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

Authors: Takechi, Hajime | Yoshino, Hiroshi

Article Type: Research Article

Abstract: Background: As the number of patients with dementia increases, so do the social costs. In recent years, attempts have been made to reduce risk to be dementia and treat it from the early stages of the disease, making it important to estimate the costs of the early stages. Objective: To estimate the medical and social costs of the early stages of Alzheimer’s disease (AD), which include mild cognitive impairment (MCI) due to AD and mild AD. Methods: Questionnaires were used to obtain basic information (e.g., age, cognitive function) and medical costs, social care costs, family caregiver …medical costs, and family caregiver informal care costs from patients with MCI due to AD or mild AD who were attending a memory clinic. A comparison was then conducted between these two groups. Results: Patients with mild AD had higher total costs, patient medical costs, patient social care costs, and family caregiver informal care costs than did patients with MCI; however, only patient medical costs were significantly different (p  = 0.022). A detailed analysis of patient medical costs revealed that anti-dementia drug treatment costs were significantly higher in patients with mild AD (p  <  0.001). Conclusion: Compared with patients with mild AD, those with MCI may have lower patient and family caregiver costs. As it is important to reduce social costs through risk reduction and therapeutic interventions from the early stages of AD, the present findings could help estimate the social costs and verify the cost-effectiveness of early interventions for AD. Show more

Keywords: Alzheimer’s disease, caregiver, cost, dementia, mild cognitive impairment, resource use

DOI: 10.3233/ADR-230032

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 731-738, 2023

Authors: Keleman, Audrey A. | Nicosia, Jessica | Bollinger, Rebecca M. | Wisch, Julie K. | Hassenstab, Jason | Morris, John C. | Ances, Beau M. | Balota, David A. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Individuals with Alzheimer’s disease (AD) are more than twice as likely to incur a serious fall as the general population of older adults. Although AD is commonly associated with cognitive changes, impairments in other clinical measures such as strength or functional mobility (i.e., gait and balance) may precede symptomatic cognitive impairment in preclinical AD and lead to increased fall risk. Objective: To examine mechanisms (i.e., functional mobility, cognition, AD biomarkers) associated with increased falls in cognitively normal older adults. Methods: This 1-year study was part of an ongoing longitudinal cohort study. We examined the relationships …among falls, clinical measures of functional mobility and cognition, and neuroimaging AD biomarkers in cognitively normal older adults. We also investigated which domain(s) best predicted fall propensity and severity through multiple regression models. Results: A total of 182 older adults were included (mean age 75 years, 53% female). A total of 227 falls were reported over the year; falls per person ranged from 0–16 with a median of 1. Measures of functional mobility were the best predictors of fall propensity and severity. Cognition and AD biomarkers were associated with each other but not with the fall outcome measures. Conclusion: These results suggest that, although subtle changes in cognition may be more closely associated with AD neuropathology, functional mobility indicators better predict falls in cognitively normal older adults. This study adds to our understanding of the mechanisms underlying falls in older adults and could lead to the development of targeted fall prevention strategies. Show more

Keywords: Alzheimer’s disease, cognition, falls, functional mobility

DOI: 10.3233/ADR-230002

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 739-750, 2023

Authors: de la Monte, Suzanne M. | Goel, Anuva | Tong, Ming | Delikkaya, Busra

Article Type: Research Article

Abstract: Background: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS). Objective: This study examines the potential contribution of Agent Orange exposures to neurodegeneration. Methods: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer’s disease (AD)-related proteins. Results: Treatment with 250μg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial …function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-β protein precursor (AβPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05 < p<0.10) increase in Aβ. Finally, altered cholinergic function due to 2,4,5-T and 2,4-D exposures was marked by significantly increased choline acetyltransferase and decreased acetylcholinesterase expression, corresponding with responses in early-stage AD. Conclusion: Exposures to Agent Orange herbicidal chemicals rapidly damage CNS neurons, initiating a path toward AD-type neurodegeneration. Additional research is needed to understand the permanency of these neuropathologic processes and the added risks of developing AD in Agent Orange-exposed aging Vietnam Veterans. Show more

Keywords: Agent Orange, Alzheimer’s disease, herbicide, neurodegeneration, neurons, pesticide, Veterans, Vietnam, 2, 4-D, 2, 4, 5-T

DOI: 10.3233/ADR-230046

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 751-766, 2023

Authors: Morrow, Christopher B. | Leoutsakos, Jeannie | Yan, Haijuan | Onyike, Chiadi | Kamath, Vidyulata

Article Type: Short Communication

Abstract: Weight changes, neuropsychiatric symptoms (NPS), and cognitive decline often coincide in Alzheimer’s disease (AD) and frontotemporal dementia (FTD); however, the direction of their relationship remains unclear. This study aims to clarify the connection between weight changes, NPS, and cognition in AD and FTD. We found that cognitive decline was associated with decreased body mass index (BMI) in AD, while BMI gain was associated with increased conversion to FTD. Elevated NPS were associated with decreased BMI in AD and increased BMI in FTD. Identifying early changes in NPS and BMI may facilitate the detection of cognitive decline, providing an opportunity for …early intervention. Show more

Keywords: Alzheimer’s disease, body mass index, cognition, cognitive decline, frontotemporal dementia, neuropsychiatric symptoms, weight changes

DOI: 10.3233/ADR-230034

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 767-774, 2023

Authors: Tran, Todd | Finlayson, Marcia | Nalder, Emily | Trothen, Tracy | Donnelly, Catherine

Article Type: Research Article

Abstract: Background: Community-dwelling older adults with early cognitive deficits experience less efficiency in performing everyday life tasks, resulting in decreased satisfaction and other adverse psychological outcomes. Mindfulness training has been linked to cognitive and psychological improvements and, most recently, has been identified as a potential intervention supporting performance of everyday life activities. Objective: This study aimed to evaluate whether mindfulness practice can improve perceived performance and satisfaction with everyday life activity and secondary psychological outcomes. Methods: This study is a pilot randomized controlled trial (RCT) in an interprofessional primary care team practice in Toronto, Ontario, Canada. The …participants were 27 older adults aged 60 years of age or older living with early cognitive deficits. Participants were randomized into an 8-Week mindfulness training program (n  = 14) group or a Wait-List Control (WLC; n  = 13) group compared at baseline, post-intervention and 4-weeks follow-up. MANOVAs with post-hoc independent t-tests were used to compare between groups at different time points. Results: There was a significant improvement in anxiety for the intervention group compared to the WLC group at post-intervention; Time-2 (mean difference = 3.90; CI  = 0.04-7.75; p  = 0.04) with large effect size (d  = 0.80). Conclusion: Mindfulness training significantly improved anxiety scores for patients with early cognitive deficits post-intervention. Further work is required to test the sustainability of reduced anxiety over time, but this study demonstrated that MBSR is a promising primary care intervention for those living with early cognitive deficits. This study warrants the pursuit of a future study in exploring how long the reduced anxiety effects would be sustained. Show more

Keywords: Activities of daily living, Alzheimer’s disease, anxiety, health promotion, mild cognitive impairment, mindfulness meditation, occupational therapy, older adults, primary care, psychological outcomes, subjective cognitive decline

DOI: 10.3233/ADR-230006

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 775-790, 2023

Authors: Behera, Anindita | Sa, Nishigandha | Pradhan, Sweta Priyadarshini | Swain, Sunsita | Sahu, Pratap Kumar

Article Type: Review Article

Abstract: Nanotechnology has emerged in different fields of biomedical application, including lifestyle diseases like diabetes, hypertension, and chronic kidney disease, neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease, and different types of cancers. Metal nanoparticles are one of the most used drug delivery systems due to the benefits of their enhanced physicochemical properties as compared to bulk metals. Neurodegenerative diseases are the second most cause affecting mortality worldwide after cancer. Hence, they require the most specific and targeted drug delivery systems for maximum therapeutic benefits. Metal nanoparticles are the preferred drug delivery system, possessing greater blood-brain barrier permeability, biocompatibility, and enhanced …bioavailability. But some metal nanoparticles exhibit neurotoxic activity owing to their shape, size, surface charge, or surface modification. This review article has discussed the pathophysiology of AD. The neuroprotective mechanism of gold, silver, selenium, ruthenium, cerium oxide, zinc oxide, and iron oxide nanoparticles are discussed. Again, the neurotoxic mechanisms of gold, iron oxide, titanium dioxide, and cobalt oxide are also included. The neuroprotective and neurotoxic effects of nanoparticles targeted for treating AD are discussed elaborately. The review also focusses on the biocompatibility of metal nanoparticles for targeting the brain in treating AD. The clinical trials and the requirement to develop new drug delivery systems are critically analyzed. This review can show a path for the researchers involved in the brain-targeted drug delivery for AD. Show more

Keywords: Alzheimer’s disease, biocompatibility, clinical trials, metal nanoparticles, neuroprotective, neurotoxicity

DOI: 10.3233/ADR-220112

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 791-810, 2023

Authors: Wei, Tao | Shi, Xiaolei | Sun, Wei | Song, Weiyi | Zhou, Shaojiong | Zhao, Yiwei | Wang, Zhibin | Tang, Yi

Article Type: Research Article

Abstract: Background: Neurological disorders, such as Alzheimer’s disease (AD), comprise a major cause of health-related disabilities in human. However, biomarkers towards pathogenesis or novel targets are still limited. Objective: To identify the causality between plasma proteins and the risk of AD and other eight common neurological diseases using a Mendelian randomization (MR) study. Methods: Exposure data were obtained from a genome-wide association study (GWAS) of 2,994 plasma proteins in 3,301 healthy adults, and outcome datasets included GWAS summary statistics of nine neurological disorders. Inverse variance-weighted MR method as the primary analysis was used to estimate causal effects. …Results: Higher genetically proxied plasma myeloid cell surface antigen CD33 level was found to be associated with increased risk of AD (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.047–1.112, p  = 8.39×10-7 ). We also discovered the causality between genetically proxied elevated prolactin and higher risk of epilepsy (OR = 1.068, 95% CI = 1.034–1.102; p  = 5.46×10-5 ). Negative associations were identified between cyclin-dependent kinase 8 and ischemic stroke (OR = 0.927, 95% CI = 0.896–0.959, p  = 9.32×10-6 ), between neuralized E3 ubiquitin-protein ligase 1 and migraine (OR = 0.914, 95% CI = 0.878–0.952, p  = 1.48×10-5 ), and between Fc receptor-like protein 4 and multiple sclerosis (MS) (OR = 0.929, 95% CI = 0.897–0.963, p  = 4.27×10-5 ). Conclusion: The findings identified MR-level protein-disease associations for AD, epilepsy, ischemic stroke, migraine, and MS. Show more

Keywords: Alzheimer’s disease, causality, Mendelian randomization, neurological disorders, plasma proteins

DOI: 10.3233/ADR-230058

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 811-822, 2023

Authors: Mehramiz, Mehrane | Porter, Tenielle | O’Brien, Eleanor K. | Rainey-Smith, Stephanie R. | Laws, Simon M.

Article Type: Review Article

Abstract: Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing …the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, SIRT1, sirtuin-1

DOI: 10.3233/ADR-220088

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 823-843, 2023

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Nuccetelli, Marzia | Placidi, Fabio | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Sancesario, Giuseppe | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep impairment has been commonly reported in Alzheimer’s disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18 F-fluoro-deoxy-glucose positron emission tomography (18 F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18 F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the …study (9 MCI and 26 AD patients). 18 F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p  = 0.013) and positively with REM sleep (p  = 0.033). 18 F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p  = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p  = 0.042), Non-REM stage 1 of sleep (p  = 0.031), wake after sleep onset (p  = 0.028), and lower sleep efficiency (p  = 0.045). CSF levels of Aβ42 correlated negatively with the wake bouts index (p  = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p  = 0.045) and time in bed (p  = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers. Show more

Keywords: Alzheimer’s disease, biomarkers, brain, cerebrospinal fluid, dementia, orexin, positron emission tomography, sleep

DOI: 10.3233/ADR-220111

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 845-854, 2023

Authors: Yu, Zhentao | Shi, Zhuoyu | Dan, Tingting | Dere, Mustafa | Kim, Minjeong | Li, Quefeng | Wu, Guorong

Article Type: Research Article

Abstract: Background: The AT[N] research framework focuses on three major biomarkers in Alzheimer’s disease (AD): amyloid-β deposition (A), pathologic tau (T), and neurodegeneration [N]. Objective: We hypothesize that the diverse mechanisms such as A⟶T and A⟶[N] pathways from one brain region to others, may underlie the wide variation in clinical symptoms. We aim to uncover the causal-like effect of regional AT[N] biomarkers on cognitive decline as well as the interaction with non-modifiable risk factors such as age and APOE4 . Methods: We apply multi-variate statistical inference to uncover all possible mechanistic spreading pathways through which the aggregation …of an upstream biomarker (e.g., increased amyloid level) in a particular brain region indirectly impacts cognitive decline, via the cascade build-up of a downstream biomarker (e.g., reduced metabolism level) in another brain region. Furthermore, we investigate the survival time for each identified region-to-region pathological pathway toward the AD onset. Results: We have identified a collection of critical brain regions on which the amyloid burdens exert an indirect effect on the decline in memory and executive function (EF) domain, being mediated by the reduction of metabolism level at other brain regions. APOE4 status has been found not only involved in many A⟶N mechanistic pathways but also significantly contributes to the risk of developing AD. Conclusion: Our major findings include 1) the region-to-region A⟶N⟶MEM and A⟶N⟶MEM pathways exhibit distinct spatial patterns; 2) APOE4 is significantly associated with both direct and indirect effects on the cognitive decline while sex difference has not been identified in the mediation analysis. Show more

Keywords: Alzheimer’s disease, biomarkers, mediation analysis, multi-variate variable selection, pathogenesis mechanism

DOI: 10.3233/ADR-230081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 855-872, 2023