Current Alzheimer Research - Volume 18, Issue 5, 2021

Background: There is an increased effort to better understand neuropsychiatric symptoms of Alzheimer’s Disease (AD) as an important feature of symptomatic burden as well as potential modifiable factors of the disease process. Anxiety is one of the most common neuropsychiatric symptoms in Alzheimer’s Disease (AD). A growing body of work has emerged that addresses the epidemiology and biological correlations of anxiety in AD. Methods: Here, we review human studies in research and clinical cohorts that examined anxiety in AD. We focused on work related to prevalence across AD stages, correlation with established biomarkers, relationship with AD neuropathology and genetic risk factors, and impact on progression. Results: Anxiety is prominent in the early stages and increases across the spectrum of functional stages. Biomarker relationships are strongest at the level of FDG-PET and amyloid measured via PET or cerebrospinal fluid analysis. Neuropathologically, anxiety emerges with early Braak stage tau pathology. The presence of the apolipoprotein E e4 allele is associated with increased anxiety at all stages, most notably at mild cognitive impairment. Anxiety portended a faster progression at all predementia stages. Conclusion: This body of work suggests a close biological relationship between anxiety and AD that begins in early stages and influences functional decline. As such, we discuss future work that would improve our understanding of this relationship and test the validity of anxiolytic treatment as disease modifying therapy for AD.

Introduction: Dementia becomes a major public health challenge in both the Czech Republic and worldwide. The most common form of dementia is Alzheimer’s disease (AD). Objective: We conducted two successive epidemiological projects in 2012-2015 and 2016-2019. Their aim was to study the effect of selected potential genetic, vascular and psychosocial risk factors on the development of AD by comparing their frequencies in AD patients and controls. Methods: Epidemiological case-control studies were conducted. In total, data from 2106 participants (1096 cases, 1010 controls) were analyzed. Results: Three times more females than males suffered from AD. The highest proportion of cases were those with primary education, unlike controls. There were statistically significantly more manual workers among cases than among controls. Of selected vascular risk factors, coronary heart disease was found to be statistically significantly more frequent in cases than in controls. The onset of hypertension and diabetes mellitus was earlier in controls than in cases. As for hobbies and interests, there were statistically significant differences in physical activity, reading and solving crosswords between the groups, with these activities being more common in controls. Conclusion: The prevalence of chronic neurodegenerative diseases, in particular AD, is currently increasing. Given the aging of the population, these conditions may be expected to rise in prevalence. Potential risk of AD needs to be studied, analyzed and confirmed; a detailed knowledge of the risks of AD and early detection of the pathology may therefore be very beneficial for prevention and early treatment of this condition.

Introduction: Understanding the social networks of professionals in psychiatric hospitals and communities working with Persons With Alzheimer’s (PWA) disease helps tackle the knowledge management in patient care and the centrality of team members in providing information and advice to colleagues. Objectives: To use Social Network Analysis (SNA) to confirm or reject the hypothesis that psychiatric professionals have equal status in sharing information and advice on the care of PWA and have reciprocal ties in a social network. Methods: The sample consisting of 50 psychiatric professionals working in geriatric psychiatry in the UK completed an anonymous online survey asking them to select the professional categories of the colleagues in the interprofessional team who are most frequently approached when providing or receiving advice about patient care and gathering patient information. SNA is both a descriptive qualitative analysis and a quantitative method that investigates the degree of the prestige of professionals in their working network, the reciprocity of their ties with other team members, and knowledge management. Results: The social network graphs and numerical outcomes showed that interprofessional teams in geriatric psychiatry have health carers who play central roles in providing the whole team with the knowledge necessary for patient care; these are primarily senior professionals in nursing and medical roles. However, the study reported that only 13% of professionals had reciprocal ties with knowledge sharing within teams. Conclusion: The current research findings show that knowledge management in interprofessional teams caring for PWA is not evenly distributed. Those with apparently higher seniority and experience are more frequently consulted; however, other more peripheral figures can be equally valuable in integrated care.

Background: Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. Methods: We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. Results: Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. Conclusion: Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

Background: A role for neutrophils in the pathogenesis of Alzheimer’s disease (AD) is emerging. We previously showed that the neutrophil granule proteins cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE) directly bind the amyloid-beta peptide Aβ1-42, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ1-42 at different sites and with different catalytic activities. Objective: In this study, we compared the effects of these three proteins on Aβ1-42 fibrillation and neurotoxicity. Methods: Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ1-42. This cleavage correlates well with the inhibition of Aβ1-42 aggregation into fibrils. In contrast, CAP37 did not efficiently cleave Aβ1-42, but was still able to inhibit its fibrillation, most likely through a quenching effect. Inhibition of Aβ1-42 aggregation by NE and CG neutralized its toxicity measured in cultured neurons. In contrast, inhibition of Aβ1-42 aggregation by CAP37 did not inhibit its neurotoxicity. Results: We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ1-42 aggregation effects of the full-length protein. Additionally, this peptide was able to inhibit the neurotoxicity of the most toxic Aβ1-42 aggregate, an effect that was not found with the full-length CAP37. Conclusion: These results shed light on the mechanisms of action of neutrophil granule proteins with regard to inhibition of Aβ1-42 aggregation and neurotoxicity and open up a possible strategy for the discovery of new disease-modifying drugs for AD.

Background: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-β (Aβ) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aβ transport. The purpose of the study is to investigate whether high cholesterol regulates Aβ transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD. Methods: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aβ transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and β-catenin inhibitor XAV-939. Results: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aβ40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/β-catenin signaling pathway. Conclusion: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aβ transport disorder in the blood-brain barrier. Increased Aβ deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

Background: There is strong evidence that epigenetic age acceleration is associated with increased risk of later-life diseases and all-cause mortality. However, there is currently limited evidence that suggests accelerated epigenetic age is associated with dementia risk. Objective: This study aims to clarify whether epigenetic biomarkers of accelerated aging can predict dementia risk, which is an important consideration as aging is the greatest risk factor for the disease. Methods: DNA methylation was measured in peripheral blood samples provided by 160 participants from the ASPirin in Reducing Events in the Elderly study, including 73 pre-symptomatic dementia cases and 87 controls matched for age, sex, and smoking and education status. Epigenetic age was calculated using Horvath, Hannum, GrimAge and PhenoAge DNA methylation clocks, and age acceleration (the disparity between chronological age and epigenetic age) was determined. Results: There was no difference in age acceleration between dementia cases and controls. In males, only Hannum’s intrinsic epigenetic age acceleration was increased in pre-symptomatic dementia cases compared to controls (Δ +1.8 years, p = 0.03). Conclusion: These findings provide no strong evidence that accelerated epigenetic aging measured in peripheral blood can predict dementia risk.