Journal of Alzheimer's Disease - Volume 99, issue 3

Authors: McLaren, Alexandra M.R. | Kawaja, Michael D.

Article Type: Review Article

Abstract:  Alzheimer’s disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer’s disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer’s disease. While a correlation between olfactory dysfunction and Alzheimer’s disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current …state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer’s disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer’s disease including amyloid-β protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid-beta protein precursor, Apolipoprotein E, impaired olfaction, presenilins

DOI: 10.3233/JAD-231377

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 811-827, 2024

Authors: Carcavilla-González, Nuria | Escalada San Adrián, Gema | Minobes-Molina, Eduard | Pàmies-Tejedor, Sandra | Roncal-Belzunce, Victoria | Atarés-Rodríguez, Laura | García-Navarro, José Augusto

Article Type: Review Article

Abstract: This narrative explores the impact of deinstitutionalization policies on the quality of life and care outcomes for individuals with Alzheimer’s disease and related dementias. We offer a historical perspective on these policies, their implications on dementia care, and the barriers to deinstitutionalization. The potential benefits of deinstitutionalization, such as improved quality of life and access to community-based support and services, are highlighted. Challenges and controversies surrounding safety, caregiver burden, and resource allocation are also examined. Ethical considerations related to the autonomy and decision-making capacity of people living with dementia are discussed. We present best practices and innovative models in dementia …care that balance deinstitutionalization with appropriate care. We further put forth recommendations for future research and policy development in dementia care and deinstitutionalization, emphasizing the need for a balanced approach that respects the autonomy and preferences of people living with dementia while ensuring their safety and well-being. Show more

Keywords: Alzheimer’s disease, care outcomes, caregiver burden, community-based support, deinstitutionalization, dementia care, ethical considerations, policy development, quality of life, resource allocation

DOI: 10.3233/JAD-231180

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 829-841, 2024

Authors: Duchesne, Simon | Rousseau, Louis-Simon | Belzile-Marsolais, Florence | Welch, Laurie-Ann | Cournoyer, Béatrice | Arseneau, Marianne | Lapierre, Véronick | Poulin, Sara-Maude | Potvin, Olivier | Hudon, Carol

Article Type: Review Article

Abstract: Background: There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Objective: To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. Results: We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. …Results: Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. Conclusions: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity. Show more

Keywords: Alzheimers disease, amyloid, cerebrovascular disease, hypothesis, metabolism, mitochondrial dysfunction, scoping review, theory

DOI: 10.3233/JAD-230772

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 843-856, 2024

Authors: Irfan, Bilal | Ankouni, Ghadeer | Reader, Jonathan | Seraji-Bozorgzad, Navid | Giordani, Bruno | Bakulski, Kelly | Bhaumik, Arijit | Hampstead, Benjamin M. | Rahman-Filipiak, Annalise

Article Type: Review Article

Abstract: Alzheimer’s disease and related dementias (ADRD) present significant challenges including cognitive and functional loss, behavioral disruption, emotional distress, and significant financial burden. These stressors are amplified in minority groups, who experience higher rates of ADRD but less frequent and later diagnosis. There is therefore a critical need to identify tangible approaches to culturally informed dementia assessment and care for patients from diverse communities. Muslim patients and particularly Muslim women are among the populations most understudied in the ADRD space. Muslim patients may hold unique religious, spiritual, and cultural beliefs and practices that can impact care-seeking for dementia symptoms, diagnostic accuracy, …and treatment uptake. This paper outlines culturally informed approaches to assessing and treating Muslim women and families at each stage of ADRD care, though many recommendations extend to the broader Muslim community and others of diverse racial-ethnic backgrounds. We provide concrete suggestions for building rapport within and leveraging common family structures, respecting principles of modesty and privacy for all women including those who observe hijab or niqab, and communicating dementia diagnosis and care in the context of spiritual and ethical beliefs. While not intended as a comprehensive and prescriptive guide, this review provides important points of consideration and discussion with patients of Muslim backgrounds. Show more

Keywords: Alzheimer’s disease, culturally informed care, Islam, religious ethics

DOI: 10.3233/JAD-240064

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 857-867, 2024

Authors: Diaz-Asper, Catherine | Chandler, Chelsea | Elvevåg, Brita

Article Type: Short Communication

Abstract:  This study surveyed 51 specialist clinicians for their views on existing cognitive screening tests for mild cognitive impairment and their opinions about a hypothetical remote screener driven by artificial intelligence (AI). Responses revealed significant concerns regarding the sensitivity, specificity, and time taken to administer current tests, along with a general willingness to consider adopting telephone-based screening driven by AI. Findings highlight the need to design screeners that address the challenges of recognizing the earliest stages of cognitive decline and that prioritize not only accuracy but also stakeholder input.

Keywords: Alzheimer’s disease, artificial intelligence, attitude of health personnel, mental status and dementia test, mild cognitive impairment

DOI: 10.3233/JAD-240293

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 869-876, 2024

Authors: Espay, Alberto J. | Herrup, Karl | Imbimbo, Bruno P. | Kepp, Kasper P. | Daly, Timothy

Article Type: Article Commentary

Abstract: Three recent anti-amyloid-β antibody trials for Alzheimer’s disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond …removing amyloid. Show more

Keywords: Alzheimer’s disease, ARIA, amyloid-β, Aβ42, placebo, RCT

DOI: 10.3233/JAD-240171

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 877-881, 2024

Authors: McIntire, Laura Beth

Article Type: Article Commentary

Abstract: With the advent of therapeutics with potential to slow Alzheimer’s disease progression the necessity of understanding the diagnostic value of plasma biomarkers is critical, not only for understanding the etiology and progression of Alzheimer’s disease, but also for access and response to potentially disease modifying therapeutic agents. Multiple studies are currently assessing the sensitivity and specificity of plasma biomarkers in large cohorts such as the Alzheimer’s Disease Neuroimaging Initiative. This study uses machine learning to predict the progression from mild cognitive impairment using plasma biomarkers in conjunction with well-established cerebrospinal fluid and imaging biomarkers of disease progression.

Keywords: Alzheimer’s disease, neurofilament light, phospho-tau (p-tau181), plasma biomarkers

DOI: 10.3233/JAD-240126

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 883-885, 2024

Authors: Reyes Bueno, José A. | Sánchez-Guijo, Guillermo | Ráez, Pablo Doblas | García-Arnés, Juan A. | Garzón-Maldonado, Francisco J. | Castro, Vicente Serrano | de la Cruz-Cosme, Carlos | Alba-Linero, Carmen | Gutiérrez-Bedmar, Mario | García-Casares, Natalia

Article Type: Research Article

Abstract: Background: Diabetes is one of the main risk factors for developing mild cognitive impairment (MCI) and Alzheimer’s disease. Most studies have demonstrated a worse performance in executive function, verbal fluency, and information processing speed in patients with diabetes. Objective: To assess the cognitive functioning of persons with type 2 diabetes and amnesic mild cognitive impairment (aMCI-T2DM) compared to persons with aMCI without diabetes and persons without diabetes or aMCI as controls, to understand the role of diabetes in the neuropsychological profile. Methods: Cross-sectional study involving a sample of 83 patients, ranging in age from 61 to …85 years and divided into three groups: aMCI-T2DM (27 patients), aMCI (29 patients), Controls (27 individuals). All the participants undertook an exhaustive neuropsychological assessment (auditory-verbal and visual memory, attention, information processing speed, language, executive function, and depression). Results: Both groups of aMCI patients performed significantly worse than the controls in all the neuropsychological tests. A significant linear tendency (p trend < 0.05) was found between groups, with the aMCI-T2DM group presenting worse results in global cognition assessed by the Mini-Mental State Examination and Montreal Cognitive Assessment; Rey-Osterrieth Complex Figure Test; Auditory Verbal Learning Test; Trail Making Test A and B, Verbal Fluency Test, and Hamilton Depression Rating Scale. Conclusions: aMCI patients with or without diabetes showed worse cognitive function compared to persons without diabetes or aMCI. Additionally, aMCI patients without T2DM presented a different cognitive profile than aMCI patients with T2DM, which tended towards presenting worse cognitive functions such as global cognition, memory, attention, executive function, and language. Show more

Keywords: Alzheimer’s disease, cognition, diabetes mellitus, mild cognitive impairment, neuropsychological test, type 2 diabetes

DOI: 10.3233/JAD-230791

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 887-897, 2024

Authors: Tuena, Cosimo | Serino, Silvia | Goulene, Karine Marie | Pedroli, Elisa | Stramba-Badiale, Marco | Riva, Giuseppe

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) syndrome often report navigation difficulties, accompanied by impairments in egocentric and allocentric spatial memory. However, studies have shown that both bodily (e.g., motor commands, proprioception, vestibular information) and visual-cognitive (e.g., maps, directional arrows, attentional markers) cues can support spatial memory in MCI. Objective: We aimed to assess navigation cues for innovative spatial training in aging. Methods: Fifteen MCI patients were recruited for this study. Their egocentric and allocentric memory recall performances were tested through a navigation task with five different virtual reality (VR) assistive encoding navigation procedures (bodily, vision …only, interactive allocentric map, reduced executive load, free navigation without cues). Bodily condition consisted of an immersive VR setup to engage self-motion cues, vision only condition consisted of passive navigation without interaction, in the interactive allocentric map condition patients could use a bird-view map, in the reduced executive load condition directional cues and attentional markers were employed, and during free navigation no aid was implemented. Results: Bodily condition improved spatial memory compared to vision only and free navigation without cues. In addition, the interactive allocentric map was superior to the free navigation without cues. Surprisingly, the reduced executive load was comparable to vison only condition. Moreover, a detrimental impact of free navigation was observed on allocentric memory across testing trials. Conclusions: These findings challenge the notion of an amodal representation of space in aging, suggesting that spatial maps can be influenced by the modality in which the environment was originally encoded. Show more

Keywords: Alzheimer’s disease, dementia, embodied cognition, mild cognitive impairment, rehabilitation, spatial cognition

DOI: 10.3233/JAD-240122

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 899-910, 2024

Authors: Zhu, Mengxin | Liu, Yang | Chen, Chen | Chen, Hao | Ni, Wanyan | Song, Yuanjian | Lv, Bingchen | Hua, Fang | Cui, Guiyun | Zhang, Zuohui

Article Type: Research Article

Abstract: Background: Neuroinflammation plays a crucial part in the initial onset and progression of Alzheimer’s disease (AD). NLRP3 inflammasome was demonstrated to get involved in amyloid-β (Aβ)-induced neuroinflammation. However, the mechanism of Aβ-triggered activation of NLRP3 inflammasome remains poorly understood. Objective: Based on our previous data, the study aimed to identify the downstream signals that bridge the activation of TLR4 and NLRP3 inflammasome associated with Aβ. Methods: BV-2 cells were transfected with TLR4siRNA or pretreated with a CLI-095 or NSC23766, followed by Aβ1–42 treatment. APP/PS1 mice were injected intraperitoneally with CLI-095 or NSC23766. NLRP3 inflammasome and …microglia activation was detected with immunostaining and western blot. G-LISA and Rac1 pull-down activation test were performed to investigate the activation of Rac1. Real-time PCR and ELISA were used to detect the inflammatory cytokines. Aβ plaques were assessed by western blotting and immunofluorescence staining. Morris water maze test was conducted to determine the spatial memory in mice. Results: Rac1 and NLRP3 inflammasome were activated by Aβ in both in vitro and in vivo experiments. Inhibition of TLR4 reduced the activity of Rac1 and NLRP3 inflammasome induced by Aβ1–42 . Furthermore, inhibition of Rac1 blocked NLRP3 inflammasome activation mediated by TLR4. Blocking the pathway by CLI095 or NSC23766 suppressed Aβ1–42 -triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Conclusions: Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aβ-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β , microglia, neuroinflammation, NLRP3 inflammasome, Rac1, TLR4

DOI: 10.3233/JAD-240012

Citation: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 911-925, 2024