Journal of Alzheimer's Disease - Volume 101, issue 1

Authors: Lee, Jae-Hong | Jia, Jianping | Ji, Yong | Kandiah, Nagaendran | Kim, SangYun | Mok, Vincent | Pai, Ming-Chyi | Senanarong, Vorapun | Suh, Chong Hyun | Chen, Christopher

Article Type: Review Article

Abstract: Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer’s disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek …diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, Asia, best practice, mild cognitive impairment

DOI: 10.3233/JAD-240684

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 1-12, 2024

Authors: Boulares, Ayoub | Pichon, Aurélien | Faucher, Corentin | Bragazzi, Nicola Luigi | Dupuy, Olivier

Article Type: Systematic Review

Abstract: Background: The rise in the aging population highlights the need to address cognitive decline and neurodegenerative diseases. Intermittent hypoxia (IH) protocols show promise in enhancing cognitive abilities and brain health. Objective: This review evaluates IH protocols’ benefits on cognition and brain health in older adults, regardless of cognitive status. Methods: A systematic search following PRISMA guidelines was conducted across four databases (PubMed, Scopus, Web of Science, and Cochrane Library) and two registers, covering records from inception to May 2024 (PROSPERO: CRD42023462177). Inclusion criteria were: 1) original research with quantitative details; 2) studies involving older adults, with …or without cognitive impairment; 3) studies including IH protocols; 4) articles analyzing cognition and brain health in older adults. Results: Seven studies and five registered trials met the criteria. Findings indicate that Intermittent Hypoxia Training (IHT) and Intermittent Hypoxia-Hyperoxia Training (IHHT) improved cognitive functions and brain health. Intermittent Hypoxic Exposure (IHE) improved cerebral tissue oxygen saturation, middle cerebral arterial flow velocity, and cerebral vascular conductance, particularly in cognitively impaired populations. IHT and IHHT had no significant effect on BDNF levels. There is a lack of studies on IHHE in older adults with and without cognitive impairment. Conclusions: IH protocols may benefit cognition regardless of cognitive status. IHT and IHE positively affect cerebral outcomes, with all protocols having limited effects on BDNF levels. Future research should standardize IH protocols, investigate long-term cognitive effects, and explore neuroprotective biomarkers. Combining these protocols with physical exercise across diverse populations could refine interventions and guide targeted therapeutic strategies. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, cognitive performance, intermittent hypoxia, mild cognitive impairment, older adults, physical exercise

DOI: 10.3233/JAD-240711

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 13-30, 2024

Authors: Liu, Yan | Xu, Weiyue | Yang, Pan | Liu, Xingshun

Article Type: Research Article

Abstract: Background: Various virus infections are known to predispose to Alzheimer’s disease (AD), and a linkage between COVID-19 and AD has been established. COVID-19 infection modulates the gene expression of the genes implicated in progression of AD. Objective: Determination of molecular patterns and codon usage and context analysis for the genes that are modulated during COVID-19 infection and are implicated in AD was the target of the study. Methods: Our study employed a comprehensive array of research methods, including relative synonymous codon usage, Codon adaptation index analysis, Neutrality and parity analysis, Rare codon analyses, and codon context …analysis. This meticulous approach was crucial in determining the molecular patterns present in genes up or downregulated during COVID-19 infection. Results: G/C ending codons were preferred in upregulated genes while not in downregulated genes, and in both gene sets, longer genes have high expressivity. Similarly, T over A nucleotide was preferred, and selection was the major evolutionary force in shaping codon usage in both gene sets. Apart from stops codons, codons CGU – Arg, AUA – Ile, UUA – Leu, UCG – Ser, GUA – Val, and CGA – Arg in upregulated genes, while CUA – Leu, UCG – Ser, and UUA – Leu in downregulated genes were present below the 0.5%. Glutamine-initiated codon pairs have high residual values in upregulated genes. Identical codon pairs GAG-GAG and GUG-GUG were preferred in both gene sets. Conclusions: The shared and unique molecular features in the up- and downregulated gene sets provide insights into the complex interplay between COVID-19 infection and AD. Further studies are required to elucidate the relationship of these molecular patterns with AD pathology. Show more

Keywords: Alzheimer’s disease, codon context, codon usage, COVID-19, relative synonymous codon usage

DOI: 10.3233/JAD-240609

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 31-48, 2024

Authors: Foster, Stuart G. | Mathew, Shibi | Labarre, Audrey | Parker, J. Alex | Tompkins, Thomas A. | Binda, Sylvie

Article Type: Research Article

Abstract: Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer’s disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aβ-induced paralysis. Methods: Using C. elegans expressing human amyloid-β (Aβ)1–42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of …amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD. Show more

Keywords: Age-related diseases, Alzheimer’s disease, amyloid, B. subtilis R0179, Caenorhabditis elegans, L. rhamnosus HA-114, lipid metabolism, probiotics

DOI: 10.3233/JAD-230948

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 49-60, 2024

Authors: Setiadi, Tania M. | Marsman, Jan-Bernard C. | Martens, Sander | Tumati, Shankar | Opmeer, Esther M. | Reesink, Fransje E. | De Deyn, Peter P. | Atienza, Mercedes | Aleman, André | Cantero, Jose L.

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI), considered as the prodromal stage of Alzheimer’s disease, is characterized by isolated memory impairment and cerebral gray matter volume (GMV) alterations. Previous structural MRI studies in aMCI have been mainly based on univariate statistics using voxel-based morphometry. Objective: We investigated structural network differences between aMCI patients and cognitively normal older adults by using source-based morphometry, a multivariate approach that considers the relationship between voxels of various parts of the brain. Methods: Ninety-one aMCI patients and 80 cognitively normal controls underwent structural MRI and neuropsychological assessment. Spatially independent components (ICs) that …covaried between participants were estimated and a multivariate analysis of covariance was performed with ICs as dependent variables, diagnosis as independent variable, and age, sex, education level, and site as covariates. Results: aMCI patients exhibited reduced GMV in the precentral, temporo-cerebellar, frontal, and temporal network, and increased GMV in the left superior parietal network compared to controls (pFWER < 0.05, Holm-Bonferroni correction). Moreover, we found that diagnosis, more specifically aMCI, moderated the positive relationship between occipital network and Mini-Mental State Examination scores (pFWER < 0.05, Holm-Bonferroni correction). Conclusions: Our results showed GMV alterations in temporo-fronto-parieto-cerebellar networks in aMCI, extending previous results obtained with univariate approaches. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, magnetic resonance imaging, source-based morphometry, structural network

DOI: 10.3233/JAD-231196

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 61-73, 2024

Authors: Qi, Hengnian | Zhu, Xiaorong | Ren, Yinxia | Zhang, Xiaoya | Tang, Qizhe | Zhang, Chu | Lang, Qing | Wang, Lina

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is not easily detected in the early stage. Handwriting and walking have been shown to be potential indicators of cognitive decline and are often affected by AD. Objective: This study proposes an assisted screening framework for AD based on multimodal analysis of handwriting and gait and explores whether using a combination of multiple modalities can improve the accuracy of single modality classification. Methods: We recruited 90 participants (38 AD patients and 52 healthy controls). The handwriting data was collected under four handwriting tasks using dot-matrix digital …pens, and the gait data was collected using an electronic trail. The two kinds of features were fused as inputs for several different machine learning models (Logistic Regression, SVM, XGBoost, Adaboost, LightGBM), and the model performance was compared. Results: The accuracy of each model ranged from 71.95% to 96.17%. Among them, the model constructed by LightGBM had the best performance, with an accuracy of 96.17%, sensitivity of 95.32%, specificity of 96.78%, PPV of 95.94%, NPV of 96.74%, and AUC of 0.991. However, the highest accuracy of a single modality was 93.53%, which was achieved by XGBoost in gait features. Conclusions: The research results show that the combination of handwriting features and gait features can achieve better classification results than a single modality. In addition, the assisted screening model proposed in this study can achieve effective classification of AD, which has development and application prospects. Show more

Keywords: Alzheimer’s disease, feature fusion, gait, handwriting, machine learning

DOI: 10.3233/JAD-240362

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 75-89, 2024

Authors: Byeon, Gihwan | Byun, Min Soo | Yi, Dahyun | Ahn, Hyejin | Jung, Gijung | Lee, Yun-Sang | Kim, Yu Kyeong | Kang, Koung Mi | Sohn, Chul-Ho | Lee, Dong Young

Article Type: Research Article

Abstract: Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily …analyzed to test amyloid positivity’s moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI. Show more

Keywords: Alzheimer’s disease, amyloid-β, cholinesterase inhibitor, cognitive change, mild cognitive impairment

DOI: 10.3233/JAD-240380

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 91-97, 2024

Authors: Wing, Jeffrey J. | Rajczyk, Jenna I. | Burke, James F.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) prevalence varies geographically in the United States. Objective: To assess whether the geographic variation of ADRD in Central Appalachia is explained by county-level sociodemographics or access to care. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2015– 2018 were used to estimate county-level ADRD prevalence among all fee-for-service (FFS) beneficiaries with≥1 inpatient, skilled nursing facility, home health agency, hospital outpatient or Carrier claim with a valid ADRD ICD-9/10 code over three-years in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression …was used to estimate prevalence overall, by Appalachian/non-Appalachian designation, and by rural/urban classification. Models were then adjusted for county-level: 1) FFS demographics (age, gender, and Medicaid eligibility), comorbidities; 2) population sociodemographics (race/ethnicity, education, aging population distribution, and renter-occupied housing); and 3) diagnostic access (PCP visits, neurology visits, and imaging scans). Results: Across the 591 counties in the Central Appalachian region, the average prevalence of ADRD from 2015– 2018 was 11.8%. ADRD prevalence was modestly higher for Appalachian counties both overall (PR: 1.03; 95% CI: 1.02, 1.04) and after adjustment (PR: 1.02; 95% CI: 1.00, 1.03) compared to non-Appalachian counties. This difference was similar among rural and urban counties (p  = 0.326) but varied by state (p  = 0.004). Conclusions: The relative variation in ADRD prevalence in the Appalachian region was smaller than hypothesized. The case mixture of the dual eligible population, accuracy of the outcome measurement, and impact of educational attainment in this region may contribute to this observation. Show more

Keywords: Alzheimer’s disease, Appalachian region, dementia, rural population, sociodemographic factors

DOI: 10.3233/JAD-240528

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 99-109, 2024

Authors: L’Esperance, Oliver J. | McGhee, Joshua | Davidson, Garett | Niraula, Suraj | Smith, Adam S. | Sosunov, Alexandre A. | Yan, Shirley Shidu | Subramanian, Jaichandar

Article Type: Research Article

Abstract: Background: While Alzheimer’s disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods: c-Fos+ cell density, functional connectivity, and their …experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4–6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. Conclusions: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions. Show more

Keywords: Alzheimer’s disease, c-fos protein, neuronal plasticity, presynaptic terminals, visual cortex

DOI: 10.3233/JAD-240776

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 111-131, 2024

Authors: Alipour-Haris, Golnoosh | Armstrong, Melissa J. | Goodin, Amie J. | Guo, Jingchuan Serena | Brown, Joshua D.

Article Type: Research Article

Abstract: Background: Lewy body dementia (LBD) is the second most common neurodegenerative dementia in the US, presenting unique end-of-life challenges. Objective: This study examined healthcare utilization and care continuity in the last year of life in LBD. Methods: Medicare claims for enrollees with LBD, continuously enrolled in the year preceding death, were examined from 2011–2018. We assessed hospital stays, emergency department (ED) visits, intensive care unit (ICU) admissions, life-extending procedures, medications, and care continuity. Results: We identified 45,762 LBD decedents, predominantly female (51.8%), White (85.9%), with average age of 84.1 years (SD 7.5). There was …a median of 2 ED visits (IQR 1–5) and 1 inpatient stay (IQR 0–2). Higher age was inversely associated with ICU stays (Odds Ratio [OR] 0.96; 95% Confidence Interval [CI] 0.96–0.97) and life-extending procedures (OR 0.96; 95% CI 0.95–0.96). Black and Hispanic patients experienced higher rates of ED visits, inpatient hospitalizations, ICU admissions, life-extending procedures, and in-hospital deaths relative to White patients. On average, 15 (7.5) medications were prescribed in the last year. Enhanced care continuity correlated with reduced hospital (OR 0.72; 95% CI 0.70–0.74) and ED visits (OR 0.71; 95% CI 0.69–0.87) and fewer life-extending procedures (OR 0.71; 95% CI 0.64–0.79). Conclusions: This study underscored the complex healthcare needs of people with LBD during their final year, which was influenced by age and race. Care continuity may reduce hospital and ED visits and life-extending procedures. Show more

Keywords: Alzheimer’s disease, care continuity, dementia, demographics, end-of-life care, healthcare outcomes, ICU admissions, inpatient visits, Lewy body disease, life-extending procedures, medication utilization

DOI: 10.3233/JAD-240194

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 133-145, 2024