Journal of Alzheimer's Disease - Volume 81, issue 3

Authors: Müller, Luisa | Kirschstein, Timo | Köhling, Rüdiger | Kuhla, Angela | Teipel, Stefan

Article Type: Review Article

Abstract: Transgenic mouse models serve a better understanding of Alzheimer’s disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD models are APPswe/PS1dE9 mice, which are able to reproduce features of amyloid-β (Aβ) plaque formations as well as neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. The most prominent findings include abnormal synaptic function and synaptic reorganization as well as changes in membrane threshold and spontaneous neuronal firing activities leading to generalized excitation-inhibition imbalances in larger neuronal circuits and networks. Importantly, these findings in APPswe/PS1dE9 mice are at least partly consistent with results of electrophysiological …studies in humans with sporadic AD. This underscores the potential to transfer mechanistic insights into amyloid related neuronal dysfunction from animal models to humans. This is of high relevance for targeted downstream interventions into neuronal hyperexcitability, for example based on repurposing of existing antiepileptic drugs, as well as the use of combinations of imaging and electrophysiological readouts to monitor effects of upstream interventions into amyloid build-up and processing on neuronal function in animal models and human studies. This article gives an overview on the pathogenic and methodological basis for recording of neuronal hyperexcitability in AD mouse models and on key findings in APPswe/PS1dE9 mice. We point at several instances to the translational perspective into clinical intervention and observation studies in humans. We particularly focus on bi-directional relations between hyperexcitability and cerebral amyloidosis, including build-up as well as clearance of amyloid, possibly related to sleep and so called glymphatic system function. Show more

Keywords: Alzheimer’s disease, amyloid-β, APPswe/PS1dE9 mice, neuronal hyperexcitability, sleep-wake cycle

DOI: 10.3233/JAD-201540

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 855-869, 2021

Authors: Krivanek, Taylor J. | Gale, Seth A. | McFeeley, Brittany M. | Nicastri, Casey M. | Daffner, Kirk R.

Article Type: Review Article

Abstract: A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human …proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors. Show more

Keywords: Cognitive aging, cognitive decline, cognitive reserve, dementia, healthy aging, healthy lifestyle, mild cognitive impairment, preventive medicine, risk reduction

DOI: 10.3233/JAD-201462

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 871-920, 2021

Authors: Norins, Leslie C.

Article Type: Review Article

Abstract: Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing …drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, cognitive dysfunction

DOI: 10.3233/JAD-210080

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 921-932, 2021

Authors: Jaul, Efraim | Meiron, Oded

Article Type: Review Article

Abstract: There is an urgent need in advanced dementia for evidence-based clinical prognostic predictors that could positively influence ethical decisions allowing health provider and family preparation for early mortality. Accordingly, the authors review and discuss the prognostic utility of clinical assessments and objective measures of pathological brain states in advanced dementia patients associated with accelerated mortality. Overall, due to the paucity of brain-activity and clinical-comorbidity predictors of survival in advanced dementia, authors outline the potential prognostic value of brain-state electroencephalography (EEG) measures and reliable clinical indicators for forecasting early mortality in advanced dementia patients. In conclusion, two consistent risk-factors for predicting …accelerated mortality in terminal-stage patients with advanced dementia were identified: pressure ulcers and paroxysmal slow-wave EEG parameters associated with cognitive impairment severity and organic disease progression. In parallel, immobility, malnutrition, and co-morbid systemic diseases are highly associated with the risk for early mortality in advanced dementia patients. Importantly, the authors’ conclusions suggest utilizing reliable quantitative-parameters of disease progression for estimating accelerated mortality in dementia patients entering the terminal disease-stages characterized by severe intellectual deficits and functional disability. Show more

Keywords: Disease comorbidity, electroencephalography, pressure ulcers, prognostic predictors, terminal stage

DOI: 10.3233/JAD-201563

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 933-941, 2021

Authors: Ren, Dianxu | Lopez, Oscar L. | Lingler, Jennifer H. | Conley, Yvette

Article Type: Short Communication

Abstract: We examined the association between APOE ɛ 2/ɛ 4 with incident Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer’s Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ 3/ɛ 3 carriers, ɛ 2/ɛ 4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOE …ɛ 2/ɛ 4 genotype is not associated with the incidence of AD and MCI among African Americans. Show more

Keywords: African American, Alzheimer’s disease, APOE , ɛ2/ɛ4 genotype, mild cognitive impairment

DOI: 10.3233/JAD-201613

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 943-948, 2021

Authors: Pais, Marcos | Loureiro, Júlia | do Vale, Vagner | Radanovic, Marcia | Talib, Leda | Stella, Florindo | Forlenza, Orestes

Article Type: Research Article

Abstract: Background: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer’s disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. Objective: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. Methods: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n  = 60, 29.4%); MCI (n  = 84, 41.2%); or normal …cognition (NC, n  = 60, 29.4%). CSF concentrations of Aβ42 , T-tau, and 181 Thr-P-tau were determined, and Aβ42 /P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. Results: The majority (73.7%) of patients in the AD group had the Aβ42 /P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A +, 28 (46.7%) as T +, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A +, 78.3%as T +, and 80%as N+. Conclusion: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, mild cognitive impairment

DOI: 10.3233/JAD-210144

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 949-962, 2021

Authors: Choi, Joon Yul | Lee, Seunghyun | Lee, Wanhyung

Article Type: Research Article

Abstract: Background: Dementia and cognitive impairment were significantly associated with hearing loss. The impact of hearing loss on dementia and cognitive impairment is understudied, particularly for different effect on cognitive impairment according to types of hearing loss. Objective: The present study was conducted to elucidate the association between clinically diagnosed dementia and hearing loss with consideration of the type of hearing loss among an elderly population, and to explore the effects of different types of hearing loss on preclinical cognitive impairment. Methods: Data (n  = 59,675) from the Korean National Health Insurance Service–Health Screening were used to calculate …odds ratios (OR) for cognitive impairment according to type of hearing loss (conductive, sensorineural, mixed, and noise-induced hearing losses, and presbycusis). Cognitive impairment was assessed using the Korean Dementia Screening Questionnaire-Prescreening (KDSQ-P). Results: Cognitive impairment was significantly associated with conductive (OR: 1.45, 95% confidence interval (CI): 1.20–1.77), sensorineural (OR: 1.23, CI: 1.12–1.36), and noise-induced hearing loss (OR: 1.32, CI: 1.12–1.56), and presbycusis (OR: 1.53, CI: 1.25–1.87). Among participants scoring positive on the KDSQ-P (score≥4), the KDSQ-P score was significantly elevated in the mixed and noise-induced hearing loss groups. Conclusion: This study revealed a significant correlation between different types of hearing loss and cognitive impairment. Noise-induced hearing loss is especially important because it occurs earlier than other types of hearing loss and has large effects on cognitive impairment. Show more

Keywords: Cognitive function, cognitive impairment, dementia, hearing loss, National Health Insurance Service in Korea, noise

DOI: 10.3233/JAD-210074

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 963-972, 2021

Authors: Habeych, Miguel E. | Falcone, Tatiana | Dagar, Anjali | Ford, Lisa | Castilla-Puentes, Ruby

Article Type: Research Article

Abstract: Background: Seizure disorders have been identified in patients suffering from different types of dementia. However, the risks associated with the seizure subtypes have not been characterized. Objective: To compare the occurrence and risk of various seizure subtypes (focal and generalized) between patients with and without a dementia diagnosis. Methods: Data from 40.7 million private insured patient individual electronic health records from the U.S., were utilized. Patients 60 years of age or more from the Optum Insight Clinformatics-data Mart database were included in this study. Using ICD-9 diagnoses, the occurrence of generalized or focal seizure disorders was …identified. The risk of new-onset seizures and the types of seizures associated with a dementia diagnosis were estimated in a cohort of 2,885,336 patients followed from 2005 to 2014. Group differences were analyzed using continuity-adjusted chi-square and hazard ratios with 95%confidence intervals calculated after a logistic regression analysis Results: A total of 79,561 patient records had a dementia diagnosis, and 56.38%of them were females. Patients with dementia when compared to those without dementia had higher risk for seizure disorders [Hazard ratio (HR) = 6.5 95%CI = 4.4–9.5]; grand mal status (HR = 6.5, 95%CI = 5.7–7.3); focal seizures (HR = 6.0, 95%CI = 5.5–6.6); motor simple focal status (HR = 5.6, 95%CI = 3.5–9.0); epilepsy (HR = 5.0, 95%CI = 4.8–5.2); generalized convulsive epilepsy (HR = 4.8, 95%CI = 4.5–5.0); localization-related epilepsy (HR = 4.5, 95%CI = 4.1–4.9); focal status (HR = 4.2, 95%CI = 2.9–6.1); and fits convulsions (HR = 3.5, 95%CI = 3.4–3.6). Conclusion: The study confirms that patients with dementia have higher risks of generalized or focal seizure than patients without dementia. Show more

Keywords: Databases, dementia, epilepsy, new-onset seizures

DOI: 10.3233/JAD-210028

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 973-980, 2021

Authors: Zhou, Jin-wu | Zhao, Man | Rang, Wen-liang | Zhang, Xiao-yan | Liu, Zhen-ming | Zhang, Liang-ren | Wang, Tong-xing | Wu, Chu-Tse | Cheng, Xiao-rui | Zhou, Wen-xia

Article Type: Research Article

Abstract: Background: The toxicity of excessive glutamate release has been implicated in various acute and chronic neurodegenerative conditions. Vesicular glutamate transporters (VGLUTs) are the major mediators for the uptake of glutamate into synaptic vesicles. However, the dynamics and mechanism of this process in glutamatergic neurons are still largely unknown. Objective: This study aimed to investigate the candidate protein partners of VGLUT1 and their regulatory roles in the vesicles in rat brain. Methods: Pull down assay, co-immunoprecipitation assay, or split-ubiquitin membrane yeast two hybrid screening coupled with nanoRPLC-MS/MS were used to identify the candidate protein partners of VGLUT1 …in the vesicles in rat brain. The in vitro and in vivo models were used to test effects of AβPP, Atp6ap2, Gja1, and Synataxin on VGLUT1 expression. Results: A total of 255 and 225 proteins and 172 known genes were identified in the pull down assay, co-immunoprecipitation assay, or split-ubiquitin yeast two-hybrid screening respectively. The physiological interactions of SV2A, Syntaxin 12, Gja1, AβPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AβPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AβPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models. Conclusion: These results elucidate that the AβPP and VGLUT1 interacts at vesicular level and AβPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities. Show more

Keywords: AβPP, protein-protein interactions, VGLUT1

DOI: 10.3233/JAD-210117

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 981-1038, 2021

Authors: Gardener, Samantha L. | Weinborn, Michael | Sohrabi, Hamid R. | Doecke, James D. | Bourgeat, Pierrick | Rainey-Smith, Stephanie R. | Shen, Kai-kai | Fripp, Jurgen | Taddei, Kevin | Maruff, Paul | Salvado, Olivier | Savage, Greg | Ames, David | Masters, Colin L. | Rowe, Christopher C. | Martins, Ralph N. | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous …literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age. Show more

Keywords: Cognitive aging, cortical thickness, cortical thinning, cerebral volume atrophy, older adult superior cognitive performance, super-aging

DOI: 10.3233/JAD-201243

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1039-1052, 2021