Journal of Alzheimer's Disease - Volume 87, issue 1

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education, subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 161-172, 2022

Authors: Panzarella, Vera | Mauceri, Rodolfo | Baschi, Roberta | Maniscalco, Laura | Campisi, Giuseppina | Monastero, Roberto

Article Type: Research Article

Abstract: Background: The relationship between Alzheimer’s disease (AD) and periodontitis has been recently investigated with heterogenous results. Objective: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in a rural community in Sicily, Italy. Methods: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment [aMCI], and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related …quality of life (OHR-QoL) were evaluated. Results: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than aMCI (p  = 0.009) and controls (p  = 0.001). Furthermore, the “M” component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p  < 0.001) and controls (p  < 0.001). A Poisson regression model revealed that age (p  < 0.001), male gender (p  = 0.001), and AD (p  = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p  = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p  = 0.004). OHR-QoL scores did not differ among the groups. Conclusion: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum . These data remain to be confirmed in larger population-based cohorts. Show more

Keywords: Alzheimer’s disease, cognitive impairment, epidemiology, oral health, periodontitis, tooth loss

DOI: 10.3233/JAD-200385

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 173-183, 2022

Authors: Kučikienė, Domantė | Costa, Ana Sofia | Banning, Leonie C.P. | van Gils, Veerle | Schulz, Jörg B. | Ramakers, Inez H.G.B. | Verhey, Frans R.J. | Vos, Stephanie J.B. | Reetz, Kathrin

Article Type: Research Article

Abstract: Background: The relation between vascular risk factors (VRFs) and Alzheimer’s disease (AD) is important due to possible pathophysiological association. Objective: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context. Methods: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD …change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site. Results: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition. Conclusion: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia. Show more

Keywords: Alzheimer’s disease, ambulatory care facilities, biomarkers, classification, risk factors, vascular diseases

DOI: 10.3233/JAD-215391

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 185-195, 2022

Authors: Liu, Ying | Han, Pei-Ran | Hu, Hao | Wang, Zuo-Teng | Guo, Yu | Ou, Ya-Nan | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: In the 2018 AT(N) framework, neurodegenerative (N) biomarkers plays an essential role in the research and staging of Alzheimer’s disease (AD); however, the different choice of N may result in discordances. Objective: We aimed to compare different potential N biomarkers. Methods: We examined these N biomarkers among 1,238 participants from Alzheimer’s Disease Neuroimaging Initiative (ADNI) in their 1) diagnostic utility, 2) cross-sectional and longitudinal correlations between different N biomarkers and clinical variables, and 3) the conversion risk of different N profiles. Results: Six neurodegenerative biomarkers changed significantly from preclinical AD, through prodromal AD …to AD dementia stage, thus they were chosen as the candidate N biomarkers: hippocampal volume (HV), 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET), cerebrospinal fluid (CSF), total tau (T-tau), plasma neurofilament light chain (NFL), CSF NFL, and CSF neurogranin (Ng). Results indicated that FDG-PET not only had the greatest diagnostic utility in differentiating AD from controls (area under the curve: FDG-PET, 0.922), but also had the strongest association with cognitive scores. Furthermore, FDG-PET positive group showed the fastest memory decline (hazard ratio: FDG-PET, 3.45), which was also true even in the presence of amyloid-β pathology. Moreover, we observed great discordances between three valuable N biomarkers (FDG-PET, HV, and T-tau). Conclusion: These results underline the importance of using FDG-PET as N in terms of cognitive decline and AD conversion, followed by HV, and could be a great complement to the AT(N) framework. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuroimaging initiative, AT(N), biomarker, FDG, neurodegeneration

DOI: 10.3233/JAD-215724

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 197-209, 2022

Authors: Ning, Jing | Huang, Shu-Yi | Chen, Shi-Dong | Zhang, Ya-Ru | Huang, Yu-Yuan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Objective: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. Methods: We selected genetic variants associated with gut microbiota traits (N  = 18,340) and gut microbiota-derived metabolites (N  = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, …17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. Results: Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103–1.405; p  = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. Conclusion: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, gastrointestinal microbiome, mendelian randomization analysis, Parkinson’s disease

DOI: 10.3233/JAD-215411

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 211-222, 2022

Authors: Kreft, Daniel | Doblhammer, Gabriele

Article Type: Research Article

Abstract: Background: There is an ongoing debate about whether environmental characteristics influence dementia risk like individual traits do, and whether these differ by sex and gender. Objective: This study examines the influence of regional characteristics on the incidence of dementia and explores sex and gender differences using individual-level health information and regional characteristics. Methods: Using a random sample of 250,000 people aged 70 + insured through Germany’s largest German public health agency, we analyzed quarterly data about diagnoses and place of residence from 2014 to 2019. Using five-digit postal codes, we added data on various dimensions of regional characteristics …offered by the INKAR database and the 2011 Census database. We used multilevel survival regressions to tease out regional incidence differences while accounting for spatial clustering. Results: After adjusting for multi-morbidity and relocation-related selection bias, we saw that people living in regions with the highest tertile of income (HR = 0.87, p  < 0.001), and who had the highest tertile of remaining life expectancy at age 60 (HR = 0.93, p  = 0.012) had lower dementia risks. There was no gender difference in the regional income effect, but the effect of education (HR = 0.91, p  = 0.015) was significant only for men and remaining life-expectancy was significant only for women (HR = 0.93, p  = 0.026). Conclusion: Environmental characteristics related to wealth and health resources of a region influence the risk of dementia among the elderly in Germany. This effect is independent of the health profiles of the individuals and differs between the two genders. Health policies need to acknowledge these modifiable risk factors and consider how they affect men and women differently. Show more

Keywords: Cohort study, dementia, environment, gender, health inequality, incidence, multi-morbidity, multilevel analysis, routinely collected health data, sex, survival analysis

DOI: 10.3233/JAD-215030

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 223-237, 2022

Authors: Tyler, Samantha L. | Maltby, John | Paterson, Kevin B. | Hutchinson, Claire V.

Article Type: Research Article

Abstract: Background: Despite experimental evidence for concurrent dementia and visual impairment, there are no currently validated vision-related quality of life measures for use in this population. Objective: To establish the extent to which individuals with mild to moderate dementia self-report visual impairment and determine the efficacy of established vision-related quality of life measures for use in a dementia population. Methods: We compared vision-related quality of life in participants with mild-moderate dementia to healthy (dementia-free) older adults using two existing questionnaire measures already validated for use in older adults. These were the Visual Activities Questionnaire (VAQ) and the …25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Results: Responses on both the VAQ and VFQ-25 revealed a significant effect of dementia on self-reported vision-related quality of life. Visual impairment in dementia was identified in the domains of color discrimination, disability glare, light/dark adaption, acuity/spatial vision, depth perception, peripheral vision, visual search, and visual processing speed. Factor analysis of the data suggested that existing vision-related quality of life measures, designed for use in older adult populations, are likely to provide a robust means of assessing vision-related quality of life in older adults with dementia. This is particularly true of the VAQ, for which one latent factor emerged for both dementia and dementia-free samples. Conclusion: Using existing measures designed for use in older adult populations, we have shown that people with dementia experience reduced vision-related quality of life. Show more

Keywords: Dementia, visual activities scale (VAQ), visual function questionnaire (VFQ-25), visual impairment, vision-related quality of life

DOI: 10.3233/JAD-215435

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 239-246, 2022

Authors: Cirstea, Mihai S. | Kliger, Daniel | MacLellan, Abbey D. | Yu, Adam C. | Langlois, Jenna | Fan, Mannie | Boroomand, Seti | Kharazyan, Faezeh | Hsiung, Robin G.Y. | MacVicar, Brian A. | Chertkow, Howard | Whitehead, Victor | Brett Finlay, B. | Appel-Cresswell, Silke

Article Type: Research Article

Abstract: Background: Despite decades of research, our understanding of Alzheimer’s disease (AD) etiology remains incomplete. In recent years, appreciation has grown for potential roles for the microbiota in shaping neurological health. Objective: This study aimed to examine associations between the microbiota and AD in a human cross-sectional cohort. Methods: Forty-five AD patients and 54 matched controls were recruited in Vancouver, Canada. Fecal and oral samples underwent 16S microbiota sequencing. A wide array of demographic and clinical data were collected. Differences between participant groups were assessed, and associations between microbes and clinical variables were examined within the AD population. …Results: The gut microbiota of AD patients displayed lower diversity relative to controls, although taxonomic differences were sparse. In contrast, the AD oral microbiota displayed higher diversity, with several taxonomic differences relative to controls, including a lower abundance of the families Streptococcaceae and Actinomycetaceae, and a higher abundance of Weeksellaceae, among others. The periodontitis-associated oral microbe Porphyromonas gingivalis was 5 times more prevalent among patients. No significant associations between gut or oral microbes and cognition were detected, but several correlations existed between microbes and mood disorders and BMI among patients, including a strong positive correlation between Alphaproteobacteria and depression score. Conclusion: The gut microbiota of AD patients was not overtly different from controls, although it displayed lower diversity, an overall marker of microbiota health. The oral microbiota did display marked differences. Cognition was not associated with a microbial signature, but other relevant AD factors including mood and BMI did demonstrate an association. Show more

Keywords: Alzheimer’s disease, depression, microbiome, oral microbiome

DOI: 10.3233/JAD-215520

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 247-258, 2022

Authors: Clement, Amalie | Madsen, Marianne Juul | Kastaniegaard, Kenneth | Wiborg, Ove | Asuni, Ayodeji A. | Stensballe, Allan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. Despite decades of investigation, the etiology of AD is not fully understood, although emerging evidence suggest that chronic environmental and psychological stress plays a role in the mechanisms and contributes to the risk of developing AD. Thus, dissecting the impact of stress on the brain could improve our understanding of the pathological mechanisms. Objective: We aimed to study the effect of chronic stress on the hippocampal proteome in male APPPS1 transgenic mice and wildtype (WT) littermates. Methods: APPPS1 and WT …mice were subjected to 4 weeks of chronic stress followed by 3 weeks of continued diurnal disruption. Hippocampal tissue was used for proteomics analysis using label-free quantitative DIA based LC-MS/MS analysis. Results: We identified significantly up- and downregulated proteins in both APPPS1 and WT mice exposed to chronic stress compared to the control groups. Via interaction network mapping, significant proteins could be annotated to specific pathways of mitochondrial function (oxidative phosphorylation and TCA cycle), metabolic pathways, AD pathway and synaptic functions (long term potentiation). In WT mice, chronic stress showed the highest impact on complex I of the oxidative phosphorylation pathway, while in APPPS1 mice this pathway was compromised broadly by chronic stress. Conclusion: Our data shows that chronic stress and amyloidosis additively contribute to mitochondrial damage in hippocampus. Although these results do not explain all effects of chronic stress in AD, they add to the scientific knowledge on the topic. Show more

Keywords: Alzheimer’s disease, chronic stress, hippocampus, mass spectrometry, mitochondrial function, oxidative phosphorylation, proteomics

DOI: 10.3233/JAD-220064

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 259-272, 2022

Authors: Androuin, Alexandre | Thierry, Manon | Boluda, Susana | Brainbank NeuroCEB Neuropathology Network | Baskaran, Asha | Langui, Dominique | Duyckaerts, Charles | Potier, Marie-Claude | El Hachimi, Khalid Hamid | Delatour, Benoît | Marty, Serge

Article Type: Research Article

Abstract: Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer’s disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42 ) intracellularly. Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology. Methods: We used immunolabeling and various electron microscopy techniques on APP x presenilin1 - knock-in mice and on human cortical biopsies and postmortem samples. Results: We …found an accumulation of Aβ fibrils in lipofuscin granule-like organelles in APP x presenilin1 - knock-in mice. Electron microscopy of human cortical biopsies also showed an accumulation of undigested material in enlarged lipofuscin granules in neurons from AD compared to age-matched non-AD patients. However, in those biopsies or in postmortem samples we could not detect intraneuronal accumulations of Aβ fibrils, neither in the lipofuscin granules nor in other intraneuronal compartments. Conclusion: The intralysosomal accumulation of Aβ fibrils in specific neuronal populations in APPxPS1-KI mice likely results from a high concentration of Aβ42 in the endosome-lysosome system due to the high expression of the transgene in these neurons. Show more

Keywords: Alzheimer’s disease, amyloid-β, electron microscopy, lysosome

DOI: 10.3233/JAD-215692

Citation: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 273-284, 2022