Hypothesis Of Alzheimer's Disease Research Articles

Alzheimer's disease hypotheses

Current work on Alzheimer's disease shows that there is no shortage of hypotheses-generating research attesting to a will to understand, says George Winter

Failure of current Alzheimer's disease hypotheses.

Failure of current Alzheimer's disease hypotheses.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics.

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD - Aβ plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.

The Disconnection Hypothesis inAlzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging.

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p < 0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

Benefits of deep encoding in Alzheimer's disease. Analysis of performance in a memory task using the Item Specific Deficit Approach

IntroductionThe aim of this study was to test the encoding deficit hypothesis in Alzheimer disease (AD) using a recent method for correcting memory tests. To this end, a Spanish-language adaptation of the Free and Cued Selective Reminding Test was interpreted using the Item Specific Deficit Approach (ISDA), which provides three indices: Encoding Deficit Index, Consolidation Deficit Index, and Retrieval Deficit Index. MethodsWe compared the performances of 15 patients with AD and 20 healthy control subjects and analysed results using either the task instructions or the ISDA. ResultsPatients with AD displayed deficient encoding of more than half the information, but items that were encoded properly could be retrieved later with the help of the same semantic clues provided individually during encoding. Virtually all the information retained over the long term was retrieved by using semantic clues. Encoding was shown to be the most impaired process, followed by retrieval and consolidation. Discriminant function analyses showed that ISDA indices are more sensitive and specific for detecting memory impairments in AD than are raw scores. ConclusionsThese results indicate that patients with AD present impaired information encoding, but they benefit from semantic hints that help them recover previously learned information. This should be taken into account for intervention techniques focusing on memory impairments in AD.

β-Amyloid Fibrils in Alzheimer Disease Are Not Inert When Bound to Copper Ions but Can Degrade Hydrogen Peroxide and Generate Reactive Oxygen Species

According to the "amyloid cascade" hypothesis of Alzheimer disease, the formation of Aβ fibrils and senile plaques in the brain initiates a cascade of events leading to the formation of neurofibrillary tangles, neurodegeneration, and the symptom of dementia. Recently, however, emphasis has shifted away from amyloid fibrils as the predominant toxic form of Aβ toward smaller aggregates, referred to as "soluble oligomers." These oligomers have become one of the prime suspects for involvement in the early oxidative damage that is evident in this disease. This raises the question whether or not Aβ fibrils are actually "inert tombstones" present at the end of the aggregation process. Here we show that, when Aβ(1-42) aggregates, including fibrils, are bound to Cu(II) ions, they retain their redox activity and are able to degrade hydrogen peroxide (H2O2) with the formation of hydroxyl radicals and the consequent oxidation of the peptide (detected by formation of carbonyl groups). We find that this ability increases as the Cu(II):peptide ratio increases and is accompanied by changes in aggregate morphology, as determined by atomic force microscopy. When aggregates are prepared in the copresence of Cu(II) and Zn(II) ions, the ratio of Cu(II):Zn(II) becomes an important factor in the degeneration of H2O2, the formation of carbonyl groups in the peptide, and in aggregate morphology. We believe, therefore, that Aβ fibrils can destroy H2O2 and generate damaging hydroxyl radicals and, so, are not necessarily inert end points.

Beneficios de la codificación profunda en la enfermedad de Alzheimer. Análisis del rendimiento en una tarea de memoria mediante el Item Specific Deficit Approach

Introductionthe aim of this study is to test the encoding deficit hypothesis in Alzheimer disease (AD) using a recent method for correcting memory tests. To this end, a Spanish-language adaptation of the Free and Cued Selective Reminding Test was interpreted using the Item Specific Deficit Approach (ISDA), which provides three indices: Encoding Deficit Index, Consolidation Deficit Index, and Retrieval Deficit Index. MethodsWe compared the performances of 15 patients with AD and 20 healthy control subjects and analysed results using either the task instructions or the ISDA approach. Resultspatients with AD displayed deficient encoding of more than half the information, but items that were encoded properly could be retrieved later with the help of the same semantic clues provided individually during encoding. Virtually all the information retained over the long-term was retrieved by using semantic clues. Encoding was shown to be the most impaired process, followed by retrieval and consolidation. Discriminant function analyses showed that ISDA indices are more sensitive and specific for detecting memory impairments in AD than are raw scores. ConclusionsThese results indicate that patients with AD present impaired information encoding, but they benefit from semantic hints that help them recover previously learned information. This should be taken into account for intervention techniques focusing on memory impairments in AD.

Lack of reliable evidence for a distinctive ε4−related cognitive phenotype that is independent from clinical diagnostic status: findings from the Australian Imaging, Biomarkers and Lifestyle Study

Individuals who carry the apolipoprotein E ε4 polymorphism have an increased risk of late-onset Alzheimer's disease. However, because possession of the ε4 allele confers an increased risk for the diagnosis of dementia, it has proven problematic in older individuals to dissociate the influence of ε4 on cognitive capacity per se as distinct from its influence on clinical diagnostic status. We report a statistical approach that attempts to partial out the influence of diagnostic group membership (Alzheimer's disease, mild cognitive impairment, healthy control) from the influence of apolipoprotein ε4 genetic status on cognitive functioning. The cognitive phenotype hypothesis predicts that ε4-positive individuals will show cognitive deficits (relative to matched ε4-negative individuals) independent of the development of Alzheimer's disease. By contrast, the prodromal/preclinical Alzheimer's disease hypothesis proposes that the effect of apolipoprotein E status on cognitive performance is a function of the increased risk of dementia in individuals with the ε4 allele. We evaluated these hypotheses in the Australian Imaging, Biomarkers and Lifestyle cohort (n = 1112). We first determined whether previously reported findings concerning ε4 status and age-related neuropsychological performance could be explained by the inadvertent recruitment of people with mild cognitive impairment into the healthy control group. We then tested each diagnostic group in isolation to identify any neuropsychological patterns that may be attributed to the ε4 allele. Finally, as interactions between the ε4 allele and age have previously been reported in cognitive functioning within healthy elderly populations, we attempted to determine whether the inclusion of mild cognitively impaired individuals in the sample may drive this relationship. An extensive battery of standardized, well-validated neuropsychological tasks was administered to a final sample of 764 healthy control subjects, 131 individuals with mild cognitive impairment and 168 individuals with Alzheimer's disease. The effect of the ε4 allele on cognitive performance was assessed using a statistical mediation analysis and supplemented with Bayesian methods to address a number of the limitations associated with Fisherian/Neyman-Pearsonian significance testing. Our findings support the prodromal/preclinical Alzheimer's disease hypothesis and do not support the concept of a distinctive ε4-related cognitive phenotype.

N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody

BackgroundThe amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology.ResultsUsing different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD.ConclusionsAβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.

Path planning in the hippocampo-prefrontal cortex pathway: An adaptive model based receding horizon planner

Four characteristic properties of human path planning strategy are course and fine planning, supervised planning, adaptation and robustness, and complexity reduction. These four characteristics are also observed in "model predictive controller" and its modified version, "receding horizon planner". We hypothesize that the human brain performs path planning tasks, literally like a receding horizon planner. The similarities between human brain and a receding horizon planner are: (1) hippocampus contains the course model and the parietal cortex is responsible for the fine model. (2) Replanning and trajectory tuning using the visual data in parietal cortex and prefrontal cortex is exploited in an adaptive restricted receding horizon. Prefrontal cortex plays the role of the supervisor. (3) Adjusting the sampling time of the planner is implemented based on changes in the complexity of the environment and tasks. This is in fact, the adaptation, which exists both in human behavior and in receding horizon planner. (4) The brain simplifies path-finding problems to reduce computational loads, exactly similar to what engineering controllers intend to do. The visual data is smoothed by clustering of obstacles, before performing any computational task. Finally, we have discussed the consequence of our hypothesis in Alzheimer disease as an optimal planning disorder. Based on some experimental data, Alzheimer patients have a reduced predictive horizon, making the system less robust and exposed to hazardous conditions in sophisticated environments. Patients with mild Alzheimer disease have little trouble with simple optimization problems; working memory of the prefrontal cortex is sufficient for this purpose. However, in complicated tasks, the brain needs huge extended memory. This memory is available through hippocampo-prefrontal pathway, which is to some extent disturbed in Alzheimer patients. We suggest that this fact may be a basis for future experimental diagnosis tests. We predict that Alzheimer patients should have problems with planning for far future; because they have a weak memory, insufficient for heavy optimization tasks, such as moving through moving obstacles in a dynamic environment. Alzheimer disease could be early detected by designing new tests in which the ability of patients to predict the future events is checked. These tests could be accompanied with a multi-step optimization problem. We believe that paying attention to this opinion may provide a good help in diagnosing Alzheimer disease in earlier stages. Surely, experimental studies are needed to validate our hypothesis.

An Alzheimer's disease hypothesis based on transcriptional dysregulation

Alzheimer's diseuse (AD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by progressive loss of memory and other cognitive skills. Neurons in the limbic and association cortices become progressively dysfunctional affecting almost all cognitive functions and memory. The PS1-regulated ε-secretase cleavage of type I transmembrane receptors controls production of transcriptionally active intracellular fragments (ICFs) suggesting that this cleavage is a key factor in surface-to-nucleus signal transduction and gene expression. Signal-induced gene expression mediates neuronal responses to environmental changes and is a key event in neuronal survival and synaptic function. Familial Alzheimer's Disease (FAD) mutations may interfere with nuclear signaling and transcription by interfering with the PS1/ε-secretase cleavage and production of transcriptionally active ICFs. This raises the possibility that, similar to polyglutamine induced neurodegeneration like Huntington's chorea, transcriptional abnormalities are involved in the development of FAD.

Protein aging hypothesis of Alzheimer disease

Alzheimer disease (AD), the most common form of aging-related neurodegenerative disorders, is associated with formation of fibrillar deposits of amyloid β-protein (Aβ). While the direct involvement of Aβ in AD has been well documented, the relations between Aβ production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein aging-related structural transformation in soluble Aβ. We hypothesize that spontaneous chemical modification of aspartyl residues in Aβ to transient succinimide induces a non-native conformation in a fraction of soluble Aβ, rendering it amyloidogenic and neurotoxic. Conformationally altered Aβ is characterized by increased stability in solution and the presence of a non-native β-turn that determines folding of Aβ in solution and the structure of Aβ subunits incorporated into amyloid fibrils. While the soluble ‘non-native’ Aβ is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events...

A unifying hypothesis of Alzheimer's disease. I. Ageing sets the stage

In a series of five papers, evidence from neurobiology, endocrinology and immunology is integrated into a holistic, coherent hypothesis accommodating genetic, medical and environmental risk factors into a cascade of pathophysiological events that leads to the clinical manifestation of Alzheimer's disease (AD). The perturbation of the calcium-energy-oxidative stress triangle emerges as pathophysiological leitmotif of ageing and AD. Cellular Ca2+ homeostasis and energy metabolism are closely interdependent. Ca2+ ions regulate the activity of a variety of rate-limiting enzymes of the tricarboxylic acid cycle and respiratory chain. Under physiological circumstances, the supply of energy according to demand is regulated by Ca2+ cycling across mitochondrial membranes. In certain pathological conditions, Ca2+ uncouples electron transfer and oxidative phosphorylation and increases the mitochondrial production of oxygen radicals which in tandem with Ca2+ precipitate the breakdown of mitochondrial function and structure. As most important risk factor, ageing sets the stage for the development of AD. The delicate regulation of the neuroendocrine network which physiologically modulates the Ca2+-energy-redox homeostasis, deteriorates in ageing, compromising the hormonal balance between neurotrophic/protective and neuroaggressive factors. Thus, levels and/or signal transduction pathways of neurotrophic-factors such as neuropeptide Y, neurotrophins, DHEA/DHEAS, gonadal hormones, melatonin, insulin, insulin-like growth factors, somatostatin, thyroid hormones, and substance P decay, paralleled by the compromise of the hypothalmic-pituitary-adrenal (HPA)-axis feedback inhibition leading to a hyperresponsiveness to stress and a loss of diurnal rhythm of secretion of neuroaggressive glucocorticoids. Both add up to disrupt Ca2+ and energy homeostasis, put the nerve cells under metabolic and oxidative stress and lead to a compromise of neuronal excitability, signal transduction processes and neuronal plasticity. Subject to the same endocrinological dysregulation, the ageing immune system exhibits a primitive response pattern with impairment of specific cellular and activation of unspecific humoral and microglial immune responses. Thus, the ageing-related concerted perturbation of the homeostatic control in the neuroendocrino-immunological network creates phenomena which in many aspects are qualitatively similar to changes in AD and lay the foundations for the development of the disease. Copyright © 1999 John Wiley & Sons, Ltd.

807 Evidence supporting the inflammatory hypothesis of Alzheimer disease

807 Evidence supporting the inflammatory hypothesis of Alzheimer disease

RS 86 in manic disorder

Recently, the spiropiperidyl derivate RS 86, a specific muscarinic agonist, attracted attention in the context of the cholinergic hypothesis of Alzheimer's disease. This compound revived the interest in the clinical usefulness of cholinergic agents in mania. In the present report, the findings in eight patients subjected to the same design will be summarized