Journal of Alzheimer's Disease - Volume 100, issue 1

Authors: Huang, Lei | Ma, Jingxuan | Jiang, Fugui | Zhang, Shushan | Lan, Yajia | Zhang, Yang

Article Type: Research Article

Abstract: Background: Noise exposure and the risk of cognitive impairment are currently major public health issues. Objective: This study aimed to analyze the relationship between noise exposure and early impairment of cognitive function from the perspective of occupational epidemiology and to provide evidence for the long-term prevention and treatment of dementia in the context of aging. Methods: This study was conducted in China between May and August 2021. The independent variables were the type of hazardous factors, duration of noise exposure, perceived noise intensity, and cumulative noise exposure (CNE). The dependent variable was cognitive function, which was …measured using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Multiple linear and logistic regression were used to analyze the relationship between noise exposure and cognitive function and to establish an effect curve. Results: The detection rates of cognitive dysfunction using the MMSE and MoCA were 1.1% and 36.2%, respectively. The predicted MMSE and MoCA scores showed a downward trend within the CNE value ranging from 90–140 dB.time. Each unit increase in CNE decreased cognitive function scores by 0.025 (0.037, 0.013) and 0.020 (0.037, 0.003) points,respectively. Conclusions: From the perspective of occupational epidemiology, these findings reveal a potential link between long-term noise exposure and early cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognitive impairment, cumulative dose, noise, occupational exposure

DOI: 10.3233/JAD-240061

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 151-161, 2024

Authors: Gibbons, Laura E. | Mobley, Taylor | Mayeda, Elizabeth Rose | Lee, Cecilia S. | Gatto, Nicole M. | LaCroix, Andrea Z. | McEvoy, Linda K. | Crane, Paul K. | Hayes-Larson, Eleanor

Article Type: Research Article

Abstract: Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994. Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer’s disease generalized to all older adults in the Seattle Metropolitan Region. Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer’s disease incidence. Cox proportional hazards …models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights. Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer’s disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT. Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights. Show more

Keywords: Alzheimer’s disease, bias, dementia, epidemiological research design, eye diseases, generalizability, integrated health-care delivery systems, prevalence, transportability

DOI: 10.3233/JAD-240247

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 163-174, 2024

Authors: Cheng, Chia-Hsiung | Hsieh, Yu-Wei | Chang, Chiung-Chih | Hsiao, Fu-Jung | Chen, Li-Fen | Wang, Pei-Ning

Article Type: Research Article

Abstract: Background: Multidomain intervention may delay or ameliorate cognitive decline in older adults at risk of Alzheimer’s disease, particularly in the memory and inhibitory functions. However, no study systematically investigates the changes of brain function in cognitively-normal elderly with subjective cognitive decline (SCD) when they receive multidomain intervention. Objective: We aimed to examine whether a multidomain intervention could improve neuropsychological function and neurophysiological activities related to memory and inhibitory function in SCD subjects. Methods: Eight clusters with a total of 50 community-dwelling SCD older adults were single-blind, randomized into intervention group, which received physical and cognitive training, …or control group, which received treatment as usual. For the neuropsychological function, a composite Z score from six cognitive tests was calculated and compared between two groups. For the neurophysiological activities, event-related potentials (ERPs) of memory function, including mismatch negativity (MMN) and memory-P3, as well as ERPs of inhibitory function, including sensory gating (SG) and inhibition-P3, were measured. Assessments were performed at baseline (T1), end of the intervention (T2), and 6 months after T2 (T3). Results: For the neuropsychological function, the effect was not observed after the intervention. For the neurophysiological activities, improved MMN responses of ΔT2–T1 were observed in the intervention group versus the control group. The multidomain intervention produced a sustained effect on memory-P3 latencies of ΔT3–T1. However, there were no significant differences in changes of SG and inhibition-P3 between intervention and control groups. Conclusions: While not impactful on neuropsychological function, multidomain intervention enhances specific neurophysiological activities associated with memory function. Show more

Keywords: Alzheimer’s disease, event-related potential, lifestyle intervention, mismatch negativity, multidomain intervention, occupational therapy, P3

DOI: 10.3233/JAD-231257

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 175-192, 2024

Authors: Sannemann, Lena | Bartels, Claudia | Brosseron, Frederic | Buerger, Katharina | Fliessbach, Klaus | Freiesleben, Silka Dawn | Frommann, Ingo | Glanz, Wenzel | Heneka, Michael T. | Janowitz, Daniel | Kilimann, Ingo | Kleineidam, Luca | Lammerding, Dominik | Laske, Christoph | Munk, Matthias H.J. | Perneczky, Robert | Peters, Oliver | Priller, Josef | Rauchmann, Boris-Stephan | Rostamzadeh, Ayda | Roy-Kluth, Nina | Schild, Ann-Katrin | Schneider, Anja | Schneider, Luisa-Sophie | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Duezel, Emrah | Jessen, Frank

Article Type: Research Article

Abstract: Background: The NIA-AA Research Framework on Alzheimer’s disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N  = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle …objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42 /ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, amyloid, cerebrospinal fluid biomarkers, NIA-AA stage 2, neuropsychiatric symptoms, preclinical Alzheimer’s disease, subjective cognitive decline

DOI: 10.3233/JAD-231335

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 193-205, 2024

Authors: Sun, Cheng-Kun | Guo, Fan | Ou, Ya-Nan | Zhang, Ming-Zhan | Tan, Lan | Tan, Meng-Shan

Article Type: Research Article

Abstract: Background: The association between carotid plaque and cognitive decline has recently been reported. However, the current research evidence is insufficient, and the possible causes of cognitive changes are unknown. Objective: This study aims to explore the relationships between carotid plaque and cognition functions, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in cognitively intact adults, and try to study the underlying mechanisms. Methods: We enrolled 165 cognitively normal participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, who had CSF AD biomarker measurements and carotid ultrasound. Linear modeling was used to assess the association of carotid …plaque with CSF biomarkers and cognition. Additionally, mediation analysis was conducted through 10,000 bootstrapped iterations to explore potential links between carotid plaque, AD pathology, and cognition. Results: We found that carotid plaque exhibited significant correlations with Aβ42 (β = –1.173, p  = 0.022), Aβ42 /Aβ40 (β = –0.092, p  < 0.001), P-tau/Aβ42 (β = 0.110, p  = 0.045), and T-tau/Aβ42 (β = 0.451, p  = 0.010). A significant correlation between carotid plaque and cognition decline was also found in men (β = –0.129, p  = 0.021), and mediation analyses revealed that the effect of carotid plaque on cognitive function could be mediated by Aβ42 /Aβ40 (proportion of mediation = 55.8%), P-tau/Aβ42 (proportion of mediation = 51.6%, p  = 0.015) and T-tau/Aβ42 (proportion of mediation = 43.8%, p  = 0.015) mediated. Conclusions: This study demonstrated the link between carotid plaque and CSF AD biomarkers in cognitively intact adults, and the important role that AD pathology may play in the correlation between carotid plaque and cognitive changes. Show more

Keywords: Alzheimer’s disease, biomarkers, carotid plaque, cognitive function, pathogenesis

DOI: 10.3233/JAD-240131

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 207-217, 2024

Authors: Fukui, Yusuke | Tadokoro, Koh | Hamada, Minaki | Asada, Kyoichi | Lee, Lyang-Ja | Tachiki, Hidehisa | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: With the aging of populations worldwide, Alzheimer’s disease (AD) has become a concern due to its high prevalence and the continued lack of established treatments. Early diagnosis is required as a preventive intervention to modify the disease’s progression. In our previous study, we performed peptidomic analysis of serum samples obtained from AD patients and age-matched healthy subjects to seek peptide biomarker candidates for AD by using BLOTCHIP-MS analysis, and identified four peptides as AD biomarker candidates. Objective: The objective was to validate the serum biomarker peptides to distinguish mild cognitive impairment (MCI) and AD in comparison to …cognitively healthy controls using a new peptidome technology, the Dementia Risk Test. Methods: We enrolled 195 subjects with normal cognitive function (NC; n  = 70), MCI (n  = 55), and AD (n  = 70), The concentrations of cognitive impairment marker peptides (Fibrinogen α chain (FAC), Fibrinogen β chain (FBC), Plasma protease C1 inhibitor (PPC1I), α 2-HS-glycoprotein (AHSG)) were quantified by using a selected reaction monitoring assay based on liquid chromatography-MS/MS. Results: The present study confirmed that three peptides, FAC, FBC, and PPC1I, were significantly upregulated during the onset of AD. This three-peptide set was both highly sensitive in determining AD (sensitivity: 85.7%, specificity: 95.7%, AUC: 0.900) and useful in distinguishing MCI (sensitivity: 61.8%, specificity: 98.6%, AUC: 0.824) from NC. Conclusions: In this validation study, we confirmed the high diagnostic potential of the three peptides identified in our previous study as candidate serum biomarkers for AD. The Dementia Risk Test may be a powerful tool for detecting AD-related pathological changes. Show more

Keywords: Alzheimer’s disease, biochemical marker, dementia risk test, liquid chromatography-MS/MS, mild cognitive impairment, peptidome, selected reaction monitoring

DOI: 10.3233/JAD-230915

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 219-228, 2024

Authors: Ning, Min | An, Lina | Dong, Liang | Zhu, Ranran | Hao, Jingjing | Liu, Xueyuan | Zhang, Yuanyuan

Article Type: Research Article

Abstract: Background: Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer’s disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored. Objective: Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods. Methods: We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related …single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence. Results: Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%). Conclusions: Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect. Show more

Keywords: Alzheimer’s disease, gut microbiome, Mendelian randomization, metabolites

DOI: 10.3233/JAD-240082

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 229-237, 2024

Authors: Patel, Hemal | Wisely, C. Ellis | Robbins, Cason B. | Parker, Daniel | Challa, Pratap | Grewal, Dilraj S. | Fekrat, Sharon

Article Type: Research Article

Abstract: Background: Plasma and cerebrospinal fluid (CSF) levels of p-tau181 have been associated with Alzheimer’s disease (AD). The retina and vitreous have shown measurable quantities of phosphorylated tau 181 (p-tau181). The aqueous humor, which can be collected during cataract surgery, may have measurable concentrations of p-tau181. Objective: To determine whether p-tau181 is detectable in the aqueous humor and if so, whether it is associated with other measures that might be consistent with AD such as higher plasma p-tau181 concentration and lower Montreal Cognitive Assessment (MoCA-BLIND version 7.1) score. Methods: Aqueous humor samples, blood samples, and MoCA-BLIND scores …were collected from patients who did not carry a clinical diagnosis of cognitive impairment at the time of cataract surgery. Aqueous p-tau181 concentrations and plasma p-tau181 concentrations were then measured using ultra-sensitive single-molecule assay ELISA technology. A rank-transformed mixed-effects multivariate regression model was used to determine associations between aqueous concentrations, plasma concentrations, and MoCA-BLIND scores. Results: 16 eyes of 16 participants were enrolled with an average age of 71.6. Average MoCA-BLIND score was 20.6/22, average aqueous p-tau181 concentration was 6.4 pg/mL, and average plasma p-tau181 concentration was 3.1 pg/mL. Higher plasma p-tau181 was significantly associated with higher aqueous p-tau181 (p  = 0.02). Aqueous p-tau181 and plasma p-tau181 were negatively associated with MoCA-BLIND scores (p  = 0.005 and p  = 0.001 respectively) in these patients. Conclusions: Aqueous p-tau181 is positively correlated with plasma p-tau181 and is negatively correlated with MoCA-BLIND scores. Further study in individuals with mild cognitive impairment or AD characterized by cerebrospinal fluid and volumetric MRI metrics may yield further insights. Show more

Keywords: Alzheimer’s disease, aqueous humor, enzyme-linked immunosorbent assay, tau proteins

DOI: 10.3233/JAD-240279

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 239-245, 2024

Authors: Kemiläinen, Benjam | Tiainen, Sonja | Rauramaa, Tuomas | Luikku, Antti J. | Herukka, Sanna-Kaisa | Koivisto, Anne | Hiltunen, Mikko | Verdooner, Steven | Johnson, Ken | Chambers, Mieko | Kaarniranta, Kai | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Association between visual field test indices and The Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB) is unknown. Idiopathic normal pressure hydrocephalus (iNPH) patients provide a unique set of patient data for analysis. Objective: To assess the reliability of visual field testing using the CERAD-NB in patients with iNPH and to investigate the association between visual field test results and cognitive function. Methods: 62 probable iNPH patients were subjected to comprehensive ophthalmological examination, ophthalmological optical coherence tomography imaging studies, visual field testing, and CERAD-NB. Based on visual field indices, the patients were …divided into two groups: unreliable (n  = 19) and reliable (n  = 43). Independent T-test analysis was performed to examine the relationship between visual field test results and cognitive function. Pearson Chi-square test was used for non-continuous variables. Results: The unreliable group performed worse in CERAD-NB subtests compared to the reliable group. Statistically significant differences were observed in nine out of ten subtests, with only Clock Drawing showing no statistical significance. Pairwise comparison of the groups showed no statistical significance between amyloid-β (Aβ) biopsy, hyperphosphorylated tau biopsy, apolipoprotein E allele or the ophthalmological status of the patient. But there was a statistically significant difference in cerebrospinal fluid Aβ42 and age between the groups. Conclusions: Patients with unreliable visual field tests performed worse on CERAD-NB subtests. CERAD-NB subtests do not provide a specific cut-off value to refrain patients from visual field testing. Should patients with unreliable visual field tests be screened for cognitive impairment? Show more

Keywords: Alzheimer’s disease, amyloid-β , APOE , CERAD-NB, cognitive impairment, normal pressure hydrocephalus, optical coherence tomography, visual field tests

DOI: 10.3233/JAD-231414

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 247-260, 2024

Authors: Li, Dazhi | Xie, Qiang | Xie, Jikui | Ni, Ming | Wang, Jinliang | Gao, Yuru | Wang, Yaxin | Tang, Qiqiang

Article Type: Research Article

Abstract: Background: Early-onset Alzheimer’s disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer’s disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. Objective: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. Methods: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients …with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. Results: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results Conclusions: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins. Show more

Keywords: Alzheimer’s disease, early-onset Alzheimer’s disease, biomarker, cerebrospinal fluid, machine learning, proteomics

DOI: 10.3233/JAD-240022

Citation: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 261-277, 2024