Journal of Alzheimer's Disease - Volume 81, issue 2

Authors: Olson, Nancy L. | Albensi, Benedict C.

Article Type: Review Article

Abstract: Persons with dementia (PWD) make up a large portion of the long-term care (LTC) population the world over. Before a global pandemic swept the world, governments and healthcare providers struggled with how to best care for this unique population. One of the greatest challenges is a PWD’s tendency to “walk with purpose” and exhibit unsafe wayfinding and elopement, which places them at risk of falls and injury. Past solutions included increased use of restraints and pharmacological interventions, but these have fallen out of favor over the years and are not optimal. These challenges put enormous strain on staff and caregivers, …who are often poorly trained in dementia care, underpaid, overworked, and overstressed. PWD are impacted by these stresses, and unmet needs in LTC places an even greater stress on them and increases their risks of morbidity and mortality. The physical design of their environments contributes to the problem. Old, institutionalized buildings have poor lighting, poor ventilation, long dead-end hallways, poor visual cues, lack of home-like décor, shared bedrooms and bathrooms, and are often dense and overcrowded. These design elements contribute to the four ‘A’s’ of dementia: apathy, anxiety, agitation, and aggression, and they also contributed to the rapid spread of COVID-19 in these facilities the world over. In this review, we present current “dementia friendly” design models in the home, community, and LTC, and argue how they could have saved lives during the pandemic and reduced the stresses on both the dementia resident and the caregiver/staff. Show more

Keywords: Alzheimer’s café, Alzheimer’s disease, butterfly care, COVID-19, dementia, dementia friendly, dementia village, green care, green house, long-term care, wayfinding

DOI: 10.3233/JAD-210017

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 427-450, 2021

Authors: Hashimoto, Makoto | Ho, Gilbert | Sugama, Shuei | Takenouchi, Takato | Waragai, Masaaki | Sugino, Hiromu | Inoue, Satoshi | Masliah, Eliezer

Article Type: Review Article

Abstract: Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of …APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target. Show more

Keywords: Activin, adiponectin paradox, Alzheimer’s disease, amyloidogenic proteins, antagonistic pleiotropy, evolvability, transforming growth factor β

DOI: 10.3233/JAD-210206

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 451-458, 2021

Authors: Tsamou, Maria | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Review Article

Abstract: The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss …is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, environmental impact, memory loss, neurotoxicity, tauopathy

DOI: 10.3233/JAD-201418

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 459-485, 2021

Authors: Pillai, Jagan A. | Bena, James | Bekris, Lynn M. | Foldvary-Schaefer, Nancy | Heinzinger, Catherine | Rao, Sujata | Rao, Stephen M. | Leverenz, James B. | Mehra, Reena

Article Type: Short Communication

Abstract: Sleep dysfunction has been identified in the pathophysiology of Alzheimer’s disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Keywords: Alzheimer’s disease, circadian, immunity, inflammation, neurodegeneration, sleep

DOI: 10.3233/JAD-201573

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 487-492, 2021

Authors: Bernier, Francois | Ohno, Kazuya | Katsumata, Noriko | Shimizu, Takashi | Xiao, Jinzhong

Article Type: Short Communication

Abstract: We demonstrated the benefit of the probiotic strain, Bifidobacterium breve MCC1274 (synonym B. breve A1), at improving cognition in our previous double-blind, placebo-controlled clinical study. Analysis of the association of blood parameters changes with the improvement of cognitive function revealed an inverse correlation of HbA1c with total RBANS score amelioration after the study only in the probiotic group (ρ = –0.4218, p  = 0.0067). A stratified analysis based on baseline HbA1c with a median value showed a more remarkable benefit by the probiotic supplementation in the higher median subgroup. These data support the mechanism of anti-inflammation in improving cognition by …the probiotic strain. Show more

Keywords: Bifidobacterium, clinical trial, HbA1c, dementia, memory, mild cognitive impairment, probiotics

DOI: 10.3233/JAD-201488

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 493-497, 2021

Authors: Liu, Xin | Chen, Ke-Liang | Wang, Yi | Huang, Yu-Yuan | Chen, Shi-Dong | Dong, Qiang | Cui, Mei | Yu, Jin-Tai

Article Type: Short Communication

Abstract: Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p.* 267Leuext* 11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B ; p.* 267Leuext* 11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and …extend the ethnic distribution of ITM2B mutations. Show more

Keywords: Bri2, familial British dementia, familial Danish dementia, familial dementia, ITM2B

DOI: 10.3233/JAD-210176

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 499-505, 2021

Authors: Liu, Quan Feng | Kanmani, Suganya | Lee, Jinhyuk | Kim, Geun-Woo | Jeon, Songhee | Koo, Byung-Soo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. Objective: We offer the investigation of the effects of neoline in AD. Methods: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. Results: Neoline improved memory …and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice. Conclusion: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD. Show more

Keywords: Alzheimer’s disease, AMPK, BACE1, cognitive function, neoline, tau

DOI: 10.3233/JAD-201614

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 507-516, 2021

Authors: Qiu, Hongyan | Zhao, Ruoqi | Fei, Guoqiang | Pan, Xiaoli | Sang, Shaoming | Xu, Yangqi | Jin, Boru | Jin, Lirong | Cheng, Xiaoqin | Zhong, Chunjiu

Article Type: Research Article

Abstract: Background: Microglia play diverse roles in Alzheimer’s disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. Objective: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. Methods: Microglia were extracted from APPSwe /PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by …immunofluorescence staining. Results: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. Conclusion: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-β deposition. Show more

Keywords: Alzheimer’s disease, metabolism, microglia, transcriptomics

DOI: 10.3233/JAD-210213

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 517-531, 2021

Authors: Wang, Xuewei | Bui, Hai | Vemuri, Prashanthi | Graff-Radford, Jonathan | Jack Jr, Clifford R. | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: Lipid alterations contribute to Alzheimer’s disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. Objective: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groups Methods: Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used …to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. Results: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4 . Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. Conclusion: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, lipid, lipidomics, mild cognitive impairment, network analysis, systems biology

DOI: 10.3233/JAD-201347

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 533-543, 2021

Authors: Rodríguez, Danelly | Ayers, Emmeline | Weiss, Erica F. | Verghese, Joe

Article Type: Research Article

Abstract: Background: Very few studies have explored the utility of subjective cognitive complaints (SCCs) in primary care settings. Objective: We aim to investigate associations between SCCs (item-level), objective cognitive function (across domains and global), and mood in a diverse primary care population, including subjects with mild cognitive impairment. Methods: We studied 199 (75.9%females; 57.8%Hispanics; 42.2%African Americans) older adults (mean age 72.5 years) with memory concerns at a primary care clinic. A five-item SCC questionnaire, and objective cognitive assessments, including the Montreal Cognitive Assessment (MoCA) and the Geriatric Depression Scale, were administered. Results: …Logistic regression analyses showed associations between SCC score and depressive symptoms. A memory-specific (“memory worsening”) SCC predicted scores on the MoCA (p  = 0.005) in Hispanics. Conclusion: SCCs are strongly linked to depressive symptoms in African Americans and Hispanics in a primary care setting; a specific type of SCC is related to global cognitive function in Hispanics. Show more

Keywords: Cognitive function, cross-sectional, depressive symptoms, primary care, subjective health complaint, underserved populations

DOI: 10.3233/JAD-201399

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 545-555, 2021