Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Zhu, Haohao | Lu, Rongrong | Zhou, Qin | Du, Zhiqiang | Jiang, Ying

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder whose etiology involves multiple genetic and environmental factors. Sphingomyelin (SM) is a type of sphingolipid found in cell membranes, and recent evidence suggests a potential link between SM and AD. However, the nature of this relationship remains unclear. Objective: To elucidate the potential causal relationship between SM levels and the risk of developing AD using a two-sample Mendelian randomization approach. Methods: The study utilized data extracted from the genome wide association study database. The primary analysis method was the inverse variance weighted (IVW) method, which was supplemented …by weighted median, weighted mode, and MR Egger methods. The study specifically investigated the bidirectional causal relationship between SM and AD, evaluating odds ratios (OR) with a 95% confidence interval (95% CI). Results: Elevated levels of SM were found to be a risk factor for AD, as shown by IVW(MRE) [OR: 1.001, 95% CI: 1.000 to 1.002; p  = 0.020 < 0.05], IVW(FE) [OR: 1.001, 95% CI: 1.001 to 1.002; p  = 3.36e-07 < 0.05], and MR Egger. Conversely, AD was demonstrated to lead to an increase in SM levels [IVW(MRE): OR: 5.64e+08, 95% CI: 1.69e+05 to 1.89e+12; p  = 1.14e-06 < 0.05], with consistent findings across the IVW(FE), MR Egger, weighted median, and weighted mode methods. Conclusions: The study establishes a bidirectional positive correlation between SM and AD. Increased SM levels are associated with a higher risk of developing AD, and the presence of AD can further elevate SM levels, potentially exacerbating the disease’s progression. Show more

Keywords: Alzheimer’s disease, bidirectional Mendelian randomization, genome-wide association study, relationship, sphingomyelin

DOI: 10.3233/ADR-230126

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1289-1297, 2023

Authors: van Gils, Veerle | Ramakers, Inez | Jansen, Willemijn J. | Banning, Leonie | Kučikienė, Domantė | Costa, Ana Sofia | Schulz, Jörg B. | Visser, Pieter Jelle | Verhey, Frans | Reetz, Kathrin | Vos, Stephanie J.B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline. Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population. Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive …functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions. Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ – 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions. Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cardiovascular risk, cognitive decline, magnetic resonance imaging, vascular diseases

DOI: 10.3233/ADR-230040

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1299-1311, 2023

Authors: Feldner, Alyssa C. | Turner, Andrew K. | Simpson, James F. | Estus, Steven

Article Type: Research Article

Abstract: Background: Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer’s disease (AD) may provide insights into treatments that could reduce AD risk. Objective: Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2. Methods: AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR. Results: The protein encoded by FCER1G, FcRγ , is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon …2 (D2-FCER1G ) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype. Conclusions: In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902. Show more

Keywords: Alzheimer’s disease, genetics, microglia, polymorphism, RNA splicing

DOI: 10.3233/ADR-230076

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1313-1322, 2023

Authors: Mudalige, Dinithi | Guan, Dylan X. | Ghahremani, Maryam | Ismail, Zahinoor

Article Type: Research Article

Abstract: Background: Clinical guidelines recommend incorporating non-cognitive markers like mild behavioral impairment (MBI) and sleep disturbance (SD) into dementia screening to improve detection. Objective: We investigated the longitudinal associations between MBI, SD, and incident dementia. Methods: Participant data were from the National Alzheimer’s Coordinating Center in the United States. MBI was derived from the Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. SD was determined using the NPI-Q nighttime behaviors item. Cox proportional hazard regressions with time-dependant variables for MBI, SD, and cognitive diagnosis were used to model associations between baseline 1) MBI and incident SD (n … = 11,277); 2) SD and incident MBI (n  = 10,535); 3) MBI with concurrent SD and incident dementia (n  = 13,544); and 4) MBI without concurrent SD and incident dementia (n  = 11,921). Models were adjusted for first-visit age, sex, education, cognitive diagnosis, race, and for multiple comparisons using the Benjamini-Hochberg method. Results: The rate of developing SD was 3.1-fold higher in older adults with MBI at baseline compared to those without MBI (95% CI: 2.8–3.3). The rate of developing MBI was 1.5-fold higher in older adults with baseline SD than those without SD (95% CI: 1.3–1.8). The rate of developing dementia was 2.2-fold greater in older adults with both MBI and SD, as opposed to SD alone (95% CI:1.9–2.6). Conclusions: There is a bidirectional relationship between MBI and SD. Older adults with SD develop dementia at higher rates when co-occurring with MBI. Future studies should explore the mechanisms underlying these relationships, and dementia screening may be improved by assessing for both MBI and SD. Show more

Keywords: Alzheimer’s disease, dementia, longitudinal studies, neurobehavioral manifestations, sleep disorders

DOI: 10.3233/ADR-230086

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1323-1334, 2023

Authors: Zainuddin, Muhammad-Safuan | Bhuvanendran, Saatheeyavaane | Radhakrishnan, Ammu K. | Azman, Adzzie-Shazleen

Article Type: Review Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. Objective: To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Methods: Research articles published between 2010 and 2021 were collected from five databases and 83 …relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. Results: A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. Conclusions: The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD’s early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended. Show more

Keywords: Alzheimer’s disease, amyloid-β , secondary metabolites, Streptomyces sp

DOI: 10.3233/ADR-230065

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1335-1350, 2023

Authors: Zhang, Hongwei | Liu, Da | Duan, Yuanyuan | Liu, Yan | Liu, Jianyu | Bai, Na | Zhou, Qiang | Xu, Zhiyao | Li, Linyan | Liu, Hua

Article Type: Systematic Review

Abstract: Background: The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer’s disease (AD) has been widely studied across populations; however, the results are inconsistent. Objective: This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis. Methods: Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I2 …metric was used to evaluate heterogeneity, and Egger’s test and Funnel plot were used to assess publication bias. Results: A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47–0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12–2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38–3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26–0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results. Conclusions: Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results. Show more

Keywords: Alpha 2-macroglobulin, Alzheimer’s disease, A2M, meta-analysis, SNPs, systematic review

DOI: 10.3233/ADR-230131

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1351-1370, 2023

Authors: Tsapanou, Angeliki | Zoi, Panagiota | Kalligerou, Faidra | Blekou, Patra | Sakka, Paraskevi

Article Type: Short Communication

Abstract: What is the impact of long COVID-19 on people with mild cognitive impairment (MCI) or dementia? Self-reported questionnaire was used for the report of long COVID-19 symptoms. People with MCI or dementia or their caregivers regarding patients’ health were recruited COVID-19 throughout from the Athens Alzheimer’s Association. We included 72 participants. Thirty had the diagnosis of MCI and 39 had dementia. Most symptoms lasted for 3-4 weeks. The majority of patients reported having all the symptoms, with fatigue being the major disturbance. The diagnosis and the management of long COVID-19 symptoms requires a more holistic and comprehensive approach.

Keywords: Alzheimer’s disease, COVID-19, dementia, long COVID, mild cognitive impairment

DOI: 10.3233/ADR-230119

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1371-1375, 2023

Authors: Tsatali, Marianna | Angelidou, Ioanna Antigoni | Tsolaki, Magda | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Measuring dementia knowledge can be a valuable tool for assessing the effectiveness of dementia awareness activities, identifying the potential benefits of dementia training programs, and breaking down common myths and stereotypes about dementia. Objective: To compare the psychometric properties of three widely used dementia knowledge tools, the Dementia Knowledge Assessment Tool 2 (DKAT2-G), the Dementia Knowledge Assessment Scale (DKAS-G), and the Knowledge in Dementia Scale (KIDE-G) in the Greek adult population. Methods: A convenience sample of 252 participants from the general population completed the survey online. Statistical analyses included Cronbach’s internal reliability, retest reliability, factor …analysis, concurrent and construct validity, and floor and ceiling effects. Results: The DKAS-G had the most appropriate reliability levels (Cronbach’s alpha  =  0.845; retest reliability  =  0.921), whereas the DKAT2-G had satisfactory indexes (Cronbach’s α = 0.760; retest reliability  =  0.630). The KIDE-G showed unsatisfactory reliability (Cronbach’s α = 0.419; retest reliability  =  0.619). Construct validity was confirmed for all questionnaires, showing that all of them detected participants with pre-existing knowledge of dementia. Confirmatory factor analysis revealed a four-factor model for the DKAS-G and proposed the removal of 5 items. Floor and ceiling effects were found for the DKAT2-G and the KIDE-G, mainly among those who had previously participated in dementia training. Conclusions: The DKAS-G was found to have the highest levels of reliability and validity. The results prove that the DKAS-G meets the requirements for measuring dementia knowledge and evaluating dementia training programs in health professionals, caregivers, and the general population. Show more

Keywords: Alzheimer’s disease, knowledge, reliability and validity, test-retest reliability, validation study

DOI: 10.3233/ADR-230161

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1377-1393, 2023

Authors: André, Séverine | Verteneuil, Sébastien | Ris, Laurence | Kahvecioglu, Zehra-Cagla | Nonclercq, Denis | De Winter, Julien | Vander Elst, Luce | Laurent, Sophie | Muller, Robert N. | Burtea, Carmen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2 -IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2 -IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2 -IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic …acid dosage [AA], cPLA2 -IVA cellular translocation) before being tested in vivo . We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2 -IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2 -IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2 -IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2 -IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, amyloid plaques, cytosolic phospholipase A2, peptides, phage display, tau protein

DOI: 10.3233/ADR-230075

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1395-1426, 2023

Authors: Goodman, Max J. | Li, Xin Ran | Livschitz, Jennifer | Huang, Chiang-Ching | Bendlin, Barbara B. | Granadillo, Elias D.

Article Type: Research Article

Abstract: Background: Physicians may soon be able to diagnose Alzheimer’s disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. Objective: To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-β42 (Aβ42 ). Methods: Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and …biomarker concentrations were obtained from the Alzheimer’s Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Results: Aβ42 (p  = 0.65) and symmetric dimethylarginine (p  = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aβ42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p  < 0.05) that generally decreased in time. There were no significant associations between Aβ42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Conclusions: Correlations were smaller between Aβ42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, methylarginines, SDMA, serum markers

DOI: 10.3233/ADR-230054

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1427-1444, 2023