Journal of Alzheimer's Disease - Volume 83, issue 4

Authors: Mukhopadhyay, Sanchari | Banerjee, Debanjan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a Clinico-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval …of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of ‘amyloid cascade hypothesis’ itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidative stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder. Show more

Keywords: Aducanumab, Alzheimer’s disease, amyloid, anti-dementia drugs, dementia, monoclonal antibody

DOI: 10.3233/JAD-215065

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1537-1552, 2021

Authors: Ge, Feifei | Zhu, Donglin | Tian, Minjie | Shi, Jingping

Article Type: Review Article

Abstract: The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer’s disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.

Keywords: Alzheimer’s disease, biomarkers, cognitive impairment, thyroid

DOI: 10.3233/JAD-210339

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1553-1562, 2021

Authors: Morris, Kevin | Nami, Mohammad | Bolanos, Joe F. | Lobo, Maria A. | Sadri-Naini, Melody | Fiallos, John | Sanchez, Gilberto E. | Bustos, Teshia | Chintam, Nikita | Amaya, Marco | Strand, Susanne E. | Mayuku-Dore, Alero | Sakibova, Indira | Biso, Grace Maria Nicole | DeFilippis, Alejandro | Bravo, Daniela | Tarhan, Nevzat | Claussen, Carsten | Mercado, Alejandro | Braun, Serge | Yuge, Louis | Okabe, Shigeo | Taghizadeh-Hesary, Farhad | Kotliar, Konstantin | Sadowsky, Christina | Chandra, P. Sarat | Tripathi, Manjari | Katsaros, Vasileios | Mehling, Brian | Noroozian, Maryam | Abbasioun, Kazem | Amirjamshidi, Abbas | Hossein-Zadeh, Gholam-Ali | Naraghi, Faridedin | Barzegar, Mojtaba | Asadi-Pooya, Ali A. | Sahab-Negah, Sajad | Sadeghian, Saeid | Fahnestock, Margaret | Dilbaz, Nesrin | Hussain, Namath | Mari, Zoltan | Thatcher, Robert W. | Sipple, Daniel | Sidhu, Kuldip | Chopra, Deepak | Costa, Francesco | Spena, Giannantonio | Berger, Ted | Zelinsky, Deborah | Wheeler, Christopher J. | Ashford, J. Wesson | Schulte, Reinhard | Nezami, M. A. | Kloor, Harry | Filler, Aaron | Eliashiv, Dawn S. | Sinha, Dipen | DeSalles, Antonio A.F. | Sadanand, Venkatraman | Suchkov, Sergey | Green, Ken | Metin, Barish | Hariri, Robert | Cormier, Jason | Yamamoto, Vicky | Kateb, Babak

Article Type: Review Article

Abstract: Neurological disorders significantly impact the world’s economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the …need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population’s economic and health burden, specifically regarding neurological/brain, spine, and mental disorders. Show more

Keywords: Brain20, global brain initiatives, Mental20, mental disorders cost, neurological disorders cost, Neuroscience20, Spine20, spine disorders cost

DOI: 10.3233/JAD-215190

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1563-1601, 2021

Authors: Lim, Yen Ying | Ayton, Darshini | Perin, Stephanie | Lavale, Alexandra | Yassi, Nawaf | Buckley, Rachel | Barton, Christopher | Bruns Jr, Loren | Morello, Renata | Pirotta, Stephanie | Rosenich, Emily | Rajaratnam, Shantha M.W. | Sinnott, Richard | Brodtmann, Amy | Bush, Ashley I. | Maruff , Paul | Churilov, Leonid | Barker, Anna | Pase, Matthew P. | on behalf of the BetterBrains Research Group

Article Type: Research Article

Abstract: Background: Several modifiable risk factors for dementia have been identified, although the extent to which their modification leads to improved cognitive outcomes remains unclear. Objective: The primary aim is to test the hypothesis that a behavior modification intervention program targeting personalized risk factors prevents cognitive decline in community-dwelling, middle-aged adults with a family history of dementia. Methods: This is a prospective, risk factor management, blinded endpoint, randomized, controlled trial, where 1510 cognitively normal, community-dwelling adults aged 40–70 years old will be recruited. Participants will be screened for risk factors related to vascular health (including physical inactivity), …mental health, sleep, and cognitive/social engagement. The intervention is an online person-centered risk factor management program: BetterBrains. Participants randomized to intervention will receive telehealth-based person-centered goal setting, motivational interviewing, and follow-up support, health care provider communication and community linkage for management of known modifiable risk factors of dementia. Psychoeducational health information will be provided to both control and intervention groups. Results: The primary outcome is favorable cognitive performance at 24-months post-baseline, defined as the absence of decline on one or more of the following cognitive tests: (a) Cogstate Detection, (b) Cogstate One Card Learning, (c) Cogstate One Back, and (d) Cognitive Function Instrument total score. Conclusion: We will test the hypothesis that the BetterBrains intervention program can prevent cognitive decline. By leveraging existing community services and using a risk factor management pathway that tailors the intervention to each participant, we maximize likelihood for engagement, long-term adherence, and for preserving cognitive function in at-risk individuals. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive decline, dementia, lifestyle intervention, non-pharmacological, randomized control trial

DOI: 10.3233/JAD-210589

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1603-1622, 2021

Authors: Hill, Nikki L. | Bhargava, Sakshi | Bratlee-Whitaker, Emily | Turner, Jennifer R. | Brown, Monique J. | Mogle, Jacqueline

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early indicator of cognitive impairment, but depressive symptoms can confound this relationship. Associations may be influenced by differences between individuals (i.e., between-persons) or how each individual changes in their experiences over time (i.e., within-persons). Objective: We examined depressive symptoms as a mediator of the between- and within-person associations of SCD and objective memory in older adults. Methods: Coordinated analyses were conducted across four datasets drawn from large longitudinal studies. Samples (range: n  = 1,889 to n  = 15,841) included participants 65 years of age or older with no dementia at …baseline. We used multilevel structural equation modeling to examine the mediation of SCD and objective memory through depressive symptoms, as well as direct relationships among SCD, objective memory, and depressive symptoms. Results: Older adults who were more likely to report SCD had lower objective memory on average (between-person associations), and depressive symptoms partially mediated this relationship in three of four datasets. However, changes in depressive symptoms did not mediate the relationship between reports of SCD and declines in objective memory in three of four datasets (within-person associations). Conclusion: Individual differences in depressive symptoms, and not changes in an individual’s depressive symptoms over time, partially explain the link between SCD and objective memory. Older adults with SCD and depressive symptoms may be at greater risk for poor cognitive outcomes. Future research should explore how perceived changes in memory affect other aspects of psychological well-being, and how these relationships influence cognitive decline and Alzheimer’s disease risk. Show more

Keywords: Aging, cognition, depression, memory

DOI: 10.3233/JAD-210230

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1623-1636, 2021

Authors: Atkins, Kelly J. | Scott, David A. | Silbert, Brendan | Pike, Kerryn E. | Evered, Lis

Article Type: Research Article

Abstract: Background: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia. Objective: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline. Methods: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention …targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline. Results: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes. Conclusion: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults. Show more

Keywords: Anesthesia and analgesia, cognition, delirium, dementia, healthy aging, perioperative medicine, prehabilitation, preventive medicine, rehabilitation

DOI: 10.3233/JAD-210438

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1637-1649, 2021

Authors: Skaaraas, Gry H.E. Syverstad | Melbye, Christoffer | Puchades, Maja A. | Leung, Doreen Siu Yi | Jacobsen, Øyvind | Rao, Shreyas B. | Ottersen, Ole Petter | Leergaard, Trygve B. | Torp, Reidun

Article Type: Research Article

Abstract: Background: Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome. Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and …vessel density. Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques. Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density. Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors. Show more

Keywords: Alzheimer’s disease, amyloid-β , angiogenesis, cerebral amyloid angiopathy, HIF1a, mouse model, pericytes, VEGF

DOI: 10.3233/JAD-210571

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1651-1663, 2021

Authors: Wang, Cuiling | Katz, Mindy J. | Chang, Katherine H. | Qin, Jiyue | Lipton, Richard B. | Zwerling, Jessica L. | Sliwinski, Martin J. | Derby, Carol A. | Rabin, Laura A.

Article Type: Research Article

Abstract: Background: The Uniform Data Set, Version 3 Neuropsychological Battery (UDSNB3.0), from the database of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), is widely used to characterize cognitive performance in clinical and research settings; however, norms for underrepresented community-based samples are scarce. Objective: We compared UDSNB 3.0 test scores between the Einstein Aging Study (EAS), composed of racially/ethnically diverse, community-dwelling older adults aged≥70 and the NACC, and report normative data from the EAS. Methods: Analyses included 225 cognitively normal EAS participants and comparable data from 5,031 NACC database participants. Linear regression models …compared performance between the samples, adjusting for demographics (sex, age, education, race/ethnicity), depressive symptoms, and whether English was the first language. Linear regression models to examine demographic factors including age, sex, education and race/ethnicity as predictors for the neuropsychological tests were applied in EAS and NACC separately and were used to create a demographically adjusted z-score calculator. Results: Cognitive performance across all domains was worse in the EAS than in the NACC, adjusting for age, sex, education, race/ethnicity, and depression, and the differences remained in visuo-construction, visuospatial memory, confrontation naming, visual attention/processing speed, and executive functioning after further adjusting for whether English was the first language. In both samples, non-Hispanic Whites outperformed non-Hispanic Blacks and more education was associated with better cognitive performance. Conclusion: Differences observed in demographic, clinical, and cognitive characteristics between the community-based EAS sample and the nationwide NACC sample suggest that separate normative data that more accurately reflect non-clinic, community-based populations should be established. Show more

Keywords: Aging, cognitive test norms, community sample, mild cognitive impairment, neuropsychology, racial/ethnic diversity

DOI: 10.3233/JAD-210538

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1665-1678, 2021

Authors: Qureshi, Zaina P. | Thiel, Ellen | Nelson, James | Khandker, Rezaul

Article Type: Research Article

Abstract: Background: Insomnia is associated with worsened clinical outcomes among Alzheimer’s disease dementia (AD) patients, increased caregiver burden, and healthcare utilization. Objective: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data. Methods: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period. Results: A total of 3,500 insomnia AD …patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p  < 0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p  < 0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8%versus 32.3%), emergency room services (56.4%versus 48.0%), and skilled-nursing services (42.6%versus 31.9%) (all p  < 0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p  < 0.001). Conclusion: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications. Show more

Keywords: Alzheimer’s disease, dementia, facilities and services utilization, health care economics, sleep initiation and maintenance disorders

DOI: 10.3233/JAD-210713

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1679-1690, 2021

Authors: Sierra-Fonseca, Jorge A. | Rodriguez, Minerva | Themann, Anapaula | Lira, Omar | Flores-Ramirez, Francisco J. | Vargas-Medrano, Javier | Gadad, Bharathi S. | Iñiguez, Sergio D.

Article Type: Research Article

Abstract: Background: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Objective: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure …on these pathways, using mice as a model system. Methods: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. Results: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortex Conclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life. Show more

Keywords: Abnormal protein accumulation, Alzheimer’s disease, antidepressant, drug safety, juvenile, LC3-II, long-term effects, p62, proteostasis, SSRI

DOI: 10.3233/JAD-210475

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1691-1702, 2021