Journal of Alzheimer's Disease - Volume 98, issue 3

Authors: Cao, Jing | Tang, Yating | Chen, Shujian | Yu, Siqi | Wan, Ke | Yin, Wenwen | Zhen, Wenhui | Zhao, Wenming | Zhou, Xia | Zhu, Xiaoqun | Sun, Zhongwu

Article Type: Research Article

Abstract: Background: The hippocampus consists of histologically and functionally distinct subfields, which shows differential vulnerabilities to Alzheimer’s disease (AD)-associated pathological changes. Objective: To investigate the atrophy patterns of the main hippocampal subfields in patients with mild cognitive impairment (MCI) and AD and the relationships among the hippocampal subfield volumes, plasma biomarkers and cognitive performance. Methods: This cross-sectional study included 119 patients stratified into three categories: normal cognition (CN; N  = 40), MCI (N  = 39), and AD (N  = 40). AD-related plasma biomarkers were measured, including amyloid-β (Aβ)42 , Aβ40 , Aβ42 /Aβ40 ratio, p-tau181, and …p-tau217, and the hippocampal subfield volumes were calculated using automated segmentation and volumetric procedures implemented in FreeSurfer. Results: The subiculum body, cornu ammonis (CA) 1-head, CA1-body, CA4-body, molecular_layer_HP-head, molecular_layer_HP-body, and GC-ML-DG-body volumes were smaller in the MCI group than in the CN group. The subiculum body and CA1-body volumes accurately distinguished MCI from CN (area under the curve [AUC] = 0.647–0.657). The subiculum-body, GC-ML-DG-body, CA4-body, and molecular_layer_HP-body volumes accurately distinguished AD from MCI (AUC = 0.822–0.833) and AD from CN (AUC = 0.903–0.905). The p-tau 217 level served as the best plasma indicator of AD and correlated with broader hippocampal subfield volumes. Moreover, mediation analysis demonstrated that the subiculum-body volume mediated the associations between the p-tau217 and p-tau181 levels, and the Montreal Cognitive Assessment and Auditory Verbal Learning Test recognition scores. Conclusions: Hippocampal subfields with distinctive atrophy patterns may mediate the effects of tau pathology on cognitive function. The subiculum-body may be the most clinically meaningful hippocampal subfield, which could be an effective target region for assessing disease progression. Show more

Keywords: Alzheimer’s disease, cognitive performance, hippocampal subfield volumes, mild cognitive impairment, plasma biomarkers

DOI: 10.3233/JAD-231114

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 907-923, 2024

Authors: Cogut, Valeria | McNeely, Taylor L. | Bussian, Tyler J. | Graves, Sara I. | Baker, Darren J.

Article Type: Research Article

Abstract: Background: Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer’s disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored. Objective: To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model. Methods: We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR …regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR. Results: CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+ cells. Conclusions: Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+ cells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression. Show more

Keywords: Alzheimer’s disease, calorie restriction, microglia, spatial learning, tauopathy

DOI: 10.3233/JAD-231117

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 925-940, 2024

Authors: Xie, Xin-Yan | Huang, Lin-Ya | Cheng, Gui-Rong | Liu, Dan | Hu, Fei-Fei | Zhang, Jing-Jing | Han, Gang-Bin | Liu, Xiao-Chang | Wang, Jun-Yi | Zhou, Juan | Zeng, De-Yang | Liu, Jing | Nie, Qian-Qian | Song, Dan | Yu, Ya-Fu | Hu, Chen-Lu | Fu, Yi-Di | Li, Shi-Yue | Cai, Cheng | Cui, Yu-Yang | Cai, Wan-Ying | Li, Yi-Qing | Fan, Ren-Jia | Wan, Hong | Xu, Lang | Ou, Yang-Ming | Chen, Xing-Xing | Zhou, Yan-Ling | Chen, Yu-Shan | Li, Jin-Quan | Wei, Zhen | Wu, Qiong | Mei, Yu-Fei | Tan, Wei | Song, Shao-Jun | Zeng, Yan

Article Type: Research Article

Abstract: Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were …employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5 , PM10 , O3 , and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings. Show more

Keywords: Air pollution, Hubei Memory and Aging Cohort Study, mild cognitive impairment, older Chinese population

DOI: 10.3233/JAD-231186

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 941-955, 2024

Authors: Sánchez-Soblechero, Antonio | López-García, Sara | Lage, Carmen | Fernández-Matarrubia, Marta | Irure, Juan | López-Hoyos, Marcos | Jiménez-Bonilla, Julio | Quirce, Remedios | de Arcocha-Torres, María | Cuenca-Vera, Oriana | Martín-Arroyo, Juan | Martínez-Dubarbie, Francisco | Pozueta, Ana | García-Martínez, María | Infante, Jon | Sánchez-Juan, Pascual | Rodríguez-Rodríguez, Eloy

Article Type: Research Article

Abstract: Background: The optimal cut-off for Alzheimer’s disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11 C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aβ1–42 , pTau, tTau, and Aβ1–42 /Aβ1–40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) …were performed in all the patients. We established a cut-off for each single biomarker and Aβ1–42 /Aβ1–40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aβ1–42 /Aβ1–40  < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample’s best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer’s. Show more

Keywords: Alzheimer’s disease, amyloid positron emission tomography (a-PET), ATN classification, cerebrospinal fluid biomarkers (tTau, pTau, Aβ1–42 and Aβ1–42/Aβ1–40), 11C-Pittsburgh compound B, cut-off, data-driven cut-off, PET-driven cut-off

DOI: 10.3233/JAD-230678

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 957-967, 2024

Authors: Shui, Lan | Shibata, Dean | Chan, Kwun Chuen Gary | Zhang, Wenbo | Sung, Junhyoun | Haynor, David R.

Article Type: Research Article

Abstract: Background: Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer’s disease (AD) through the assessment of brain atrophy. Objective: Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. Methods: We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain …atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. Results: The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aβ42 values, demonstrated a tendency toward a more rapid increase of atrophy. Conclusions: The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, brain atrophy, longitudinal studies, magnetic resonance imaging

DOI: 10.3233/JAD-231149

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 969-986, 2024

Authors: Trieu, Calvin | van Harten, Argonde C. | Leeuwis, Anna E. | Exalto, Lieza G. | Hooghiemstra, Astrid M. | Verberk, Inge M.W. | Allaart, Cor P. | Brunner-La Rocca, Hans-Peter | Kappelle, L. Jaap | van Oostenbrugge, Robert J. | Biessels, Geert-Jan | Teunissen, Charlotte E. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: We hypothesize that Alzheimer’s disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40 ), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models …with terms for biomarker, time and biomarker* time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (–0.14±0.04) and memory (–0.31±0.09) and with steeper decline in global cognition (–0.07±0.02), memory (–0.09±0.04), attention (–0.05±0.02), and language (–0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (–0.22±0.05), memory (–0.43±0.10), attention (–0.14±0.06), language (–0.15±0.05), and executive functioning (–0.15±0.05) and steeper decline in global cognition (–0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (–0.16±0.04), memory (–0.28±0.09), attention (–0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases. Show more

Keywords: Alzheimer’s disease, carotid stenosis, cognitive dysfunction, heart failure, vascular dementia

DOI: 10.3233/JAD-231096

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 987-1000, 2024

Authors: Ceyzériat, Kelly | Jaques, Emma | Gloria, Yesica | Badina, Aurélien | Millet, Philippe | Koutsouvelis, Nikolaos | Dipasquale, Giovanna | Frisoni, Giovanni B. | Zilli, Thomas | Garibotto, Valentina | Tournier, Benjamin B.

Article Type: Research Article

Abstract: Background: Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer’s disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. Objective: As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Methods: Females …were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. Results: A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. Conclusions: A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD. Show more

Keywords: Alzheimer’s disease, amyloid, low-dose radiation therapy, microglial response

DOI: 10.3233/JAD-231153

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1001-1016, 2024

Authors: O’Shea, Deirdre M. | Camacho, Simone | Ezzeddine, Reem | Besser, Lilah | Tolea, Magdalena I. | Wang, Lily | Galvin, Conor | Gibbs, Gregory | Galvin, James E.

Article Type: Research Article

Abstract: Background: Lifestyle factors are linked to differences in brain aging and risk for Alzheimer’s disease, underscored by concepts like ‘cognitive reserve’ and ‘brain maintenance’. The Resilience Index (RI), a composite of 6 factors (cognitive reserve, physical and cognitive activities, social engagement, diet, and mindfulness) provides such a holistic measure. Objective: This study aims to examine the association of RI scores with cognitive function and assess the mediating role of cortical atrophy. Methods: Baseline data from 113 participants (aged 45+, 68% female) from the Healthy Brain Initiative were included. Life course resilience was estimated with the RI, …cognitive performance with Cognivue® , and brain health using a machine learning derived Cortical Atrophy Score (CAS). Mediation analysis probed the relationship between RI, cognitive outcomes, and cortical atrophy. Results: In age and sex adjusted models, the RI was significantly associated with CAS (β= –0.25, p  = 0.006) and Cognivue® scores (β= 0.32, p  < 0.001). The RI-Cognivue® association was partially mediated by CAS (β= 0.07; 95% CI [0.02, 0.14]). Conclusions: Findings revealed that the collective effect of early and late-life lifestyle resilience factors on cognition are partially explained by their association with less brain atrophy. These findings underscore the value of comprehensive lifestyle assessments in understanding the risk and progression of cognitive decline and Alzheimer’s disease in an aging population. Show more

Keywords: Alzheimer’s disease, cognitive reserve, cognitive resilience, cortical atrophy, mild cognitive impairment

DOI: 10.3233/JAD-231346

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1017-1027, 2024

Authors: Martínez-Dubarbie, Francisco | López-García, Sara | Lage, Carmen | Di Molfetta, Guglielmo | Fernández-Matarrubia, Marta | Pozueta-Cantudo, Ana | García-Martínez, María | Corrales-Pardo, Andrea | Bravo, María | Jiménez-Bonilla, Julio | Quirce, Remedios | Marco de Lucas, Enrique | Drake-Pérez, Marta | Tordesillas, Diana | López-Hoyos, Marcos | Irure-Ventura, Juan | Valeriano-Lorenzo, Elizabeth | Blennow, Kaj | Ashton, Nicholas J. | Zetterberg, Henrik | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Plasma biomarkers of Alzheimer’s disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We …also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid. Show more

Keywords: Alzheimer’s disease, longitudinal study, p-tau231, plasma biomarkers, presymptomatic stages

DOI: 10.3233/JAD-231479

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1029-1042, 2024

Authors: Cesana, Bruno Mario | Bergh, Sverre | Ciccone, Alfonso | Cognat, Emmanuel | Fabbo, Andrea | Fascendini, Sara | Frisoni, Giovanni B. | Froelich, Lutz | Handels, Ron | Jori, Maria Cristina | Mecocci, Patrizia | Merlo, Paola | Peters, Oliver | Tsolaki, Magda | Defanti, Carlo Alberto

Article Type: Research Article

Abstract: Background: Nursing home placement (NHP) can be the final step of patients with Alzheimer’s disease. Objective: We aimed to identify NHP predictors among 508 people with dementia with a 3-year follow-up. Methods: We analyzed data from the international observational RECage study, involving 508 people with especially Alzheimer’s disease and comparing a cohort enrolled by five centers with a Special Care Unit for BPSD (behavioral and psychological symptoms of dementia) and another one enrolled by six centers lacking this facility. The tertiary objective of the study was to assess the possible role of the SCU-B in delaying …NHP. We assessed the relationship of the baseline characteristics with NHP by means of univariate analysis followed by Cox’s multivariate model. Results: Patients’ mean age was 78.1 years, 54.9% were women. Diagnosis mean age was 75.4 (±8.32) years; the main diagnosis was Alzheimer’s disease (296; 58.4%). During follow-up, 96 (18.9%) patients died and 153 (30.1%) were institutionalized without a statistically significant difference between the two cohorts (p = 0.9626). The mean NHP time was 902 (95% CI: 870–934). The multivariable analysis without death as a competing risk retained four independent predictors of NHP: age increase (hazard ratio (HR) = 1.023, 95% CI: 1.000–1.046), patient education level increase (HR = 1.062, 95% CI: 1.024–1.101), Neuropsychiatric Inventory total increase (HR = 1.018; 95% CI: 1.011–1.026), and total Mini-Mental State Examination as a favorable factor (HR = 0.948, 95% CI: 0.925–0.971). Gender (females versus males: HR = 1.265, 95% CI: 0.899–1.781) was included in the final Cox’s model for adjusting the estimates for. Conclusions: Our data partially agree with the predictors of NHP in literature including the effect of high education level. No caregivers’ factors were statistically significant. Clinical trial registration: NCT03507504. Show more

Keywords: Alzheimer’s disease, dementia, nursing home placement, predictive factors

DOI: 10.3233/JAD-230878

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1043-1052, 2024

Authors: Zhang, Xueyi | Gomez, Lissette | Below, Jennifer E. | Naj, Adam C. | Martin, Eden R. | Kunkle, Brian W. | Bush, William S.

Article Type: Research Article

Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer’s disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis -regulatory window were used to train tissue-specific models of each gene. …We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer’s Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p  < 0.05, with only ARMCX6 in female brain cortex (p  = 0.008) nearing the significance threshold after adjusting for multiple testing (α  = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6 . Show more

Keywords: Alzheimer’s disease, bioinformatics, elastic net regression, gene expression, gene prediction, sex differences, transcriptome, X chromosome

DOI: 10.3233/JAD-231075

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1053-1067, 2024

Authors: Ramadan, Ferris A. | Arani, Gayatri | Jafri, Ayan | Thompson, Tingting | Bland, Victoria L. | Renquist, Benjamin | Raichlen, David A. | Alexander, Gene E. | Klimentidis, Yann C.

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n  = 115,082) and GWAS of LOAD (ncase  = 21,982, ncontrol  = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted …glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD. Show more

Keywords: Alzheimer’s disease, glutamine, Mendelian randomization, metabolites

DOI: 10.3233/JAD-231063

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1069-1078, 2024

Authors: Podger, Lauren | Stewart, Walter F. | Serrano, Daniel | Lipton, Richard B. | Gomez-Ulloa, David | Ayasse, Nicolai D. | Barnes, Frederick B. | Davis, E. Anne | Runken, M. Chris

Article Type: Research Article

Abstract: Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer’s disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized ‘target’ stages …of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (–4.0, p  = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p  = 0.0003; 2.4, p  < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework. Show more

Keywords: Alzheimer’s disease, AMBAR, cognition, endpoint staging framework, function, outcome measures, quality of life, trial endpoints

DOI: 10.3233/JAD-231197

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1079-1094, 2024

Authors: Tseng, Wen-Yih Isaac | Hsu, Yung-Chin | Huang, Li-Kai | Hong, Chien-Tai | Lu, Yueh-Hsun | Chen, Jia-Hung | Fu, Chin-Kun | Chan, Lung

Article Type: Research Article

Abstract: Background: The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer’s disease conversion from MCI. Objective: The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Methods: Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified …by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. Results: 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p  = 0.0067). Conclusions: Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI. Show more

Keywords: Alzheimer’s disease, brain age, cholinesterase inhibitor, clinical dementia rating, cognitive outcome, magnetic resonance imaging, mild cognitive impairment, mini-mental state examination

DOI: 10.3233/JAD-231109

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1095-1106, 2024

Authors: Seltmann, Henriette | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: The number of people with dementia (PwD) in acute care hospitals is steadily increasing, posing a challenge for those who work closely with patients. To date, no German study has addressed the extent to which prospective nurses benefit from dementia training in terms of their knowledge, attitudes, and confidence in caring for PwD. Objective: The aim of this study is to investigate whether a validated dementia training for registered nurses can positively change nursing students’ knowledge about dementia, their attitude toward PwD, and their confidence in caring for them, as well as the stability over …time. Methods: In the one-group pre-test, post-test design, a sample of 81 nursing students was recruited from two nursing schools in Germany between May and June 2023. They completed a questionnaire consisting of the Dementia Knowledge Assessment Scale, the Dementia Attitude Scale, and the Confidence in Dementia Scale, as well as sociodemographic questions and experiences with PwD at three measurement points. The data were analyzed using the Wilcoxon test and repeated measures ANOVA. Results: The training has a significant effect on knowledge in dementia (z  = –5.07, p  < 0.001), attitude toward PwD (z  = –4.42, p  < 0.001), and confidence in caring for them at the post-test (z  = –3. 21, p  < 0.001, r  = 0.36). The repeated measures ANOVA shows stability over time only for dementia knowledge. Conclusions: The results indicate the need for further research in this field as well as the validation of the dementia training specifically addressing nursing students. Show more

Keywords: Alzheimer’s disease, attitude, communication, confidence, dementia, intervention, knowledge, nursing students

DOI: 10.3233/JAD-231338

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1107-1119, 2024

Authors: Zhong, Ping | Cao, Qing | Yan, Zhen

Article Type: Research Article

Abstract: Background: The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer’s disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage. Objective: Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD. Methods: Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau). Results: We …found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice. Conclusions: These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions. Show more

Keywords: Alzheimer’s disease, electrophysiology, entorhinal cortex, 5×FAD, neural circuits, optogenetics, P301S Tau, prefrontal cortex, subiculum

DOI: 10.3233/JAD-231413

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1121-1131, 2024

Authors: Han, Shuang-Ling | Ou, Ya-Nan | Han, Bao-Lin | Guo, Hai-Hua | Chi, Hao-Chen | Huang, Yi-Ming | Wang, Hui-Fu | Tan, Lan

Article Type: Research Article

Abstract: Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression …analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p  = 2.828×10–2 ) and poorer cognition (CM-MMSE: p  = 1.539×10–5 , MoCA-b: p  = 4.552×10–6 ). Additionally, no discernible correlation surfaced between ICVD and amyloid-β (Aβ) 42 (p  = 6.910×10–1 ) or phosphorylated tau (p-tau) (p  = 4.324×10–1 ). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrovascular disease, cognitive decline, neurodegeneration

DOI: 10.3233/JAD-231093

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1133-1143, 2024

Authors: Papadimitriou, Amelia | Dawson, Aprill Z. | Thorgerson, Abigail | Bhandari, Sanjay | Martinez, Martin | Egede, Leonard E.

Article Type: Research Article

Abstract: Background: The prevalence of type 2 diabetes is increasing with the burden disproportionately falling on older adults and racial/ethnic minorities. Older adults with diabetes show greater cognitive decline and there are disparities in cognitive function by race/ethnicity that can be explained by social determinants such as wealth. Objective: To understand whether there is a differential relationship between wealth and cognitive function by race/ethnicity among older U.S. adults with diabetes. Methods: Data on 9,006 adults aged 50+ with diabetes from the Health and Retirement Study (2006–2016) were analyzed. The primary outcome, cognitive function, was a score ranging …from range 0–27 categorized as: normal [12–27], mild cognitive impairment (MCI) [7–11], and dementia including Alzheimer’s disease [0–6]. Three modeled outcomes were: 1) normal versus MCI, 2) normal versus dementia, 3) MCI versus dementia. Wealth was log transformed and used as continuous and binary (≥median, <median). Logistic generalized estimating equation models were used to examine the relationship between wealth and cognitive function and models were stratified by race/ethnicity. Models were adjusted for demographics, lifestyle, functional limitations, and comorbidities. Results: In adjusted models, greater wealth was significantly associated with lower odds of MCI and dementia for all groups. Similarly, having wealth less than the sample median was associated with higher odds of MCI and dementia compared to wealth≥sample median. Conclusions: Increased wealth was significantly protective against MCI and dementia for all ethnic groups. Wealth less than the sample median was associated with greater odds of dementia for NHB and NHW. Show more

Keywords: Alzheimer’s disease, cognitive function, dementia, diabetes, mild cognitive impairment, older adults, racial/ethnic disparities, wealth

DOI: 10.3233/JAD-231107

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1145-1155, 2024

Authors: Soares Martins, Tânia | Ferreira, Maria | Magalhães, Sandra | Leandro, Kevin | Almeida, Luís P. de | Vogelgsang, Jonathan | Breitling, Benedict | Hansen, Niels | Esselmann, Hermann | Wiltfang, Jens | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids. Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential. …Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs’ spectra analyzed. Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids. Conclusions: EVs’ spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, diagnosis, extracellular vesicles, lipids, nucleic acids, proteins

DOI: 10.3233/JAD-231239

Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1157-1167, 2024