Journal of Alzheimer's Disease - Volume 96, issue 2

Authors: Bredesen, Dale E. | Toups, Kat | Hathaway, Ann | Gordon, Deborah | Chung, Henrianna | Raji, Cyrus | Boyd, Alan | Hill, Benjamin D. | Hausman-Cohen, Sharon | Attarha, Mouna | Chwa, Won Jong | Kurakin, Alexei | Jarrett, Michael

Article Type: Review Article

Abstract: The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer’s disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review …the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches. Show more

Keywords: Alzheimer’s disease, clinical trial, mild cognitive impairment, MRI volumetrics, neurodegeneration, systems

DOI: 10.3233/JAD-230467

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 429-437, 2023

Authors: González-Madrid, Antonia | Calfío, Camila | González, Andrea | Lüttges, Valentina | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer’s disease. Moreover, there is consensus that the combined effects of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. The other fraction of cases are derived from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological …events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD. Show more

Keywords: Alzheimer’s disease, global prevention effort, incidence, molecular biomarkers, prevention protocols, risk factors, tau protein

DOI: 10.3233/JAD-230454

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 439-457, 2023

Authors: Liu, Yiming | Shen, Yong

Article Type: Review Article

Abstract: With the rapid aging of the global population, the prevalence of neurodegenerative diseases has become a significant concern, with Alzheimer’s disease (AD) being the most common. However, the clinical trials of many drugs targeting AD have failed due to the challenges posed by the blood-brain barrier (BBB), which makes intracerebral administration of drugs difficult. However, nanoparticles (NPs) may aid in the delivery of such drugs. NPs are materials with sizes between 1–100 nm that offer several advantages, such as improving biocompatibility, prolonging half-life, transporting large molecules, crossing the BBB to deliver to the central nervous system, and exhibiting good targeting ability. …In addition to drug delivery, NPs also have excellent diagnostic potential, and multifunctional NPs can integrate the advantages of diagnosis, targeting, and treatment. This mini-review article provides an overview of NPs, including the composition of the carrier, strategies for crossing the BBB, and different targets of AD pathology, with the aim of providing guidance for the development prospects of NPs. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, drug delivery, nanoparticles

DOI: 10.3233/JAD-230098

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 459-471, 2023

Authors: Guilliot, Solene | Gauthier, Serge | Touchon, Jacques | Soto, Maria E.

Article Type: Review Article

Abstract: After over 50 years of use, lithium-salts remain the first-line therapy for the management of bipolar disorder. Throughout this period, the potential for lithium salts has been extensively studied and numerous data favor its use in the treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). We reviewed existing evidence gathered from clinical case reports and studies on the effect of lithium on neuropsychological symptoms of AD and as a disease-modifying treatment acting on cognitive symptoms. The review summarizes the molecular pathways, involving GSK-3β inhibition and neuroprotection, through which lithium is proposed to exert its effect. Limitations to its current …use in AD are discussed and future perspectives as a potential treatment option for AD are considered in regard to ongoing clinical trials using different forms of lithium. Show more

Keywords: Alzheimer’s disease, disease modifying treatment, lithium, neurodegeneration, neuroprotection, neuropsychiatric symptoms

DOI: 10.3233/JAD-230568

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 473-482, 2023

Authors: Polin, Clément | Gellé, Thibaut | Auditeau, Emilie | Adou, Caroline | Clément, Jean-Pierre | Calvet, Benjamin

Article Type: Systematic Review

Abstract: Background: Repetitive behaviors (RBs) are a well-known symptom of Alzheimer’s disease (AD); however, they have been little studied and have not been the subject of any specific literature review. Objective: To conduct a systematic review of all studies to document RBs in AD. Methods: An extensive literature search combining five databases and a meta-analysis were conducted to investigate the frequency, nature, and cognitive correlates of RBs in AD. Results: Ten studies were included in the review. Seven studies out of ten investigated the frequency of RBs in patients with AD, which ranged from 52.3% …to 87%. A meta-analysis showed an overall frequency of 66.3% (95% CI: 55.5; 77.1) of patients exhibiting RBs in AD, but important heterogeneity was observed between studies. Three studies investigated the predominant nature of RBs in AD. Verbal RBs, complex behavioral stereotypies, and simple motor stereotypies have been identified to different degrees depending on the level of dementia. Most verbal RBs are underpinned by episodic memory impairment, while simple motor stereotypies and complex behavioral stereotypies are mostly underpinned by executive dysfunction. Conclusions: The current review seems to suggest that there are two types of mechanisms underpinning RBs involved in AD. The first is observed especially in the mild stages of the disease and is mediated by episodic memory impairment. The second occurs later and is mediated by executive impairment. Additional studies should be conducted to improve the knowledge about RBs in AD and thus improve their management. Systematic review registration number: PROSPERO 2022: CRD42022310027 Show more

Keywords: Alzheimer’s disease, meta-analysis, repetitive behaviors, systematic review

DOI: 10.3233/JAD-230380

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 483-497, 2023

Authors: Ukraintseva, Svetlana | Duan, Matt | Simanek, Amanda M. | Holmes, Rachel | Bagley, Olivia | Rajendrakumar, Aravind L. | Yashkin, Arseniy P. | Akushevich, Igor | Tropsha, Alexander | Whitson, Heather | Yashin, Anatoliy | Arbeev, Konstantin

Article Type: Short Communication

Abstract: Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer’s disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65–75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD …prevention. Show more

Keywords: Alzheimer’s disease, Cardiovascular Health Study, immunity, pneumococcal polysaccharide vaccine, seasonal flu shots, vaccine repurposing

DOI: 10.3233/JAD-230088

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 499-505, 2023

Authors: Karjadi, Cody | Xue, Chonghua | Cordella, Claire | Kiran, Swathi | Paschalidis, Ioannis Ch. | Au, Rhoda | Kolachalama, Vijaya B.

Article Type: Short Communication

Abstract: Digital voice recordings can offer affordable, accessible ways to evaluate behavior and function. We assessed how combining different low-level voice descriptors can evaluate cognitive status. Using voice recordings from neuropsychological exams at the Framingham Heart Study, we developed a machine learning framework fusing spectral, prosodic, and sound quality measures early in the training cycle. The model’s area under the receiver operating characteristic curve was 0.832 (±0.034) in differentiating persons with dementia from those who had normal cognition. This offers a data-driven framework for analyzing minimally processed voice recordings for cognitive assessment, highlighting the value of digital technologies in disease detection …and intervention. Show more

Keywords: Alzheimer’s disease, dementia, digital health, machine learning, neuropsychological testing, voice recording

DOI: 10.3233/JAD-230560

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 507-514, 2023

Authors: Ketchum, Fred B. | Erickson, Claire M. | Basche, Kristin E. | Chin, Nathaniel A. | Rosario, Hannah L. | Johnson, Sterling C. | Clark, Lindsay R.

Article Type: Short Communication

Abstract: Recommendations for communicating Alzheimer’s disease (AD) biomarkers include pre-disclosure participant education and counseling, to allow individuals to make an informed decision. In a cohort of largely non-Hispanic White, cognitively unimpaired older adults from the Wisconsin Registry for Alzheimer’s Prevention, we conducted a structured amyloid PET disclosure process that included knowledge assessment and education. Baseline participant knowledge about AD biomarkers and research was high, but information needs existed around dementia causes, early AD symptoms, genetic information, and psychosocial consequences of disclosure. Knowledge scores increased after education, highlighting the potential of brief educational interventions to improve informed decision-making about biomarker disclosure.

Keywords: Alzheimer’s disease, biomarker disclosure, dementia education, ethics, preclinical diagnosis, shared decision making

DOI: 10.3233/JAD-230732

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 515-522, 2023

Authors: Liu, Cheng-Chun | Wang, Qing-Hua | Xin, Jia-Yan | Liu, Yu-Hao | Zeng, Fan | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zeng, Gui-Hua | Wang, Yan-Jiang | Xiang, Yang | Chen, Yang

Article Type: Research Article

Abstract: Background: The correlation between plasma adipose factor levels and Alzheimer’s patients is not entirely clear. Objective: We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin. Methods: A single-center, cross-sectional study recruited AD patients (n  = 148) and cognitively normal (CN) controls (n  = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD. Results: After …adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p  < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p  < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p  < 0.0001) and was positively with CDR scores (p  < 0.0001) and age (p  < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p  < 0.0001) and positively correlated with MMSE scores (p  < 0.0001). Both adiponectin (p  < 0. 0001) and leptin (p  < 0. 0001) featured higher AUC than the random chance. Conclusions: Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD. Show more

Keywords: Adipokine, adiponectin, Alzheimer’s disease, leptin, resistin

DOI: 10.3233/JAD-220860

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 523-533, 2023

Authors: Akushevich, Igor | Yashkin, Arseniy | Ukraintseva, Svetlana | Yashin, Anatoliy I. | Kravchenko, Julia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and related dementia (ADRD) risk is affected by multiple dependent risk factors; however, there is no consensus about their relative impact in the development of these disorders. Objective: To rank the effects of potentially dependent risk factors and identify an optimal parsimonious set of measures for predicting AD/ADRD risk from a larger pool of potentially correlated predictors. Methods: We used diagnosis record, survey, and genetic data from the Health and Retirement Study to assess the relative predictive strength of AD/ADRD risk factors spanning several domains: comorbidities, demographics/socioeconomics, health-related behavior, genetics, and environmental …exposure. A modified stepwise-AIC-best-subset blanket algorithm was then used to select an optimal set of predictors. Results: The final predictive model was reduced to 10 features for AD and 19 for ADRD; concordance statistics were about 0.85 for one-year and 0.70 for ten-year follow-up. Depression, arterial hypertension, traumatic brain injury, cerebrovascular diseases, and the APOE4 proxy SNP rs769449 had the strongest individual associations with AD/ADRD risk. AD/ADRD risk-related co-morbidities provide predictive power on par with key genetic vulnerabilities. Conclusion: Results confirm the consensus that circulatory diseases are the main comorbidities associated with AD/ADRD risk and show that clinical diagnosis records outperform comparable self-reported measures in predicting AD/ADRD risk. Model construction algorithms combined with modern data allows researchers to conserve power (especially in the study of disparities where disadvantaged groups are often grossly underrepresented) while accounting for a high proportion of AD/ADRD-risk-related population heterogeneity stemming from multiple domains. Show more

Keywords: Alzheimer’s disease, environmental exposure, genetic factors, Medicare, polygenic risk scores, predictive models, risk factors

DOI: 10.3233/JAD-221292

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 535-550, 2023