Advent of Proteomic Tools for Diagnostic Biomarker Analysis in Alzheimer’s Disease

: Locating remedies for Alzheimer’s disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated- Tau (pTau) 181 and Amyloid-β (Aβ) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD.

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Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor

Brain Communications ◽

10.1093/braincomms/fcab011 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Jun Maeda ◽

Takeharu Minamihisamatsu ◽

Masafumi Shimojo ◽

Xiaoyun Zhou ◽

Maiko Ono ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Receptor Gene ◽

Amyloid Β ◽

Progressive Increase ◽

P2y12 Receptor ◽

Down Regulation ◽

Disease Etiology ◽

The Central Nervous System

Abstract Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer’s disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (P2Y12R). However, it is yet to be clarified in Alzheimer’s disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer’s disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer’s disease and non-Alzheimer’s disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and AppNL-F/NL-F mice). By contrast, neuritic plaques in Alzheimer’s disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer’s disease-related neurodegenerative processes.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

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PET Imaging of Tau Pathology and Amyloid-β, and MRI for Alzheimer’s Disease Feature Fusion and Multimodal Classification

Journal of Alzheimer s Disease ◽

10.3233/jad-210064 ◽

2021 ◽

pp. 1-18

Author(s):

Mehdi Shojaie ◽

Solale Tabarestani ◽

Mercedes Cabrerizo ◽

Steven T. DeKosky ◽

David E. Vaillancourt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Feature Selection ◽

Mutual Information ◽

Feature Fusion ◽

Early Stage ◽

Model Performance ◽

Amyloid Β ◽

Feature Ranking ◽

Promising Tool

Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition.

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Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights

Journal of Personalized Medicine ◽

10.3390/jpm10030061 ◽

2020 ◽

Vol 10 (3) ◽

pp. 61 ◽

Cited By ~ 1

Author(s):

Chiara Villa ◽

Marialuisa Lavitrano ◽

Elena Salvatore ◽

Romina Combi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Biological Fluids ◽

Imaging Techniques ◽

Amyloid Β ◽

The Elderly ◽

Diagnostic Methods ◽

Imaging Biomarkers ◽

Attractive Alternative

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.

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Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21165858 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5858 ◽

Cited By ~ 3

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Md. Sohanur Rahman ◽

Tapan Behl ◽

Philippe Jeandet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Amyloid Β ◽

Aβ Oligomers ◽

Aβ Aggregation ◽

Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

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The Retinal Inner Plexiform Synaptic Layer Mirrors Grey Matter Thickness of Primary Visual Cortex with Increased Amyloid β Load in Early Alzheimer’s Disease

Neural Plasticity ◽

10.1155/2020/8826087 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Lília Jorge ◽

Nádia Canário ◽

Ricardo Martins ◽

Beatriz Santiago ◽

Isabel Santana ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Visual Cortex ◽

Primary Visual Cortex ◽

Early Stage ◽

Amyloid Β ◽

Synaptic Function ◽

Binding Potential ◽

Inner Plexiform Layer ◽

Pet Tracer

The retina may serve as putative window into neuropathology of synaptic loss in Alzheimer’s disease (AD). Here, we investigated synapse-rich layers versus layers composed by nuclei/cell bodies in an early stage of AD. In addition, we examined the associations between retinal changes and molecular and structural markers of cortical damage. We recruited 20 AD patients and 17 healthy controls (HC). Combining optical coherence tomography (OCT), magnetic resonance (MR), and positron emission tomography (PET) imaging, we measured retinal and primary visual cortex (V1) thicknesses, along with V1 amyloid β (Aβ) retention ([11C]-PiB PET tracer) and neuroinflammation ([11C]-PK11195 PET tracer). We found that V1 showed increased amyloid-binding potential, in the absence of neuroinflammation. Although thickness changes were still absent, we identified a positive association between the synapse-rich inner plexiform layer (IPL) and V1 in AD. This retinocortical interplay might reflect changes in synaptic function resulting from Aβ deposition, contributing to early visual loss.

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Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow Is Linked to Alzheimer's Pathology

Innovation in Aging ◽

10.1093/geroni/igab046.2407 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 637-638

Author(s):

Feng Han ◽

Jing Chen ◽

Aaron Belkin-Rosen ◽

Yameng Gu ◽

Liying Luo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Resting State ◽

Early Stage ◽

Adult Population ◽

Critical Role ◽

Low Frequency ◽

Amyloid Β ◽

Blood Oxygenation

Abstract Alzheimer’s disease (AD) is the most common cause of dementia in the old adult population. AD pathogenesis has been linked to the aggregation of toxic proteins, e.g., amyloid-β and tau. The glymphatic system may play an important role in clearing out these proteins via cerebrospinal fluid (CSF) flows through perivascular and interstitial spaces. Recent studies have suggested low-frequency (<0.1 Hz), sleep-dependent global blood-oxygenation-dependent-level (gBOLD; global resting-state functional MRI signal) during resting state is coupled with CSF movements, suggesting their potential link to glymphatic function. Here, we directly investigated whether the coupling between the gBOLD and CSF signals is related to AD-related pathology. By analyzing neuroimaging, neurobiological, and neuropsychological data from 118 human subjects (58-90 years of age; AD, early-stage AD, and control subjects included) collected in the Alzheimer's Disease Neuroimaging Initiative project, we found a strong coupling between the gBOLD and CSF signals. More importantly, the strength of this gBOLD-CSF coupling was significantly correlated with cortical amyloid-β level (p = 0.019), cognitive decline in the subsequent two years (p = 0.013), disease severity (p = 0.035), and several AD-related risk factors, including aging (p = 0.011), and gender (p = 0.026). These findings provide initial evidence for the critical role of resting-state low-frequency (<0.1 Hz) neural/physiological dynamics in AD pathology. They also suggest that the gBOLD-CSF coupling may serve as a non-invasive imaging marker for gauging the glymphatic function.

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Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903671116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26230-26238 ◽

Cited By ~ 12

Author(s):

Amy F. T. Arnsten ◽

Dibyadeep Datta ◽

Shannon Leslie ◽

Sheng-Tao Yang ◽

Min Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Immunoelectron Microscopy ◽

Rhesus Monkeys ◽

Early Stage ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Association Cortex ◽

Tau Pathology

Although mouse models of Alzheimer’s disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an “endosomal traffic jam” that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

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Decreased Alpha Reactivity from Eyes-Closed to Eyes-Open in Non-Demented Older Adults with Alzheimer’s Disease: A Combined EEG and [18F]florbetaben PET Study

Journal of Alzheimer s Disease ◽

10.3233/jad-200442 ◽

2020 ◽

Vol 77 (4) ◽

pp. 1681-1692

Author(s):

Soohyun Chae ◽

Jinsick Park ◽

Min Soo Byun ◽

Dahyun Yi ◽

Jun Ho Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Memory Function ◽

Amyloid Β ◽

Clinical Predictors ◽

Eyes Closed ◽

Positron Emission ◽

Eyes Open ◽

Early Biomarker

Background: The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer’s disease (AD) dementia. Objective: We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD. Methods: Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18F]florbetaben positron emission tomography assessment, the participants were divided into Aβ+ (N = 70) and Aβ- (N = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed. Results: A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F = 5.987, p = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F = 3.984, p = 0.048). Conclusion: Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD.

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