Journal of Alzheimer's Disease - Volume 96, issue 1

Authors: Leiby, Anne-Marie C. | Scambray, Kiana A. | Nguyen, Hannah L. | Basith, Farheen | Fakhraee, Shahrzad | Melikyan, Zarui A. | Bukhari, Syed A. | Montine, Thomas J. | Corrada, María M. | Kawas, Claudia H. | Sajjadi, S. Ahmad

Article Type: Research Article

Abstract: Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. Objective: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer’s disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). Methods: In 364 autopsies of the oldest old of The 90+ Study , we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. Results: Of 31% of participants who had LATE-NC, only …5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. Conclusions: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group. Show more

Keywords: Alzheimer’s disease, case studies, dementia, oldest old, TDP-43 protein

DOI: 10.3233/JAD-230238

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 113-124, 2023

Authors: Wang, Jiao | Wang, Chun | Li, Xuan | Guo, Jie | Dove, Abigail | Cui, Zhuang | Xu, Weili

Article Type: Research Article

Abstract: Background: The association of anemia with cognitive function and dementia remains unclear. Objective: We aimed to investigate the association of anemia with cognitive function and dementia risk and to explore the role of inflammation in these associations. Methods: Within the UK Biobank, 207,203 dementia-free participants aged 60+ were followed for up to 16 years. Hemoglobin (HGB) and C-creative protein (CRP) were measured from blood samples taken at baseline. Anemia was defined as HGB <13 g/dL for males and <12 g/dL for females. Inflammation was categorized as low or high according to the median CRP level (1.50 mg/L). A subset …of 18,211 participants underwent cognitive assessments (including global and domain-specific cognitive). Data were analyzed using linear mixed-effects model, Cox regression, and Laplace regression. Results: Anemia was associated with faster declines in global cognition (β= –0.08, 95% confidence interval [CI]: –0.14, –0.01) and processing speed (β= –0.10, 95% CI: –0.19, –0.01). During the follow-up of 9.76 years (interquartile range 7.55 to 11.39), 6,272 developed dementia. The hazard ratio of dementia was 1.57 (95% CI: 1.38, 1.78) for people with anemia, and anemia accelerated dementia onset by 1.53 (95% CI: 1.08, 1.97) years. The risk of dementia tended to be higher in people with both anemia and high CRP (1.89, 95% CI: 1.60, 2.22). There was a statistically significant interaction between anemia and CRP on dementia risk (p-interaction = 0.032). Conclusions: Anemia is associated with cognitive decline (specifically for processing speed) and increased risk of dementia, especially in people with high inflammation. Show more

Keywords: Alzheimer’s disease, anemia, cognitive function, dementia, inflammation, UK Biobank

DOI: 10.3233/JAD-230483

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 125-134, 2023

Authors: Chen, Shihao | Huang, Wenting | He, Tao | Zhang, Mulan | Jin, Xing | Jiang, Lelin | Xu, Huiqin | Chen, Keyang

Article Type: Research Article

Abstract: Background: Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. Objective: In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. Methods: From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used …to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. Results: We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer’s disease (AD) (OR, 0.92; 95% CI, 0.85, 0.98; p = 0.013). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.98; p = 0.004). In reverse MR analysis, we also found that AD can affect the level of BDNF. Conclusions: Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, epilepsy, genome-wide association studies, Mendelian randomization

DOI: 10.3233/JAD-230693

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 135-148, 2023

Authors: Cavuoto, Marina G. | Robinson, Stephen R. | O’Donoghue, Fergal J. | Barnes, Maree | Howard, Mark E. | Tolson, Julie | Stevens, Bronwyn | Schembri, Rachel | Rosenzweig, Ivana | Rowe, Christopher C. | Jackson, Melinda L.

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) is associated with an increased risk of amyloid-β (Aβ) burden, the hallmark of Alzheimer’s disease, and cognitive decline. Objective: To determine the differential impacts of hypoxemia and slow-wave sleep disruption on brain amyloid burden, and to explore the effects of hypoxemia, slow-wave sleep disruption, and amyloid burden on cognition in individuals with and without OSA. Methods: Thirty-four individuals with confirmed OSA (mean±SD age 57.5±4.1 years; 19 males) and 12 healthy controls (58.5±4.2 years; 6 males) underwent a clinical polysomnogram, a NAV4694 positron emission tomography (PET) scan for Aβ burden, assessment of …APOE ɛ status and cognitive assessments. Linear hierarchical regressions were conducted to determine the contributions of demographic and sleep variables on amyloid burden and cognition. Results: Aβ burden was associated with nocturnal hypoxemia, and impaired verbal episodic memory, autobiographical memory and set shifting. Hypoxemia was correlated with impaired autobiographical memory, and only set shifting performance remained significantly associated with Aβ burden when controlling for sleep variables. Conclusions: Nocturnal hypoxemia was related to brain Aβ burden in this sample of OSA participants. Aβ burden and hypoxemia had differential impacts on cognition. This study reveals aspects of sleep disturbance in OSA that are most strongly associated with brain Aβ burden and poor cognition, which are markers of early Alzheimer’s disease. These findings add weight to the possibility that hypoxemia may be causally related to the development of dementia; however, whether it may be a therapeutic target for dementia prevention in OSA is yet to be determined. Show more

Keywords: Alzheimer’s disease, amyloid-β , apolipoprotein E gene, cognition, hypoxemia, positron emission tomography, sleep apnea syndrome, slow wave sleep

DOI: 10.3233/JAD-221049

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 149-159, 2023

Authors: Lindh-Rengifo, Magnus | Jonasson, Stina B. | Ullén, Susann | Palmqvist, Sebastian | van Westen, Danielle | Stomrud, Erik | Mattsson-Carlgren, Niklas | Nilsson, Maria H. | Hansson, Oskar

Article Type: Research Article

Abstract: Background: Impaired gait can precede dementia. The associations between gait parameters and brain pathologies are therefore of interest. Objective: To explore how different brain pathologies (i.e., vascular and Alzheimer’s) are associated with specific gait parameters from various gait components in persons with mild cognitive impairment (MCI), who have an increased risk of developing dementia. Methods: This cross-sectional study included 96 patients with MCI (mean 72, ±7.5 years; 52% women). Gait was evaluated by using an electronic walkway, GAITRite® . Four gait parameters (step velocity variability; step length; step time; stance time asymmetry) were used as dependent …variables in multivariable linear regression analyses. Independent variables included Alzheimer’s disease pathologies (amyloid-β and tau) by using PET imaging and white matter hyperintensities (WMH) by using MRI. Covariates included age, sex, comorbidities (and intracranial volume in analyses that includedWMH). Results: Increased tau-PET (Braak I–IV region of interest [ROI]) was associated with step velocity variability (standardized regression coefficient, β= 0.383, p  < 0.001) and step length (β= 0.336, p  < 0.001), which remained significant when using different Braak ROIs (I-II, III-IV, V-VI). The associations remained significant when adjusting for WMH (p  < 0.001). When also controlling for gait speed, tau was no longer significantly (p  = 0.168) associated with an increased step length. No significant associations between gait and Aβ-PET load or WMH were identified. Conclusions: The results indicate that one should pay specific attention to assess step velocity variability when targeting single task gait in patients with MCI. Future studies should address additional gait variability measures and dual tasking in larger cohorts. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease pathology, amyloid-β , electronic walkway, gait, gait variability, mild cognitive impairment, tau, white matter hyperintensities

DOI: 10.3233/JAD-221303

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 161-171, 2023

Authors: Liang, Hongtao | Yin, Xiang | Chen, Tian | Zhang, Yan | Zhang, Qin | Lin, Jie | Yin, Huan | Tang, Jinghua | He, Yingyi | Xia, Ping | Zhu, Yongping | Li, Haihua | Mo, Yongbiao | Li, Yongyong | Wang, Ying | Yang, Xiao | Hu, Zicheng

Article Type: Research Article

Abstract: Background: Cognitive impairment is commonly seen after acute ischemic stroke (AIS). Sedentary behaviors increase the risk of dementia among community dwelling population. Objective: This study aims to investigate the association of sedentary behaviors with poststroke cognitive impairment among older adults with minor AIS. Methods: This cohort study recruited 594 older subjects with minor AIS from three hospitals in China during February 1, 2016, and December 31, 2018. Participants were followed up for two years and the sedentary time per day was self-reported at the end of follow-up. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). …Participants were categorized into the high and low sedentary time group according to the median sedentary time of the participants. Results: At two years of follow-up, the long sedentary time group had significantly lower MMSE scores than the short sedentary time group [median, (IQR): 21 (18 to 25) versus 22 (18 to 25), p  = 0.368]. The long sedentary time group had a higher speed of cognitive decline than the short sedentary time group. Excessive sedentary time was associated with a higher risk of longitudinal cognitive decline (OR: 2.267, 95% CI: 1.594 to 3.225), adjusting for age, sex, education, body mass index, APOE genotype, comorbidities, symptoms of depression, anxiety, and insomnia, baseline MMSE scores and National Institute of Health Stroke Scale scores, cognitive therapy, and TOAST ischemic stroke subtypes. Conclusions: This study identified a possible link between sedentary behaviors and longitudinal cognitive decline among older patients with minor AIS, suggesting that reducing sedentary time might be helpful for preventing poststroke dementia. Show more

Keywords: Acute ischemic stroke, Alzheimer’s disease, cognitive impairment, older adults, sedentary behavior

DOI: 10.3233/JAD-230008

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 173-181, 2023

Authors: van Buuren, Cornelia Pieternella | van der Steen, Jenny Theodora | Olthof-Nefkens, Maria | Bakker, Christian | Koopmans, Raymond Theodorus Catherina Maria | Perry, Marieke | Kalf, Johanna Gezina

Article Type: Research Article

Abstract: Background: Persons with dementia are at risk of developing nutritional problems. Theoretical models on nutritional problems have been developed, but have not been evaluated with healthcare professionals. Objective: This study aimed to explore the comprehensiveness and applicability of a theoretical model of nutritional problems in persons with dementia for daily nursing home practice. Methods: A qualitative design employing a combined deductive and inductive approach was used. Healthcare professionals were eligible to participate if they 1) had expert knowledge of and experience with nutritional problems related to dementia, and 2) worked in a nursing home affiliated with …an academic network covering the east and south of the Netherlands. Three focus group interviews with 20 healthcare professionals from seven professions were held. We conducted thematic analysis and we compared themes with existing theoretical models from the literature. Results: We identified six themes, four of which corresponded with the existing models (observing and analysing nutritional problems; consequences of nutritional problems; functioning of the person with dementia; environmental factors). Interprofessional collaboration and ethical factors were identified as new themes. The analyses indicated interactions within each theme, between themes, and a bidirectional connection between themes. Conclusions: This study demonstrated the relevance of interprofessional collaboration and ethical considerations in nutritional problems related to dementia. It uncovered complex bidirectional relations within and between factors regarding nutritional problems. All aspects should be taken into account to minimize the consequences of nutritional problems for persons with dementia. Show more

Keywords: Alzheimer’s disease, dementia, feeding behavior, long-term care, nutritional disorders, theoretical model

DOI: 10.3233/JAD-230135

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 183-192, 2023

Authors: Nogueira, Dália

Article Type: Article Commentary

Abstract: Feeding and swallowing difficulties and their consequences on the nutritional status of people with dementia have been the subject of recurrent research, albeit strong evidence is still lacking. When a person no longer swallows safely, it is the caregivers who face difficulties of providing adequate care. Therefore, it is important to understand and analyze their perspectives on the topic. Despite the recent development of theoretical models to manage mealtimes and nutrition intake, the participation of health professionals and caregivers in these types of studies are still limited. The study of van Buuren et al., which this commentary refers to, aimed …to identify key factors that contribute to the development of a conceptual model to step up nutritional care in dementia. Show more

Keywords: Alzheimer’s disease, dementia, nutritional status, theoretical model

DOI: 10.3233/JAD-230970

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 193-195, 2023

Authors: Hammers, Dustin B. | Lin, Joshua H. | Polsinelli, Angelina J. | Logan, Paige E. | Risacher, Shannon L. | Schwarz, Adam J. | Apostolova, Liana G.

Article Type: Research Article

Abstract: Background: Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into “positive” or “negative” (T+ or T–). In response, some tau topographical pathologic staging schemes have been developed. Objective: The aim of the current study is to establish criterion validity to support these recently-developed staging schemes. Methods: Tau-PET data from 465 participants from the Alzheimer’s Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T– using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC …(STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods. Results: Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having “fair” sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen’s scheme, validity lagged behind others—likely due to elevated false positive rates. Conclusions: Tau-PET staging schemes appear to be valuable for Alzheimer’s disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks. Show more

Keywords: Alzheimer’s disease, amyloid, learning, memory, mild cognitive impairment, tau

DOI: 10.3233/JAD-230512

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 197-214, 2023

Authors: Smith, Gwenn S. | Kuwabara, Hiroto | Yan, Haijuan | Nassery, Najlla | Yoon, Mark | Kamath, Vidya | Kraut, Michael | Gould, Neda F. | Savonenko, Alena | Coughlin, Jennifer M. | Lodge, Martin | Pomper, Martin G. | Nandi, Ayon | Holt, Daniel | Dannals, Robert F. | Leoutsakos, Jeannie M.

Article Type: Research Article

Abstract: Background: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer’s disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). Objective: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. Methods: Forty-nine MCI participants and 45 healthy older controls …underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. Results: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. Conclusions: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, mild cognitive impairment, positron emission tomography, serotonin transporter

DOI: 10.3233/JAD-230570

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 215-227, 2023