Current Alzheimer Research - Volume 17, Issue 9, 2020

Recent studies have recognized similarities between the peptides involved in the neuropathology of Alzheimer’s disease and prions. The Tau protein and the Amyloid β peptide represent the theoretical pillars of Alzheimer’s disease development. It is probable that there is a shared mechanism for the transmission of these substances and the prion diseases development; this presumption is based on the presentation of several cases of individuals without risk factors who developed dementia decades after a neurosurgical procedure. This article aims to present the role of Aβ and Tau, which underlie the pathophysiologic mechanisms involved in the AD and their similarities with the prion diseases infective mechanisms by means of the presentation of the available evidence at molecular (in-vitro), animal, and human levels that support the controversy on whether these diseases might be transmitted in neurosurgical interventions, which may constitute a wide public health issue.

Brain aging and aging-related neurodegenerative disorders are posing a significant challenge for health systems worldwide. To date, most of the therapeutic efforts aimed at counteracting dementiarelated behavioral and cognitive impairment have been focused on addressing putative determinants of the disease, such as β-amyloid or tau. In contrast, relatively little attention has been paid to pharmacological interventions aimed at restoring or promoting the synaptic plasticity of the aging brain. The review will explore and discuss the most recent molecular, structural/functional, and behavioral evidence that supports the use of non-pharmacological approaches as well as cognitive-enhancing drugs to counteract brain aging and early-stage dementia.

Experiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein.

Background: Recent trials suggest that disease-modifying therapy (DMT) for Alzheimer’s disease may become available soon. With the expected high price and a large patient pool, the budget impact will be substantial. Objective: We explore combinations of effectiveness and price under which a DMT is cost-effective. Methods: We used an open-source model to conduct two-way scenario analyses for both payer and societal perspectives, varying price, and treatment effect size simultaneously. The analysis generates costeffectiveness threshold prices over a potential range of DMT effectiveness in patients aged 65+ with mild cognitive impairment due to Alzheimer’s disease in the US. Results: Under the willingness-to-pay a threshold of $150,000 per quality-adjusted life year and assuming 30% risk reduction relative to the standard of care, the maximum cost-effective price of a DMT per patient per year is ~$22,000 and ~$15,000 from societal and payer perspectives, respectively. Conclusion: Joint variation of price and treatment effect size can help assess the cost-effectiveness of a potential Alzheimer’s disease treatment.

Background: Oxidative stress is the main feature of several diseases including Alzheimer’s disease (AD). The involvement of oxysterols derivates has been recently reported. Objective: The aim of this study was to evaluate the implication of oxidative stress in cholesterol impairment in AD patients. Methods: A case-control study was conducted on 56 AD patients and 97 controls. Levels of oxidative biomarkers, including lipid peroxidation products and antioxidant enzyme activities were measured with spectrophotometric methods on red blood cells (RBCs) and plasma. Cholesterol precursors and oxysterols (7-Ketocholeterol (7KC), 7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), 24Shydroxycholesterol (24S-OH), 25-hyroxycholesterol (25-OHC), and 27-hydroxycholesterol (27-OHC), in plasma were quantified by gas chromatography coupled with mass spectrometry. Results: In RBCs and plasma of AD patients, a significant decrease of glutathione peroxidase (GPx) activity was detected associated with raised levels of malondialdehyde (MDA). A decreased level of lanosterol and an accumulation of 7β-OHC, 24S-OHC, 27-OHC, and 25-OHC that were higher in plasma of AD patients, compared to controls, were also observed in AD patients. Mini-Mental State Examination (MMSE) score was correlated with MDA and conjugated dienes (CD) levels in plasma. Besides, the MDA level in RBCs was correlated with 7β-OHC. Binary logistic regression revealed an association between GPx activity and AD (OR=0.895, 95%CI: 0.848-0.945. P<0.001). Conclusion: Our data consolidate the relationship between the rupture of redox homeostasis and lipid and cholesterol oxidation in AD.

Background: Dementia is an overall term of brain diseases, including Alzheimer’s disease (AD), tauopathies and synucleinopathies. To date, somatic mutations in dementia-related genes, including the amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene, PSEN2 gene, microtubule- associated protein tau (MAPT) gene, alpha-synuclein (SNCA) gene and leucine-rich repeat kinase 2 (LRRK2) gene, have been considered one cause of dementia. We have questioned the impact of somatic mutations in dementia-related genes on cancer. Methods: In the present study, we investigated somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes and the impact of these somatic mutations. Results: From The Cancer Genome Atlas (TCGA) database, we found 1,643 somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes in cancer patients. Strikingly, compared to the distributions of cancer types in total cancer patients, somatic mutations in the dementia-related genes showed an extremely low distribution in glioblastoma patients. Conclusion: To the best of our knowledge, this is the first investigation of dementia-related genes in cancer patients.

Background: Although some studies suggest that writing difficulties may be one of the early symptoms of Alzheimer's disease (AD), they have been scarcely studied compared to oral language. Particularly noteworthy is the paucity of longitudinal studies that enable the observation of writing impairment as cognitive decline progresses. Objective: The aim of this study was to examine the characteristics of writing in patients with AD and to monitor the deterioration of their performance over a follow-up period. Methods: Sixty-four participants (half with AD and half healthy elderly) were compared in a word and pseudo-word dictation task. Patients were evaluated every 6 months over a 2.5 year follow-up period Results: The evolution of patient performance and error profile shows a typical pattern of deterioration, with early damage to the lexical pathway, which later extends to the phonological pathway and eventually affects peripheral processes. Conclusion: These results confirm the presence of writing difficulties from the early stages of AD, supporting the value of this task for early diagnosis. Furthermore, it allows us to explain the contradictory data obtained in previous investigations.

Background: We have recently identified Huntingtin (Htt), the pathogenic protein in Huntington's disease, as a mediator of Alzheimer's disease (AD) pathology in an amyloid precursor protein (APP) knock-in mouse model of AD. That finding prompted us to examine if Htt is accumulated in the brains of AD patients and in which cell type Htt is present in the AD brain. Objective: To investigate whether location and levels of Htt are affected in hippocampus and frontal cortex in AD. Methods: Brains from AD patients (n=11) and controls (n=11) were stained for Htt using immunohistochemistry and signal intensity of Htt was quantified and localized in subregions and neurons. Confocal microscopy was used to characterize neuronal Htt localisation and its relationship with tau tangles and astrocytes. Results: Htt levels were increased in neuronal cells in the granular layer of the dentate gyrus, in CA1 and CA3 in hippocampus and in layer III of the frontal cortex. Htt was found in the soma, perinuclear space, thin neurites and nucleus of pyramidal neurons. Htt was present in neurons containing tau tangles but did not colocalize with astrocytes. Conclusion: Htt accumulates in pyramidal neuron-rich areas including hippocampal subregions associated with memory and frontal cortex layer III. The accumulation of Htt in AD shows distinct cellular and morphological patterns and is not present in astrocytes. Clearly, further research is warranted to elucidate the role of Htt as a mediator of AD pathology and the potential use of Htt as a target in future therapeutic strategies.