and Diabetes Mediated Chronic Inflammation: A Potential Biomarker in Alzheimer’s Disease
by Md Shahjalal Hossain Khan and Vijay Hegde
J. Pers. Med. 2020, 10(2), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020042 - 22 May 2020
Cited by 30 | Viewed by 6943
Abstract
Alzheimer’s disease (AD) is the sixth leading cause of death and is correlated with obesity, which is the second leading cause of preventable diseases in the United States. Obesity, diabetes, and AD share several common features, and inflammation emerges as the central link. [...] Read more.
Alzheimer’s disease (AD) is the sixth leading cause of death and is correlated with obesity, which is the second leading cause of preventable diseases in the United States. Obesity, diabetes, and AD share several common features, and inflammation emerges as the central link. High-calorie intake, elevated free fatty acids, and impaired endocrine function leads to insulin resistance and systemic inflammation. Systemic inflammation triggers neuro-inflammation, which eventually hinders the metabolic and regulatory function of the brain mitochondria leading to neuronal damage and subsequent AD-related cognitive decline. As an early event in the pathogenesis of AD, chronic inflammation could be considered as a potential biomarker in the treatment strategies for AD. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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27 pages, 1261 KiB  
Review
Neurophysiological Hallmarks of Neurodegenerative Cognitive Decline: The Study of Brain Connectivity as A Biomarker of Early Dementia
by Paolo Maria Rossini, Francesca Miraglia, Francesca Alù, Maria Cotelli, Florinda Ferreri, Riccardo Di Iorio, Francesco Iodice and Fabrizio Vecchio
J. Pers. Med. 2020, 10(2), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020034 - 30 Apr 2020
Cited by 26 | Viewed by 6466
Abstract
Neurodegenerative processes of various types of dementia start years before symptoms, but the presence of a “neural reserve”, which continuously feeds and supports neuroplastic mechanisms, helps the aging brain to preserve most of its functions within the “normality” frame. Mild cognitive impairment (MCI) [...] Read more.
Neurodegenerative processes of various types of dementia start years before symptoms, but the presence of a “neural reserve”, which continuously feeds and supports neuroplastic mechanisms, helps the aging brain to preserve most of its functions within the “normality” frame. Mild cognitive impairment (MCI) is an intermediate stage between dementia and normal brain aging. About 50% of MCI subjects are already in a stage that is prodromal-to-dementia and during the following 3 to 5 years will develop clinically evident symptoms, while the other 50% remains at MCI or returns to normal. If the risk factors favoring degenerative mechanisms are modified during early stages (i.e., in the prodromal), the degenerative process and the loss of abilities in daily living activities will be delayed. It is therefore extremely important to have biomarkers able to identify—in association with neuropsychological tests—prodromal-to-dementia MCI subjects as early as possible. MCI is a large (i.e., several million in EU) and substantially healthy population; therefore, biomarkers should be financially affordable, largely available and non-invasive, but still accurate in their diagnostic prediction. Neurodegeneration initially affects synaptic transmission and brain connectivity; methods exploring them would represent a 1st line screening. Neurophysiological techniques able to evaluate mechanisms of synaptic function and brain connectivity are attracting general interest and are described here. Results are quite encouraging and suggest that by the application of artificial intelligence (i.e., learning-machine), neurophysiological techniques represent valid biomarkers for screening campaigns of the MCI population. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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14 pages, 1915 KiB  
Review
New Insights into the Molecular Bases of Familial Alzheimer’s Disease
by Valeria D’Argenio and Daniela Sarnataro
J. Pers. Med. 2020, 10(2), 26; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020026 - 19 Apr 2020
Cited by 18 | Viewed by 7456
Abstract
Like several neurodegenerative disorders, such as Prion and Parkinson diseases, Alzheimer’s disease (AD) is characterized by spreading mechanism of aggregated proteins in the brain in a typical “prion-like” manner. Recent genetic studies have identified in four genes associated with inherited AD (amyloid precursor [...] Read more.
Like several neurodegenerative disorders, such as Prion and Parkinson diseases, Alzheimer’s disease (AD) is characterized by spreading mechanism of aggregated proteins in the brain in a typical “prion-like” manner. Recent genetic studies have identified in four genes associated with inherited AD (amyloid precursor protein-APP, Presenilin-1, Presenilin-2 and Apolipoprotein E), rare mutations which cause dysregulation of APP processing and alterations of folding of the derived amyloid beta peptide (Aβ). Accumulation and aggregation of Aβ in the brain can trigger a series of intracellular events, including hyperphosphorylation of tau protein, leading to the pathological features of AD. However, mutations in these four genes account for a small of the total genetic risk for familial AD (FAD). Genome-wide association studies have recently led to the identification of additional AD candidate genes. Here, we review an update of well-established, highly penetrant FAD-causing genes with correlation to the protein misfolding pathway, and novel emerging candidate FAD genes, as well as inherited risk factors. Knowledge of these genes and of their correlated biochemical cascade will provide several potential targets for treatment of AD and aging-related disorders. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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13 pages, 591 KiB  
Review
Flotillin: A Promising Biomarker for Alzheimer’s Disease
by Efthalia Angelopoulou, Yam Nath Paudel, Mohd. Farooq Shaikh and Christina Piperi
J. Pers. Med. 2020, 10(2), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020020 - 26 Mar 2020
Cited by 19 | Viewed by 6868
Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid [...] Read more.
Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid rafts, as well as the endocytic pathways in amyloidogenic amyloid precursor protein (APP) processing and AD pathogenesis. The combination of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging. However, their invasive nature, the cost, and their availability often limit their use. In this context, an easily detectable marker for AD diagnosis even at preclinical stages is highly needed. Flotillins, being hydrophobic proteins located in lipid rafts of intra- and extracellular vesicles, are mainly involved in signal transduction and membrane–protein interactions. Accumulating evidence highlights the emerging implication of flotillins in AD pathogenesis, by affecting APP endocytosis and processing, Ca2+ homeostasis, mitochondrial dysfunction, neuronal apoptosis, Aβ-induced neurotoxicity, and prion-like spreading of Aβ. Importantly, there is also clinical evidence supporting their potential use as biomarker candidates for AD, due to reduced serum and CSF levels that correlate with amyloid burden in AD patients compared with controls. This review focuses on the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, further addressing their potential usage as disease biomarkers. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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12 pages, 267 KiB  
Commentary
Biomarkers for Alzheimer’s Disease (AD) and the Application of Precision Medicine
by Walter J. Lukiw, Andrea Vergallo, Simone Lista, Harald Hampel and Yuhai Zhao
J. Pers. Med. 2020, 10(3), 138; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030138 - 21 Sep 2020
Cited by 14 | Viewed by 4607
Abstract
An accurate diagnosis of Alzheimer’s disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient’s age, [...] Read more.
An accurate diagnosis of Alzheimer’s disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient’s age, gender and lifestyle, medical and genetic history (both clinical- and family-derived), cognitive, physical, behavioral and geriatric assessment, laboratory examination of multiple AD patient biofluids, especially within the systemic circulation (blood serum) and cerebrospinal fluid (CSF), multiple neuroimaging-modalities of the brain’s limbic system and/or retina, followed up in many cases by post-mortem neuropathological examination to finally corroborate the diagnosis. More often than not, prospective AD cases are accompanied by other progressive, age-related dementing neuropathologies including, predominantly, a neurovascular and/or cardiovascular component, multiple-infarct dementia (MID), frontotemporal dementia (FTD) and/or strokes or ‘mini-strokes’ often integrated with other age-related neurological and non-neurological disorders including cardiovascular disease and cancer. Especially over the last 40 years, enormous research efforts have been undertaken to discover, characterize, and quantify more effectual and reliable biological markers for AD, especially during the pre-clinical or prodromal stages of AD so that pre-emptive therapeutic treatment strategies may be initiated. While a wealth of genetic, neurobiological, neurochemical, neuropathological, neuroimaging and other diagnostic information obtainable for a single AD patient can be immense: (i) it is currently challenging to integrate and formulate a definitive diagnosis for AD from this multifaceted and multidimensional information; and (ii) these data are unfortunately not directly comparable with the etiopathological patterns of other AD patients even when carefully matched for age, gender, familial genetics, and drug history. Four decades of AD research have repeatedly indicated that diagnostic profiles for AD are reflective of an extremely heterogeneous neurological disorder. This commentary will illuminate the heterogeneity of biomarkers for AD, comment on emerging investigative approaches and discuss why ‘precision medicine’ is emerging as our best paradigm yet for the most accurate and definitive prediction, diagnosis, and prognosis of this insidious and lethal brain disorder. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
14 pages, 274 KiB  
Protocol
The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) Study: Rationale, Design and Methods
by Anna Picca, Daniela Ronconi, Hélio J. Coelho-Junior, Riccardo Calvani, Federico Marini, Alessandra Biancolillo, Jacopo Gervasoni, Aniello Primiano, Cristina Pais, Eleonora Meloni, Domenico Fusco, Maria Rita Lo Monaco, Roberto Bernabei, Maria Camilla Cipriani, Emanuele Marzetti and Rosa Liperoti
J. Pers. Med. 2020, 10(2), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020022 - 09 Apr 2020
Cited by 5 | Viewed by 4208
Abstract
Mild cognitive impairment (MCI), also termed mild neurocognitive disorder, includes a heterogeneous group of conditions characterized by declines in one or more cognitive domains greater than that expected during “normal” aging but not severe enough to impair functional abilities. MCI has been associated [...] Read more.
Mild cognitive impairment (MCI), also termed mild neurocognitive disorder, includes a heterogeneous group of conditions characterized by declines in one or more cognitive domains greater than that expected during “normal” aging but not severe enough to impair functional abilities. MCI has been associated with an increased risk of developing dementia and even considered an early stage of it. Therefore, noninvasively accessible biomarkers of MCI are highly sought after for early identification of the condition. Systemic inflammation, metabolic perturbations, and declining physical performance have been described in people with MCI. However, whether biological and functional parameters differ across MCI neuropsychological subtypes is presently debated. Likewise, the predictive value of existing biomarkers toward MCI conversion into dementia is unclear. The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) study was conceived as a multi-dimensional investigation in which multi-marker discovery will be coupled with innovative statistical approaches to characterize patterns of systemic inflammation, metabolic perturbations, and physical performance in older adults with MCI. The ultimate aim of ODINO is to identify potential biomarkers specific for MCI subtypes and predictive of MCI conversion into Alzheimer’s disease or other forms of dementia over a three-year follow-up. Here, we describe the rationale, design, and methods of ODINO. Full article
(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)
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