Amyloid Cascade Hypothesis Research Articles

Amyloid-Beta Peptides Trigger Premature Functional and Gene Expression Alterations in Human-Induced Neurons.

Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aβ peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ1-42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. Using single-cell RNA sequencing, we also show that cell-secreted Aβ up-regulates the expression of several synapse-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and, to a lesser degree, in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of the SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Altogether, our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons, which can contribute to early alterations in neural network activity.

Transcending the amyloid-beta dominance paradigm in Alzheimer's disease: An exploration of behavioural, metabolic, and gut microbiota phenotypes in 5xFAD mice

The amyloid cascade hypothesis is widely accepted as an explanation for the neuropathological changes in Alzheimer's disease (AD). However, the role of amyloid-beta (Aβ) as the sole cause of these changes is being questioned. Using the 5xFAD mouse model of AD, we investigated various factors contributing to neuropathology, including genetic load (heterozygous (HTZ) versus homozygous (HZ) condition), behavioural phenotype, neuropathology markers, metabolic physiology, and gut microbiota composition at early (5 months of age) and late (12 months of age) stages of disease onset, and considering both sexes. At 5 months of age, both HTZ and HZ mice exhibited hippocampal alterations associated with Aβ accumulation, leading to increased neuroinflammation and disrupted PI3K-Akt pathway. However, only HZ mice showed cognitive impairment in the Y-maze and Morris water maze tests, worsening with age. Dysregulation of both insulin and insulin secretion-regulating GIP peptide were observed at 5 months of age, disappearing later. Circulating levels of metabolic-regulating hormones, such as Ghrelin and resisting helped to differentiates HTZ mice from HZ mice. Differences between HTZ and HZ mice were also observed in gut microbiota composition, disrupted intestinal barrier proteins, and increased proinflammatory products in the intestine. These findings suggest that cognitive impairment in 5xFAD mice may not solely result from Aβ aggregation. Other factors, including altered PI3K-Akt signalling, disrupted insulin-linked metabolic pathways, and changes in gut microbiota, contribute to disease progression. Targeting Aβ deposition alone may not suffice. Understanding AD pathogenesis and its multiple contributing factors is vital for effective therapies.

Portable Electrochemical Impedance Spectroscopy Device Implementation for Alzheimer's Disease-Related Protein

Electrochemical impedance spectroscopy (EIS) is an electrochemical technique to measure the impedance varieties of a system based on the alternating current (AC) potential frequency. This technique is high accuracy and frequently used to distinguish the influences between different components. The charge transfer resistance and electric double layer phenomenon commonly occur in these components in an electrochemical system. A slight sinusoidal excitation with multiple frequency has been used to process the phenomenon to impedance values. These values can be simulated as an equivalent circuit to analyze the resistance, amplitude, and phase angle in the actual electrochemical cell [1].Alzheimer's disease (AD) is the most common form of amnesia. However, AD symptoms are difficult to be conscious of in the early stage, and current screening methods are hard to popularize. Current research generally agrees that AD has a considerable association with beta-amyloid (Aβ) precipitation [2]. Aβ is the proteolytic fragment derived from amyloid precursor proteins (APP). These proteins can be used to screen the pathogenesis of AD. Biological detection chips capture these proteins and then use commercial instruments for detection. The biological detection chips are fabricated using a screen-print-electrode (SPE) chip which contains three gold electrodes, and the fabrication steps show in Figure 1(A). 11-Mercaptoundecaoic acid (11-MUA) was used as a self-assembled monolayer (SAM) to functionalize the biological chip. 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) have been used to activate the functional group on SAM to bond the antibody for specific detection of Aβ. Finally, block the residual activated groups with ethanolamine. After modifying the sensors, the protein was applied for measuring immediately.This research aims to popularize a portable device that can achieve rapid and accurate monitoring of early AD. In this study, an AD5933 chip was utilized as the main chip for a portable EIS device to compare with the commercial instrument CHI920D. This integrated circuit chip can be applied as an impedance meter. The AD5933 is embedded on a board that contains an analog front-end (AFE) circuit. This AFE circuit can bias the direct current (DC) output from 1.48 V to 0 V and AC output from 1.98V p-p to 0.1V p-p. Also, we applied a 25 kHz clock signal for AD5933 to sweep frequency in 10 Hz to 20 Hz with 1 Hz resolution. This portable device is controlled by NI Myrio1900, and NI LabVIEW system with a laptop, as shown in Figure 1(B).To analyze the signal gathered from the Aβ, a simulated actual electrochemical cell with an equivalent current is needed. The test frequency has been fixed between 10 to 20 Hz due to the limitation of AD5933. The original Randles circuit is the frequently used circuit applied to impedance calculation [1]. To optimize the current there are some conditions that can be ignored. For instance, the resistance of redox solution (RΩ), which the resistance is too small compared with the whole electrochemical cell. The Warburg element (Zw) gives a low impact on the frequency interval. Thus, the circuit can be optimized and simplified as a simple parallel resistor-capacitor (RC) circuit. To evaluate system performance, the same biological detection chips were used for both portable devices (Figure 1(B)) and CHI920D (Figure 1(C)). Both calculation method is sample charge transfer resistance (Rct) divided by blocking charge transfer resistance (Rct). The correlation coefficient R2 of these sensors is 0.97 (Figure 1(D)), which means the portable system result is identical to the CHI920D.In conclusion, our research accomplished the system with low frequency and low AC and DC measuring, indicating a higher sensitivity for early AD detection. The limitation of this research is the biological detection chips. These modified chips are time-sensitivities that lead to conservation becoming difficult. The experimental results suggest that this portable is a potential candidate for wide screening of AD, and arranging the portable device in pairs might accomplish the point of care of AD. Furthermore, this device can also develop with different biomarkers, depending on additional antibody modification. Bard, A.J., et al., Fundamentals and applications. Electrochemical Methods, 2001. 2(482): p. 580-632.Hardy, J.A., et al., Alzheimer's disease: the amyloid cascade hypothesis. Science, 1992. 256(5054): p. 184-186. Figure 1

Principles of Design of Clinical Trials for Prevention and Treatment of Alzheimer's Disease and Aging-Associated Cognitive Decline in the ACH2.0 Perspective: Potential Outcomes, Challenges, and Solutions.

With the Amyloid Cascade Hypothesis (ACH) largely discredited, the ACH2.0 theory of Alzheimer's disease (AD) has been recently introduced. Within the framework of the ACH2.0, AD is triggered by amyloid-β protein precursor (AβPP)-derived intraneuronal Aβ (iAβ) and is driven by iAβ produced in the AβPP-independent pathway and retained intraneuronally. In this paradigm, the depletion of extracellular Aβ or suppression of Aβ production by AβPP proteolysis, the two sources of AβPP-derived iAβ, would be futile in symptomatic AD, due to its reliance on iAβ generated independently of AβPP, but effective in preventing AD and treating Aging-Associated Cognitive Decline (AACD) driven, in the ACH2.0 framework, by AβPP-derived iAβ. The observed effect of lecanemab and donanemab, interpreted in the ACH2.0 perspective, supports this notion and mandates AD-preventive clinical trials. Such trials are currently in progress. They are likely, however, to fail or to yield deceptive results if conducted conventionally. The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived iAβ, in prevention of AD and treatment of AACD. It analyzes possible outcomes and explains why selection of high-risk asymptomatic participants seems reasonable but is not. It argues that outcomes of such AD preventive trials could be grossly misleading, discusses inevitable potential problems, and proposes feasible solutions. It advocates the initial evaluation of this type of drugs in clinical trials for treatment of AACD. Whereas AD protective trials of these drugs are potentially of an impractical length, AACD clinical trials are expected to yield unequivocal results within a relatively short duration. Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive iAβ depletion, contends that targeted degradation of iAβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential iAβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials.

Implication of the cooking oil-peroxidation product "hydroxynonenal" for Alzheimer's disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the "calpain-cathepsin hypothesis" as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer's disease similarly occurs by chronic ischemia via the calpain-cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid β (Aβ) peptide was thought to be a root substance of Alzheimer's disease. However, because of both the insignificant correlations between Aβ depositions and occurrence of neuronal death or dementia, and the negative results of anti-Aβ medicines tested so far in the patients with Alzheimer's disease, the strength of the "amyloid cascade hypothesis" has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer's disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that Aβ is not a culprit of Alzheimer's disease, but merely a byproduct of autophagy/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer's disease.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ =67.0, SD=2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. Additive genetics explained 44% to 52% of Aβ42, Aβ40, t-tau, and NfL. The Aβ42/40 ratio was not heritable. Aβ40 and Aβ42 were genetically near identical (rg =0.94). Both Aβ40 and Aβ42 were genetically correlated with NfL (rg =0.35 to 0.38), but genetically unrelated to t-tau. Except for Aβ42/40, plasma biomarkers are heritable. Aβ40 and Aβ42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aβs and t-tau is not consistent with the amyloid cascade hypothesis.

The Amyloid Cascade Hypothesis 2.0 for Alzheimer's Disease and Aging-Associated Cognitive Decline: From Molecular Basis to Effective Therapy.

With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer's disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-β (Aβ) in the disease, necessitated by the observation that all AD-causing mutations affect, in one way or another, Aβ. Yet, even this narrow commonality is superficial since AD-causing Aβ of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular Aβ, in the latter, it is triggered by Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ) and driven by iAβ generated independently of AβPP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of AβPP-derived iAβ, which occurs via internalization of secreted Aβ and through intracellular retention of a fraction of Aβ produced by AβPP proteolysis. When AβPP-derived iAβ reaches critical levels, it activates a self-perpetuating AβPP-independent production of iAβ that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of iAβ accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in AβPP-independent generation of iAβ, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic AβPP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of AβPP-derived iAβ can be effective only protectively for AD, the targeted degradation of iAβ is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential iAβ-degrading drugs.

BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia.

Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the "amyloid cascade hypothesis". However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca2+) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca2+ signaling may act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump might act as such Ca2+ stabilizing agents. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD.

Amyloid cascade hypothesis for Alzheimer’s disease. Does it work under physiological conditions?

<img src=” https://s3.amazonaws.com/production.scholastica/article/77826/large/prnano_942023_toc_figure.jpg?1686262046”> Plaques in the brain consisting of proteins are a hallmark of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such aggregates can be assembled spontaneously by specialized proteins such as amyloid beta (A β) proteins in the case of AD. Numerous in vitro studies made a foundation for the Amyloid Cascade Hypothesis (ACH), according to which the misfolding of proteins leads to their self-assembly into toxic oligomers along with the formation of amyloid fibrils assembled as plaques in the brain. Notably physiological concentration of A β proteins in the brain is in the low nanomolar concentration, so no spontaneous aggregation of A β protein occurs at such conditions, questioning the validity of the ACH model. However, recent studies revealed that surfaces could play a role as a catalyst of the aggregation process, so self-assembly of A β can be observed at physiologically low concentrations of A β proteins, although no spontaneous aggregation occurs in the bulk solution. The catalytic property of membrane surfaces towards A β aggregation depends on the membrane composition. This finding suggests a number of novel ideas on molecular mechanisms of amyloid self-assembly, which lay a foundation for the development of treatments and preventions for AD, as discussed in this article.

The amyloid cascade hypothesis: an updated critical review.

Results from recent clinical trials of antibodies that target β-amyloid (Aβ) for Alzheimer's disease (AD) have created excitement and have been heralded as corroboration of the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging, and biochemical data suggest a more complex etiology. Here we review the history and weaknesses of the amyloid cascade hypothesis in view of the new evidence obtained from clinical trials of anti-amyloid antibodies. These trials indicate that the treatments have either no or uncertain clinical effect on cognition. Despite the importance of amyloid in the definition of AD, we argue that the data point to Aβ and amyloid playing a minor etiological role. We also discuss data suggesting that the concerted activity of many pathogenic factors contribute to AD and propose that evolving multi-factor disease models will better underpin the search for more effective strategies to treat the disease.

Guluronic acid can inhibit copper(II) and amyloid − β peptide coordination and reduce copper-related reactive oxygen species formation associated with Alzheimer's disease

Copper-related reactive oxygen species (ROS) formation can lead to neuropathologic degradation associated with Alzheimer's disease (AD) according to amyloid cascade hypothesis. A complexing agent that can selectively chelate with copper ions and capture copper ions from the complex formed by copper ions and amyloid−β (Cu − Aβ complex) may be available in reducing ROS formation. Herein, we described applications of guluronic acid (GA), a natural oligosaccharide complexing agent obtained from enzymatic hydrolysis of brown algae, in reducing copper-related ROS formation. UV–vis absorption spectra demonstrated the coordination between GA and Cu(II). Ascorbic acid consumption and coumarin–3–carboxylic acid fluorescence assays confirmed the viability of GA in reducing ROS formation in solutions containing other metal ions and Aβ. Fluorescence kinetics, DPPH radical clearance and high resolution X − ray photoelectron spectroscopy results revealed the reductivity of GA. Human liver hepatocellular carcinoma (HepG2) cell viability demonstrated the biocompatibility of GA at concentrations lower than 320 μM. Cytotoxic results of human neuroblastoma (SH–SY5Y) cells verified that GA can inhibit copper-related ROS damage in neuronal cells. Our findings, combined with the advantages of marine drugs, make GA a promising candidate in reducing copper-related ROS formation associated with AD therapy.

A Study of HDAC6 for Ameliorating the Cognitive Function in Alzheimer's Disease

One of the most prevalent causes of dementia, Alzheimer's disease (AD) is characterized by gradual mental decline and memory loss over time. Several drugs are currently available for the treatment of AD, but they only address the disease's symptoms rather than its underlying pathogenesis. Researchers looked into epigenetic therapy and found that histone deacetylase 6 (HDAC6) could be an effective treatment for Alzheimer's disease. This paper uses a literature review approach to investigate the roles of HDAC6 inhibition in AD models and HDAC6 inhibitors, as well as the hypotheses surrounding the pathogenesis of AD. The amyloid cascade hypothesis, the tau hypothesis, and the role of oxygen species are identified as the most prominent pathogenesis hypotheses in this paper. A decrease in Hdac6 levels improves associative and spatial memory in an Alzheimer's disease mouse model and reverses the mitochondrial trafficking impairment in hippocampal neurons in vitro and in vivo. Therefore, inhibiting HDAC6 may represent a novel approach to treating AD-related cognitive decline. As a result of these issues, the FDA has yet to approve any HDAC6 inhibitor for use in the treatment of Alzheimer's disease (FDA)

An Overview of Current Research on Alzheimers Disease

Alzheimers disease, a typical neurodegenerative disease, has been one of the most chal-lenging problems for researchers and doctors. Having known many of its negative impacts such as cognitive decline and disturbed sleep, researchers are yet unable to figure out what specifically causes it and how to effectively cure it. In other words, the underlying mecha-nisms of the disease seem to be very complex, contributing to an incomplete understanding of the disease and an increasing number of patients who cannot be fully recovered. There-fore, the purpose of this article is to summarize current findings about the disease and to provide suggestions for future research. It seeks to answer the question of what can be done to find a cure for the disease. To conduct this research, information and data from academic journals will be analyzed. Some relevant theories such as the amyloid cascade hypothesis will also be covered. As a result of this research, it is suggested that researchers should fo-cus on causes of the abnormalities of different proteins, treatments for tau pathology as well as the specific relationship between healthy lifestyle and cognitive health.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

Exploring the ATN classification system using brain morphology

BackgroundThe NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.MethodsWe used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/−), CSF phospho-tau (T+/−), and adjusted hippocampal volume or CSF total-tau (N+/−). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A−T−N− towards A+T+N+ including also non-AD continuum ATN groups.ResultsThe ACH-based progression A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.ConclusionUsing the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy.Trial registrationDRKS00007966, 04/05/2015, retrospectively registered.

Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = -0.37, P = 0.03) and memory functioning (β = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.

The Amyloid Cascade Hypothesis in Alzheimer's Disease: Should We Change Our Thinking?

Old age increases the risk of Alzheimer's disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD.

BACE-1 Inhibitors Targeting Alzheimer's Disease.

The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.

Advances in the pathogenesis of Alzheimer’s disease: A re-evaluation of the Amyloid cascade hypothesis

Alzheimer's disease (AD), the most common cause of dementia in the elderly is a common neurodegenerative disease characterized clinically by progressive memory deterioration. The disease becomes clinically obvious as an insidious higher intellectual function impairment with altered mood and behavior, dramatic personality changes, disorientation, declining physical coordination and inability to care for themselves. Histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. During final stages, victims are bedridden, urinary and bowel function controls may be lost with epileptic attacks. Death is usually due to pneumonia, bedsores or secondary urinary tract infections. These manifestations may indicate severe cortical dis-function. In 5-10 year time, affected individual becomes profoundly disabled, mute and immobile. Death may ensue within an average of 8 years of diagnosis, the last 3 of which are typically spent in institutions. AD is the number one cause of institutionalization in United States of America. An appraisal of the advances in pathogenesis of Alzheimer’s disease will be helpful in updating our knowledge on possible etiologies and desired advancements in therapies, clinical care and entire management. Secondly, with the rising cases of AD in tropical regions of the world and coupled with the significant scarcity of literature on Alzheimer’s Disease, the need for this compendium becomes obviously necessary, hence we chose to write. This very review derives from focused overview of pathophysiologies and management of AD. Literature searches were sourced from PubMed, Science Direct, Scopus and Google Scholar.