Aspects Of Alzheimer's Disease Research Articles

Novel drug discovery: Advancing Alzheimer's therapy through machine learning and network pharmacology

Alzheimer's disease (AD), marked by tau tangles and amyloid-beta plaques, leads to cognitive decline. Despite extensive research, its complex etiology remains elusive, necessitating new treatments. This study utilized machine learning (ML) to analyze compounds with neuroprotective potential. This approach exposed the disease's complexity and identified important proteins, namely MTOR and BCL2, as central to the pathogenic network of AD. MTOR regulates neuronal autophagy and survival, whereas BCL2 regulates apoptosis, both of which are disrupted in AD. The identified compounds, including Armepavine, Oprea1_264702,1-cyclopropyl-7-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid,(2S)-4′-Hydroxy-5,7,3′-trimethoxyflavan,Oprea1_130514,Sativanone,5-hydroxy-7,8-dimethoxyflavanone,7,4′-Dihydroxy-8,3′-dimethoxyflavanone,N,1-dicyclopropyl-6,Difluoro-Methoxy-Gatifloxacin,6,8-difluoro-1-(2-fluoroethyl),1-ethyl-6-fluoro-7-(4-methylpiperidin-1-yl),Avicenol C, demonstrated potential modulatory effects on these proteins. The potential for synergistic effects of these drugs in treating AD has been revealed via network pharmacology. By targeting numerous proteins at once, these chemicals may provide a more comprehensive therapeutic approach, addressing many aspects of AD's complex pathophysiology. A Molecular docking, dynamic simulation, and Principle Component Analysis have confirmed these drugs' efficacy by establishing substantial binding affinities and interactions with important proteins such as MTOR and BCL2. This evidence implies that various compounds may interact within the AD pathological framework, providing a sophisticated and multifaceted therapy strategy. In conclusion, our study establishes a solid foundation for the use of these drugs in AD therapy. Thus current study highlights the possibility of multi-targeted, synergistic therapeutic approaches in addressing the complex pathophysiology of AD by integrating machine learning, network pharmacology, and molecular docking simulations. This holistic technique not only advances drug development but also opens up new avenues for developing more effective treatments for this difficult and widespread disease.

Neuropsychiatric Manifestations in Alzheimer's Disease Patients: Genetics and Treatment Options.

Alzheimer's disease (AD) is characterized by neuropsychiatric symptoms (NPS), which cause great misery to those with dementia and those who care for them and may lead to early institutionalization. The present systematic review aims to discuss the various aspects of Alzheimer's, including treatment options. The databases Embase, PubMed, and Web of Science were searched to collect data. Incipient cognitive deterioration is commonly accompanied by these early warning signals of neurocognitive diseases. The neurobiology of NPSs in Alzheimer's disease, as well as particular symptoms, including psychosis, agitation, apathy, sadness, and sleep disorders, will be examined in this review. For NPSs in Alzheimer's disease, clinical trial designs, as well as regulatory issues, were also addressed. A fresh wave of research, however, is helping to push the discipline ahead. For medication development and repurposing, we highlight the most recent results in genetics, neuroimaging, and neurobiology. Even though identifying and treating psychosis in adults with dementia is still a challenging endeavor, new options are coming up that give the field fresh focus and hope. It can be concluded from the complete literature survey that Alzheimer's-related psychosis as well as other symptoms that are not psychotic, have made significant progress in the last decade. These milestones in the development of safer, more effective treatments have been achieved as a consequence of great focus on non-pharmacological interventions like DICE or WHELD; the investigation into ways to improve existing drugs like aripiprazole, risperidone, amisulpride, and Escitalopram for safer precision-based treatment; and the development of a clinical trial program for pimavanserin.

An immunological puzzle: The adaptive immune system fuels Alzheimer’s disease pathology

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a concerning rise in prevalence. It is projected that the number of affected individuals will reach a staggering 150 million by 2050. While recent advancements in monoclonal antibodies targeting Aβ have shown some clinical effects, there is an urgent need for improved therapies to effectively address the impeding surge of AD patients worldwide. To achieve this, a deeper understanding of the intricate mechanisms underlying the disease is crucial. In recent years, mounting evidence has underscored the vital role of the innate immune system in AD pathology. However, limited findings persist regarding the involvement of the adaptive immune system. Here, we report on the impact of the adaptive immune system on various aspects of AD by using AppNL-G-F mice crossed into a Rag2−/− background lacking mature adaptive immune cells. In addition, to simulate the continuous exposure to various challenges such as infections that is commonly observed in humans, the innate immune system was activated through the repetitive induction of peripheral inflammation. We observed a remarkably improved performance on complex cognitive tasks when a mature adaptive immune system is absent. Notably, this observation is pathologically associated with lower Aβ plaque accumulation, reduced glial activation, and better-preserved neuronal networks in the mice lacking a mature adaptive immune system. Collectively, these findings highlight the detrimental role of the adaptive immune system in AD and underscore the need for effective strategies to modulate it for therapeutic purposes.

Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol-induced) and aspects of Alzheimer's disease (glutamate-induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol- and glutamate-induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase-3/7 activity.

Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET

Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and synaptic density. DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univariate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r=-0.55, p <0.001, df=31) but not CN (r=0.13, p=0.62, df=15). Exploratory analyses across other regions known to be affected in AD suggested widespread inverse associations between synaptic density and MD in the AD group. In the setting of AD, an increase in gray matter MD is inversely associated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology.

Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer's Disease Based on Novel Monoterpene-Derived Hydroxamic Acids.

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer's disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer's disease.

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity

Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Neutrophils as a potential therapeutic target in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in the United States. Sporadic or late-onset AD remains incompletely understood, with age as the current greatest risk factor. Inflammation in general and neutrophils, a potent mediator of inflammation, have been shown to exacerbate AD associated dementia. This review explores the latest research on neutrophils in AD mouse models and in human cohort studies and discusses current gaps in research and needs for future studies. AD mouse models have shown neutrophil chemotactic migration towards amyloid beta plaques in the brain. Capillary blood flow stalling decreases blood perfusion to associated brain regions and mouse studies have demonstrated that anti-Ly6G antibodies lead to a decrease in capillary blood flow stalling and memory improvement. Several recent transcriptomic studies of blood and brain tissue from persons with AD have shown an upregulation in neutrophil-related genes, and studies have demonstrated neutrophil involvement in brain capillary adhesion, blood brain barrier breaching, myeloperoxidase release, and the propensity for neutrophil extracellular trap release in AD. Neutrophil-derived inflammation and regulation are a potential potent novel therapeutic target for AD progression. Future studies should further investigate neutrophil functionality in AD. In addition, other aspects of AD that may impact neutrophils including the microbiome and the APOE4 allele should be studied.

Is vitamin D supplementation of potential benefit for community-living people with Alzheimer's disease?

Background Vitamin D is associated not only with effects on calcium and bone metabolisms but also with many chronic diseases. Low vitamin D levels in patients with Alzheimer's disease have been widely reported in the literature. Aim The purpose of this study was to critically review the potential benefit of vitamin D supplementation in individuals with Alzheimer's disease living in the community. Methods: A systematic literature search was conducted in PubMed, CINAHL, EMBASE and the Cochrane Library for papers published 2011–2018. Results Seven papers were selected, consisting of one clinical trial, five cohort studies and one systematic review. Studies showed an association only between vitamin D deficiency and lower attention in older people. None of the reviewed studies provided evidence of a positive impact of vitamin D supplementation on cognitive function in older people with Alzheimer's disease. Conclusion There was no evidence that vitamin D supplementation has a direct benefit for Alzheimer's disease. The review synthesised the existing body of knowledge and concluded that optimum levels of vitamin D (neither too low nor too high) do appear to have positive effects on patient outcomes and quality of life. It is still unclear why vitamin D intake is inadequate as people age. Further research is needed to clarify vitamin-D-related aspects of Alzheimer's disease.

Is vitamin D supplementation of potential benefit for community-living people with Alzheimer's disease?

Vitamin D is associated not only with effects on calcium and bone metabolisms but also with many chronic diseases. Low vitamin D levels in patients with Alzheimer's disease have been widely reported in the literature. The purpose of this study was to critically review the potential benefit of vitamin D supplementation in individuals with Alzheimer's disease living in the community. A systematic literature search was conducted in PubMed, CINAHL, EMBASE and the Cochrane Library for papers published 2011-2018. Seven papers were selected, consisting of one clinical trial, five cohort studies and one systematic review. Studies showed an association only between vitamin D deficiency and lower attention in older people. None of the reviewed studies provided evidence of a positive impact of vitamin D supplementation on cognitive function in older people with Alzheimer's disease. There was no evidence that vitamin D supplementation has a direct benefit for Alzheimer's disease. The review synthesised the existing body of knowledge and concluded that optimum levels of vitamin D (neither too low nor too high) do appear to have positive effects on patient outcomes and quality of life. It is still unclear why vitamin D intake is inadequate as people age. Further research is needed to clarify vitamin-D-related aspects of Alzheimer's disease.

Bioinformatics analysis of diagnostic biomarkers for Alzheimer's disease in peripheral blood based on sex differences and support vector machine algorithm

BackgroundThe prevalence of Alzheimer's disease (AD) varies based on gender. Due to the lack of early stage biomarkers, most of them are diagnosed at the terminal stage. This study aimed to explore sex-specific signaling pathways and identify diagnostic biomarkers of AD.MethodsMicroarray dataset for blood was obtained from the Gene Expression Omnibus (GEO) database of GSE63060 to conduct differentially expressed genes (DEGs) analysis by R software limma. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene set enrichment analysis (GSEA) were conducted. Immune checkpoint gene expression was compared between females and males. Using CytoHubba, we identified hub genes in a protein–protein interaction network (PPI). Then, we evaluated their distinct effectiveness using unsupervised hierarchical clustering. Support vector machine (SVM) and ten-fold cross-validation were used to further verify these biomarkers. Lastly, we confirmed our findings by using another independent dataset.ResultsA total of 37 female-specific DEGs and 27 male-specific DEGs were identified from GSE63060 datasets. Analyses of enrichment showed that female-specific DEGs primarily focused on energy metabolism, while male-specific DEGs mostly involved in immune regulation. Three immune-checkpoint-relevant genes dysregulated in males. In females, however, these eight genes were not differentially expressed. SNRPG, RPS27A, COX7A2, ATP5PO, LSM3, COX7C, PFDN5, HINT1, PSMA6, RPS3A and RPL31 were regarded as hub genes for females, while SNRPG, RPL31, COX7C, RPS27A, RPL35A, RPS3A, RPS20 and PFDN5 were regarded as hub genes for males. Thirteen hub genes mentioned above was significantly lower in both AD and mild cognitive impairment (MCI). The diagnostic model of 15-marker panel (13 hub genes with sex and age) was developed. Both the training dataset and the independent validation dataset have area under the curve (AUC) with a high value (0.919, 95%CI 0.901–0.929 and 0.803, 95%CI 0.789–0.826). Based on GSEA for hub genes, they were associated with some aspects of AD pathogenesis.ConclusionDEGs in males and females contribute differently to AD pathogenesis. Algorithms combining blood-based biomarkers may improve AD diagnostic accuracy, but large validation studies are needed.

Targeted Lipidomics To Measure Phospholipids and Sphingomyelins in Plasma: A Pilot Study To Understand the Impact of Race/Ethnicity in Alzheimer's Disease.

The number of people suffering from Alzheimer's disease (AD) is increasing rapidly every year. One aspect of AD that is often overlooked is the disproportionate incidence of AD among African American/Black populations. With the recent development of novel assays for lipidomics analysis in recent times, there has been a drastic increase in the number of studies focusing on changes of lipids in AD. However, very few of these studies have focused on or even included samples from African American/Black individuals samples. In this study, we aimed to determine if the lipidome in AD is universal across non-Hispanic White and African American/Black individuals. To accomplish this, a targeted mass spectrometry lipidomics analysis was performed on plasma samples (N = 113) obtained from cognitively normal (CN, N = 54) and AD (N = 59) individuals from African American/Black (N = 56) and non-Hispanic White (N = 57) backgrounds. Five lipids (PS 18:0_18:0, PS 18:0_20:0, PC 16:0_22:6, PC 18:0_22:6, and PS 18:1_22:6) were altered between AD and CN sample groups (p value < 0.05). Upon racial stratification, there were notable differences in lipids that were unique to African American/Black or non-Hispanic White individuals. PS 20:0_20:1 was reduced in AD in samples from non-Hispanic White but not African American/Black adults. We also tested whether race/ethnicity significantly modified the association between lipids and AD status by including a race × diagnosis interaction term in a linear regression model. PS 20:0_20:1 showed a significant interaction (p = 0.004). The discovery of lipid changes in AD in this study suggests that identifying relevant lipid biomarkers for diagnosis will require diversity in sample cohorts.

ABCA7 gene as a potential therapeutic target in the management of Alzheimer's disease

ABCA7 is a gene that belong to the family of ATP-binding cassette (ABC) transporter gene superfamily. Based on their structure and sequence homology, ABC transporters are divided into seven sub families. Asides from its function in lipid transport, high levels of ABCA7 is expressed in the hippocampus and has been identified with Alzheimer's disease (AD) risk. Over time, research has been done to identify therapeutic targets in the management of Alzheimer's disease.A literature search on ABCA7 and therapeutic targets was carried out through the PubMed database. The exclusion and inclusion criteria were used to achieve reliable and accurate results.Using the string "ABCA7 AND Alzheimer's", 197 results were obtained from the search as at January 24th , 2021. The search was narrowed down by using the string "ABCA7 AND Therapeutic targets". The 2nd search yielded 17 results after which some papers were excluded. Findings revealed that 10 (59%) out of 17 papers obtained from the search associated ABCA7 with late-onset AD risk. This indicate the relevance of ABCA7 in the pathogenesis of Alzheimer's disease. Out of the 10 papers studied, 5 (50%) included ABCA7 gene in studies pertaining to therapeutic targets in Alzheimer's disease. This shows that ABCA7 is considered a therapeutic target for Alzheimer's disease.Despite the progress made so far, more work still needs to be done to validate ABCA7 gene as a therapeutic tool in AD management. It is hoped that this review will encourage more research in this aspect of Alzheimer's disease management.

Current Alzheimer disease research highlights: evidence for novel risk factors.

Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.

A Systematic Review of Clinical Decision Support Systems in Alzheimer’s Disease Domain

Dementia is one of the major public health issues faced by the world. Alzheimer’s disease (AD) is the most common form of dementia targeting old age groups around the world. It is a neurodegenerative condition with memory loss as its early symptom. Unfortunately, there is no cure for this disease currently. So various research in the medical and technical fields are being conducted to help people with Alzheimer’s. Many studies focus on early diagnosis of Alzheimer’s disease using clinical decision support system (CDSS) so that the progression of the disease can be slowed down to a great extent. In this context, we have undertaken a research to design and implement an ontology based Clinical decision support system for Alzheimer’s disease in Sultanate of Oman. A semantic knowledgebase (ontology) will be the core component of our Clinical decision support system. The objective of this research paper is two-fold (a) review the medical aspects of Alzheimer’s disease, and (b) review the available clinical decision support system based on ontology, robotics, and mobile applications in Alzheimer domain. Research articles published during 2011- 2020 in PubMed, Google scholar, Elsevier, SpringerLink and IEEE journals were reviewed. We found that there is various clinical decision support system which can aid physicians in suggesting diagnosis, and treatment of Alzheimer’s disease.

Temporal Integration of Text Transcripts and Acoustic Features for Alzheimer's Diagnosis Based on Spontaneous Speech.

Background: Advances in machine learning (ML) technology have opened new avenues for detection and monitoring of cognitive decline. In this study, a multimodal approach to Alzheimer's dementia detection based on the patient's spontaneous speech is presented. This approach was tested on a standard, publicly available Alzheimer's speech dataset for comparability. The data comprise voice samples from 156 participants (1:1 ratio of Alzheimer's to control), matched by age and gender.Materials and Methods: A recently developed Active Data Representation (ADR) technique for voice processing was employed as a framework for fusion of acoustic and textual features at sentence and word level. Temporal aspects of textual features were investigated in conjunction with acoustic features in order to shed light on the temporal interplay between paralinguistic (acoustic) and linguistic (textual) aspects of Alzheimer's speech. Combinations between several configurations of ADR features and more traditional bag-of-n-grams approaches were used in an ensemble of classifiers built and evaluated on a standardised dataset containing recorded speech of scene descriptions and textual transcripts.Results: Employing only semantic bag-of-n-grams features, an accuracy of 89.58% was achieved in distinguishing between Alzheimer's patients and healthy controls. Adding temporal and structural information by combining bag-of-n-grams features with ADR audio/textual features, the accuracy could be improved to 91.67% on the test set. An accuracy of 93.75% was achieved through late fusion of the three best feature configurations, which corresponds to a 4.7% improvement over the best result reported in the literature for this dataset.Conclusion: The proposed combination of ADR audio and textual features is capable of successfully modelling temporal aspects of the data. The machine learning approach toward dementia detection achieves best performance when ADR features are combined with strong semantic bag-of-n-grams features. This combination leads to state-of-the-art performance on the AD classification task.

Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration.

The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= -0.269, p = 0.03). Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

The effect of physical activity on CSF biomarkers of Alzheimer’s disease differs between men and women

AbstractBackgroundIncreasing evidence suggests that sex influences several aspects of Alzheimer’s disease (AD). Cardiovascular risk factors are associated with AD, and men and women differ in the prevalence of these risk factors. We aimed at determining whether (1) sex and cardiovascular risk factors have an effect on CSF biomarkers; (2) sex modifies the association between cardiovascular risk factors and CSF biomarkers in middle aged cognitively unimpaired individuals of the ALFA+ study.MethodWe measured CSF Ab42, Ab40, p‐tau, t‐tau, neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, S100, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in 381 participants of the ALFA+ study (34.4% Ab‐positive, 65.6% Ab‐negative; Ab42/40 cutoff = 0.071). Biomarker measurements were performed using MSD, Roche NeuroToolKit and Elecsys® immunoassays. The following cardiovascular risk variables were studied: hypertension, smoking, dyslipidaemia, physical activity, LDL and HDL cholesterol, glucose, Hb1Ac, triglycerides, BMI and systolic and diastolic blood pressure. ANCOVA was performed to test the effect of sex on each biomarker and potential interaction effects between sex and cardiovascular variables.ResultWe found that CSF NfL, GFAP, IL6, sVCAM1 and MCP1 were higher in men, while CSF neurogranin and YKL40 were higher in women. These differences were still significant after adjusting for Ab pathology. Regarding cardiovascular variables, men had higher diastolic blood pressure, glucose and triglycerides, while women had higher total, LDL and HDL cholesterol. After adjusting for these cardiovascular variables, sex differences in CSF NfL were still significant, suggesting that they were not confounded by cardiovascular factors (Table 1). In the whole cohort, we observed that sex modifies the association with physical activity levels and CSF NfL (interaction ‘sex x physical activity’: p=0.019). After stratifying by Ab status, we observed that higher physical activity was associated with lower CSF NfL only in Ab positive men (Figure 1).ConclusionSex affects CSF biomarkers and modifies their association with cardiovascular risk factors. Specifically, physical activity is associated with lower NfL in middle aged men in the preclinical stage of the Alzheimer’s continuum, but not in women. Our results suggest that the impact of cardiovascular risk factors on neurodegeneration differs between men and women.

Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-\u03b2 deposition in a mouse model of Alzheimer\u2019s disease

Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Evolution of the Research Literature and the Scientific Community of Alzheimer’s Disease from 1983-2017: A 35-Year Survey

This study surveys the development of Alzheimer's disease (AD) in the research literature, the scientific community, and the journals containing AD papers over a 35-year period. Research papers on AD published from 1983 to 2017 in journals indexed in the Web of Science were analyzed in seven five-year periods. The number of AD papers increased from 1,095 in 1983-1987 to 50,532 by 2013-2017 and in the same time period, the number of participating countries went from 27 to 152. The US was the most prolific country throughout, followed by several European countries, Canada, Australia, and Japan. Asian countries have emerged and by 2013-2017, China surpassed all but the US in productivity. Countries in Latin America and Africa have also contributed to AD research. Additionally, several new non-governmental institutions (e.g., ADNI, ADI) have emerged and now play a key role in the fight against AD. Likewise the AD scientific publishing universe evolved in various aspects: an increase in number of journals containing AD papers (227 journals in 1983-1987 to 3,257 in 2013-2017); appearance of several AD-focused journals, e.g., Alzheimer's & Dementia, Journal of Alzheimer's Disease; and the development of special issues dedicated to AD. Our paper complements the numerous extant papers on theoretical and clinical aspects of AD and provides a description of the research landscape of the countries and journals contributing papers related to AD.