Journal of Alzheimer's Disease - Volume 100, issue 4

Authors: Reive, Brady S. | Lau, Victor | Sánchez-Lafuente, Carla L. | Henri-Bhargava, Alexandre | Kalynchuk, Lisa E. | Tremblay, Marie-Ève | Caruncho, Hector J.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction …and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, immunity, inflammation, microglia, Reelin

DOI: 10.3233/JAD-240088

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1099-1119, 2024

Authors: Yenesew, Muluken A. | Krell-Roesch, Janina | Fekadu, Betelhem | Nigatu, Dabere | Endalamaw, Aklilu | Mekonnen, Alemtsehay | Biyadgie, Mulugeta | Wubetu, Gizachew Y. | Debiso, Alemu T. | Beyene, Kassu M. | Kelkile, Teshome S. | Enquobahrie, Daniel A. | Mersha, Tesfaye B. | Eagan, Danielle E. | Geda, Yonas E.

Article Type: Review Article

Abstract: Background: Population-based research on the prevalence and determinants of dementia, Alzheimer’s disease, and cognitive impairment is scarce in East Africa. Objective: To provide an overview of community- and population-based studies among older adults on the prevalence of dementia and cognitive impairment in East Africa, and identify research gaps. Methods: We carried out a literature search using three electronic databases (PubMed, Scopus, Google Scholar) using pertinent search terms. Results: After screening 445 publications, we identified four publications on the population-based prevalence of dementia, and three on cognitive impairment. Prevalence rates varied from 6– 23% for …dementia, and 7– 44% for cognitive impairment, among participants aged≥50–70 years. Old age and a lower education level were risk factors for dementia and cognitive impairment. Physical inactivity, lack of a ventilated kitchen, and history of central nervous system infections and chronic headache were associated with increased odds of dementia. Female sex, depression, having no spouse, increased lifetime alcohol consumption, low income, rural residence, and low family support were associated with increased odds of cognitive impairment. Potential misclassification and non-standardized data collection methods are research gaps that should be addressed in future studies. Conclusions: Establishing collaborative networks and partnering with international research institutions may enhance the capacity for conducting population-based studies on dementia and cognitive impairment in East Africa. Longitudinal studies may provide valuable insights on incidence, as well as potential risk and protective factors of dementia and cognitive impairment, and may inform the development of targeted interventions including preventive strategies in the region. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, East Africa, prevalence, scoping review

DOI: 10.3233/JAD-240381

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1121-1131, 2024

Authors: Machado, Mariane Gomes | Machado, Thais Helena | Caramelli, Paulo | Gonçalves Tosatti, Jessica Abdo | da Silva Carvalho, Sirley Alves | de Resende, Luciana Macedo

Article Type: Systematic Review

Abstract: Background: The assumption that hearing rehabilitation could improve quality of life and reduce dementia risk in people with hearing loss is a subject that needs further studies, especially clinical trials. It is necessary to determine the effects of hearing aid use, as part of hearing rehabilitation, among people diagnosed with dementia. Objective: To systematically review the literature to evaluate the effects of hearing aid use on cognition and quality of life of people with dementia. Methods: Protocol for this systematic review was registered (CRD42023387187). The Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Scopus, CINAHL, and …Web of Science databases, as well as grey literature, including Google Scholar and ResearchGate, were systematically searched for clinical trials using MeSH terms. The PICOS principle was used to develop the inclusion criteria: population (P): adults and older adults, individuals diagnosed with dementia and hearing loss; intervention (I): rehabilitation with hearing aids; control (C): not using a hearing aid; outcome (O): cognitive and/or quality of life assessment using validated tests; study design (S): clinical trial. Results: The initial search yielded 576 studies, five of which met the inclusion criteria for qualitative analyses. Two of the included studies were randomized clinical trials, and three were crossover clinical trials, demonstrating the lack of studies on the subject. Four studies included participants with Alzheimer’s disease. Quality of life was found to improve with the use of hearing aids, and hearing rehabilitation was not shown to affect cognitive outcomes. Conclusions: Hearing aid use appears to have a positive impact on quality of life. Show more

Keywords: Alzheimer’s disease, cognition, dementia, hearing aids, hearing loss, quality of life

DOI: 10.3233/JAD-231460

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1133-1143, 2024

Authors: Lepping, Rebecca J. | Hess, Benjamin J. | Taylor, Jasmine M. | Hanson-Abromeit, Deanna | Williams, Kristine N.

Article Type: Systematic Review

Abstract: Background: Recent research has shown beneficial results for music-based interventions (MBIs) for persons living with Alzheimer’s disease and related dementias (AD/ADRD), but reports often lack sufficient detail about the MBI methodology, which reduces replicability. A detailed checklist for best practices in how to report MBIs was created in 2011 by Robb and colleagues to remedy the lack of detail in MBI descriptions. The implementation of the checklist specifically in AD/ADRD research has not been established. Given the complexity of music and the variety of uses for research and health, specific MBI descriptions are necessary for rigorous replication and validation of …study results. Objective: This systematic mapping review utilized the “Checklist for Reporting Music-Based Interventions” to evaluate the current state of MBI descriptive specificity in AD/ADRD research. Methods: Research articles testing MBIs and reviews of MBI efficacy published between January 2015 and August 2023 were scored using the checklist and the results were summarized. Results: Forty-eight studies were screened, and reporting was inconsistent across the 11 checklist criteria. Ten out of 48 studies fully reported more than 5 of the 11 criteria. Only one of the 11 scoring criteria was at least partially reported across 47 of 48 studies. Conclusions: Thorough reporting of intervention detail for MBIs remains limited in AD/ADRD MBI research. This impedes study validation, replication, and slows the progress of research and potential application of music in practice. Greater implementation of the reporting guidelines provided by Robb and colleagues would move the field of MBI research for AD/ADRD forward more quickly and efficiently. Show more

Keywords: Alzheimer’s disease, dementia, interventions, music, reporting guidelines

DOI: 10.3233/JAD-240255

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1145-1159, 2024

Authors: Wu, Che-Yuan | Swardfager, Walter

Article Type: Article Commentary

Abstract: Pharmacoepidemiologic studies using routinely collected data allow researchers to propose drugs for repurposing trials for dementia prevention or treatment. A recent cohort study reported a 54% lower dementia risk among users of sildenafil compared to users of certain cardiovascular medications. We caution that “confounding by indication” can arise when outcomes are compared between a drug of interest and an inappropriate comparator. Here, we emphasize important considerations in selecting an active comparator. We assess the implications of substantial risk of confounding by indication in pharmacoepidemiologic studies linking phosphodiesterase-5 inhibitors to lower dementia risk.

Keywords: Alzheimer’s disease, confounding by indication, dementia, pharmacoepidemiology, phosphodiesterase-5 inhibitors

DOI: 10.3233/JAD-240520

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1161-1163, 2024

Authors: Rodini, Marta | Bonarota, Sabrina | Serra, Laura | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: Recently, subjective cognitive decline (SCD) was proposed as an early risk factor for future Alzheimer’s disease (AD). Objective: In this study, we investigated whether accelerated long-term forgetting (ALF), assessed with extended testing intervals than those adopted in clinical practice, might be a cognitive feature of SCD. Using an explorative MRI analysis of the SCD sample, we attempted to investigate the areas most likely involved in the ALF pattern. Methods: We recruited 31 individuals with SCD from our memory clinic and subdivided them based on their rate of memory complaints into mild SCDs (n  = 18) …and severe SCDs (n  = 13). A long-term forgetting procedure, involving the recall of verbal and visuo-spatial material at four testing delays (i.e., immediate, 30 min, 24 h, and 7 days post-encoding) was used to compare the two sub-groups of SCDs with a healthy control group (HC; n  = 16). Results: No significant between-group difference was found on the standard neuropsychological tests, nor in the immediate and 30 min recall of the experimental procedure. By contrast, on the verbal test severe SCDs forgot significantly more than HCs in the prolonged intervals (i.e., 24 h and 7 days), with the greatest decline between 30 min and 24 h. Finally, in the whole SCD sample, we found significant associations between functional connectivity values within some cortical networks involved in memory (default mode network, salience network, and fronto-parietal network) and verbal long-term measures. Conclusions: Our preliminary findings suggest that long-term forgetting procedures could be a sensitive neuropsychological tool for detecting memory concerns in SCDs, contributing to early AD detection. Show more

Keywords: Accelerated long-term forgetting, Alzheimer’s disease, functional connectivity, subjective cognitive decline

DOI: 10.3233/JAD-240218

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1165-1182, 2024

Authors: Sommerlad, Andrew | Grothe, Jessica | Umeda, Sumiyo | Ikeda, Manabu | Kanemoto, Hideki | Livingston, Gill | Luppa, Melanie | Rankin, Katherine P. | Riedel-Heller, Steffi G. | Röhr, Susanne | Suzuki, Maki | Huntley, Jonathan

Article Type: Research Article

Abstract: Background: People with dementia commonly have impaired social functioning and may not recognize this. This lack of awareness may result in worse outcomes for the person and their family carers. Objective: We aimed to characterize awareness of social functioning in dementia and describe its association with dementia severity. Methods: Multi-center cross-sectional study of people aged >65 years with dementia and family informants recruited from Germany, Japan and the United Kingdom. We used the Social Functioning in Dementia (SF-DEM) scale, assessing “spending time with other people” (domain 1), “communicating with other people” (domain 2), and “sensitivity to …other people” (domain 3), and calculated lack of awareness into social functioning as the discrepancy between patient and informant ratings. Results: 108 participants with dementia (50.9% women), mean age = 78.9 years, and mean MMSE score = 22.7. Patient and informant domain 1 ratings did not differ, but patient-rating was higher than carers for domain 2 (11.2 versus 10.1; p  = 0.003) and domain 3 (9.7 versus 8.1; p  < 0.001). Sixty people with dementia overestimated their overall social functioning, 30 underestimated, and 18 gave ratings congruent with their informant. Performance on the MMSE and its sub-domains was not associated with SF-DEM discrepancy score. Conclusions: We found that awareness of social functioning in dementia was a multidimensional concept, which varies according to subdomains of social functioning. Clinicians should help family members understand and adapt by explaining their relative with dementia’s lack of awareness about aspects of their social functioning. Show more

Keywords: Alzheimer’s disease, awareness, dementia, insight, metacognition, social functioning

DOI: 10.3233/JAD-240311

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1183-1193, 2024

Authors: Marin, Anna | Turk, Katherine W. | Schiloski, Kylie | Vives-Rodriguez, Ana | Suh, Cheongmin | Uppal, Prayerna | Dwyer, Brigid | Palumbo, Rocco | Budson, Andrew E.

Article Type: Research Article

Abstract: Background: Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer’s disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. Objective: We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Methods: Veterans aged 50–100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine …patients had a negative scan. Results: ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. Conclusions: ERP-P200 measures are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks. Show more

Keywords: Alzheimer’s disease, amyloid PET, biomarkers, event-related potentials

DOI: 10.3233/JAD-231038

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1195-1208, 2024

Authors: Elman, Jeremy A. | Schork, Nicholas J. | Rangan, Aaditya V.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). …We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n  = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters (“constellations”) driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time. Show more

Keywords: Alzheimer’s disease, biclustering, genetic risk, genetic subtypes, genotyping

DOI: 10.3233/JAD-231252

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1209-1226, 2024

Authors: Therrien, Sarah | Anthony, Mia | Turnbull, Adam | Lin, F. Vankee

Article Type: Research Article

Abstract: Background: Adequately evaluating risk and making decisions is vital but understudied for older adults living independently but with compromised cognition, as seen in those with mild cognitive impairment (MCI), specifically those with amnestic MCI (aMCI) which is associated with higher risk of conversion to Alzheimer’s disease. Objective: We propose to comprehensively evaluate risk-taking behaviors across domains important for everyday activities between an aMCI group and their cognitively healthy counterparts (HC). Methods: A case-control study design. Data on risk-taking behaviors via the Domain-Specific Risk-Taking Scale (DOSPERT), and candidate confounding mental health factors (i.e., neurodegeneration, depression, and fatigue) …were collected. Analyses on group difference and interaction between group and confounding factors on risk-taking behaviors were conducted. Results: The aMCI group showed a higher likelihood of risk-taking than HC (t  = 4.38, df = 73, p  < 0.001). Moderation analysis showed fatigue (F  = 5.91, p  = 0.018) and presence of depression (F  = 4.52, p  = 0.037), but not neurodegeneration, as significant moderators for group and DOSPERT total score, controlling for sex. In post-hoc analyses, there was a significant relationship between both fatigue (B  = –7.83, SE = 3.65, t  = –2.14, p  = 0.036), and presence of depression (B  = –20.80, SE = 9.97, t  = –2.09, p  = 0.041), with DOSPERT total score for HC but not for aMCI. There were no significant relationships between neurodegeneration, fatigue, or depression with any specific risk-taking domains after correction for multiple comparisons. Conclusions: Our results show differences in risk-taking behavior between older adults with and without intact cognition, and overall decision-making is affected by fatigue and depression in HC but not aMCI, together suggesting the importance of cognition in the ability to adjust risk-taking behaviors. Show more

Keywords: Alzheimer’s disease, decision making, functional status, mild cognitive impairment, risk-taking

DOI: 10.3233/JAD-231448

Citation: Journal of Alzheimer's Disease, vol. 100, no. 4, pp. 1227-1235, 2024