Alzheimer's Disease Dementia Patients Research Articles

Irisin Levels in Cerebrospinal Fluid Correlate with Biomarkers and Clinical Dementia Scores in Alzheimer Disease.

Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid β 1-42, hyperphosphorylated tau, and total tau [t-tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aβ42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR-SOB (r = -0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t-tau levels in all patients (r = -0.144, p = 0.082) and in the female subgroup (r = -0.189, p = 0.084). The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61-73.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Plasma oligomer beta-amyloid is associated with disease severity and cerebral amyloid deposition in Alzheimer’s disease spectrum

BackgroundMultimer detection system-oligomeric amyloid-β (MDS-OAβ) is a measure of plasma OAβ, which is associated with Alzheimer’s disease (AD) pathology. However, the relationship between MDS-OAβ and disease severity of AD is not clear. We aimed to investigate MDS-OAβ levels in different stages of AD and analyze the association between MDS-OAβ and cerebral Aβ deposition, cognitive function, and cortical thickness in subjects within the AD continuum.MethodsIn this cross-sectional study, we analyzed a total 126 participants who underwent plasma MDS-OAβ, structural magnetic resonance image of brain, and neurocognitive measures using Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease, and cerebral Aβ deposition or amyloid positron emission tomography (A-PET) assessed by [18F] flutemetamol PET. Subjects were divided into 4 groups: N = 39 for normal control (NC), N = 31 for A-PET-negative mild cognitive impairment (MCI) patients, N = 30 for A-PET-positive MCI patients, and N = 22 for AD dementia patients. The severity of cerebral Aβ deposition was expressed as standard uptake value ratio (SUVR).ResultsCompared to the NC (0.803 ± 0.27), MDS-OAβ level was higher in the A-PET-negative MCI group (0.946 ± 0.137) and highest in the A-PET-positive MCI group (1.07 ± 0.17). MDS-OAβ level in the AD dementia group was higher than in the NC, but it fell to that of the A-PET-negative MCI group level (0.958 ± 0.103). There were negative associations between MDS-OAβ and cognitive function and both global and regional cerebral Aβ deposition (SUVR). Cortical thickness of the left fusiform gyrus showed a negative association with MDS-OAβ when we excluded the AD dementia group.ConclusionsThese findings suggest that MDS-OAβ is not only associated with neurocognitive staging, but also with cerebral Aβ burden in patients along the AD continuum.

Care partner evaluation of the behaviors in the Cohen-Mansfield Agitation Inventory

IntroductionAgitation is a common symptom in patients with Alzheimer's dementia. But agitation can be a heterogeneous symptom, encompassing a diverse array of behaviors exhibited by patients. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale that is used to systematically assess the frequency and severity of agitation in older adults as rated by a primary caregiver. The CMAI was originally designed for use by professional care givers in institutional care settings. Alzheimer's dementia, however, is associated with a significant burden on family members, who provide the majority of care, and other informal care partners.MethodsOur qualitative study aimed to assess the accuracy and applicability of the CMAI according to the needs and perceptions of non-professional care partners. Specifically, we wanted to determine if the behaviors included in the instrument reflect: (a) the care partner's experience with agitation in Alzheimer's dementia patients, (b) how the behaviors and their frequency are related to the perception of agitation severity, and (c) what changes in agitation behaviors are meaningful to care partners. We interviewed 30 care partners for patients with Alzheimer's dementia in the United States.ResultsThe care partners confirmed all behaviors listed in the CMAI as relevant. The behaviors reflect a spectrum of severity, with aggressive behaviors considered more severe than non-aggressive behaviors and physical behaviors generally considered more severe than verbal behaviors. Any reduction or increase in the frequency of a behavior was meaningful to care partners. Generally, a change from physical to verbal behaviors and aggressive to non-aggressive was considered a meaningful improvement while a change from verbal to physical and non-aggressive to aggressive was considered a meaningful worsening.DiscussionThe CMAI appropriately captures relevant behaviors of agitation in Alzheimer's dementia and provides insight into the relative improvement or worsening of agitation symptoms.

Exploring the potential of fully automated LUMIPULSE G plasma assays for detecting Alzheimer’s disease pathology

BackgroundLUMIPULSE G-automated immunoassays represent a widely used method for the quantification of Alzheimer’s disease (AD) biomarkers in the cerebrospinal fluid (CSF). Less invasive blood-based markers confer a promising tool for AD diagnosis at prodromal stages (mild cognitive impairment (MCI)). Highly sensitive assays for the quantification of amyloid-beta (Aβ) and phosphorylated Tau-181 (p-Tau181) in the blood are showing promising results. In this study, we evaluated the clinical performance of the recently available fully automated LUMIPULSE plasma marker assays for detecting brain AD pathology and for predicting progression from MCI to AD dementia stage.MethodsA retrospective exploratory cohort of 138 individuals (22 neurological controls [NC], 72 MCI, and 44 AD dementia patients) was included. Data regarding baseline CSF concentrations of Aβ42, Aβ40, t-Tau, and p-Tau181 was available and used to establish the presence of AD brain pathology. Baseline Aβ42, Aβ40, and p-Tau181 concentrations were determined in stored plasma samples using high-throughput fully automated LUMIPULSE assays. Progression from MCI to AD dementia was evaluated during follow-up (mean 6.4 ± 2.5 years). Moreover, a prospective validation cohort of 72 individuals with memory complaints underwent AD biomarker quantification, closely mirroring typical clinical practice. This cohort aimed to confirm the study’s main findings.ResultsIn the exploratory cohort, correlations between CSF and plasma were moderate for p-Tau181 (ρ = 0.61, p < 0.001) and weak for Aβ42/Aβ40 ratio (ρ = 0.39, p < 0.001). Plasma p-Tau181 and p-Tau181/Aβ42 concentrations were significantly increased while Aβ42/Aβ40 was significantly decreased (p < 0.001) in patients with AD dementia and prodromal AD, as well as in individuals with CSF abnormal amyloid concentrations (A +). Plasma p-Tau181 showed a robust performance in differentiating patients clinically diagnosed as AD (AUC = 0.89; 95% CI 0.83–0.94); A + vs. A − (AUC = 0.84, 95% CI 0.77–0.91) and also in predicting conversion to AD dementia in MCI patients (AUC = 0.89, 95% CI 0.81–0.96). When tested in the validation cohort, plasma p-Tau181 displayed 83.3% of the overall percentage of agreement according to amyloid status.ConclusionsOur results show that the measurement of p-Tau181 in plasma has great potential as a non-invasive prognostic screening tool for implementation in a clinical setting.

Abdominal fat depots are related to lower cognitive functioning and brain volumes in middle-aged males at high Alzheimer's risk.

High BMI, which poorly represents specific fat depots, is linked to poorer cognition and higher dementia risk, with different associations between sexes. This study examined associations of abdominal fat depots with cognition and brain volumes and whether sex modifies this association. A total of 204 healthy middle-aged offspring of Alzheimer's dementia patients (mean age = 59.44, 60% females) underwent abdominal magnetic resonance imaging to quantify hepatic, pancreatic, visceral, and subcutaneous adipose tissue and to assess cognition and brain volumes. In the whole sample, higher hepatic fat percentage was associated with lower total gray matter volume (β = -0.17, p < 0.01). Primarily in males, higher pancreatic fat percentage was associated with lower global cognition (males: β = -0.27, p = 0.03; females: β = 0.01, p = 0.93) executive function (males: β = -0.27, p = 0.03; females: β = 0.02, p = 0.87), episodic memory (males: β = -0.28, p = 0.03; females: β = 0.07, p = 0.48), and inferior frontal gyrus volume (males: β = -0.28, p = 0.02; females: β = 0.10, p = 0.33). Visceral and subcutaneous adipose tissue was inversely associated with middle frontal and superior frontal gyrus volumes in males and females. In middle-aged males at high Alzheimer's dementia risk, but not in females, higher pancreatic fat was associated with lower cognition and brain volumes. These findings suggest a potential sex-specific link between distinct abdominal fat with brain health.

THE INFLUENCE OF THE APOEε4 ALLELE ON PRO-INFLAMMATORY CYTOKINE LEVELS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH ALZHEIMER’S DISEASE

Single nucleotide polymorphisms (SNPs) rs429358 and rs7412, the most commonly investigated variants in the apolipoprotein E gene (APOE) are crucial for APOEε4 carrier status determination. However, their association with inflammatory cytokine levels in patients with dementia due to Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the influence of the APOEε4 allele on pro-inflammatory cytokine levels in the cerebrospinal fluid of patients with AD dementia. The research was conducted on 36 patients with probable dementia due to AD. APOE rs429358 and rs7412 were analyzed using the Real-Time PCR method with allele-specific TaqMan assays, followed by the analysis of APOEε4 allele carrier status. Patients carrying at least one APOEε4 allele were assigned as APOEε4+. Core biomarkers (Aβ42/40 ratio, t-Tau, p-Tau levels), as well as pro-inflammatory cytokine (Tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b)) levels, were determined in the patient’s cerebrospinal fluid (CSF) using Enzyme-linked Immunosorbent Assay (ELISA). Seventeen patients (47.22%) were assigned as APOEε4+. CSF TNF-α levels were significantly higher in APOEε4+ AD dementia patients in comparison to APOEε4- patients (p&lt;0.001), while no significant differences in IL-1b levels between these two groups were obtained. Correlation analysis showed that TNF-α negatively correlated with the Aβ42/40 ratio (p=0.033), while positive correlation with t-Tau and p-Tau was observed (p=0.001, p=0.015, respectively). These findings highlight the potential significance of TNF-α in the context of APOEε4 positivity and its implications in AD pathology.

Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy.

Resveratrol, a naturally occurring polyphenol that activates sirtuin 1 (SIRT1), has been shown to reduce overall levels of matrix metalloprotease-9 (MMP-9) in cerebrospinal fluid (CSF) samples from patients with Alzheimer's dementia (AD). Depending on the site of release, however, MMP-9 has the potential to improve or impair cognition. In particular, its release from microglia or pericytes proximal to the blood brain barrier can damage the basement membrane, while neuronal activity-dependent release of this protease from glutamatergic neurons can instead promote dendritic spine expansion and long-term potentiation of synaptic plasticity. In the present study, we test the hypothesis that resveratrol reduces overall MMP-9 levels in CSF samples from patients with APOE4, an allele associated with increased glial inflammation. We also examine the possibility that resveratrol reduces inflammation-associated MMP release from cultured glia but spares neuronal activity-dependent release from cultured cortical neurons. We observe that resveratrol decreases overall levels of MMP-2 and MMP-9 in CSF samples from AD patients. Resveratrol also reduces CSF levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), glial-derived protein that restricts long-term potentiation of synaptic transmission, in individuals homozygous for APOE4. Consistent with these results, we observe that resveratrol reduces basal and lipopolysaccharide (LPS)-stimulated MMP and TIMP-1 release from cultured microglia and astrocytes. In contrast, however, resveratrol does not inhibit release of MMP-9 from cortical neurons. Overall, these results are consistent with the possibility that while resveratrol reduces potentially maladaptive MMP and TIMP-1 release from activated glia, neuroplasticity-promoting MMP release from neurons is spared. In contrast, resveratrol reduces release of neurocan and brevican, extracellular matrix components that restrict neuroplasticity, from both neurons and glia. These data underscore the diversity of resveratrol's actions with respect to affected cell types and molecular targets and also suggest that further studies may be warranted to determine if its effects on glial MMP release could make it a useful adjunct for AD- and/or anti-amyloid therapy-related damage to the blood brain barrier.

Effect of altered gene expression in lipid metabolism on cognitive improvement in patients with Alzheimer's dementia following fecal microbiota transplantation: a preliminary study.

The brain-gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer's dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients' fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients' genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

Evaluation of Early Diagnosis via Some Blood Parameters in Alzheimer Type Dementia and Type 2 Diabetes Mellitus Patients

Aim: Alzheimer's disease is a neurodegenerative disease with cognitive loss, which does not have a curative treatment and a bloodbased&#x0D; biomarker to make a definitive diagnosis. There is a strong relationship between Alzheimer's disease and type 2 diabetes mellitus.&#x0D; Neutrophil-lymphocyte, platelet-lymphocyte and monocyte-lymphocyte ratios are recommended parameters as inflammation markers.&#x0D; It was aimed to compare blood parameters and their ratios to each other in terms of their potential to provide early diagnosis in patients&#x0D; with Alzheimer's disease and type 2 diabetes mellitus.&#x0D; Material and Methods: 80 healthy controls, 47 type 2 diabetes mellitus and 45 Alzheimer's type dementia patients were included in this&#x0D; study. Various blood parameters and their ratios to each other were scanned. One way ANOVA and post hoc Scheffe tests were used for&#x0D; statistical analysis.&#x0D; Results: Serum iron levels were lower in type 2 diabetes mellitus (53.21±29.28 μg/dL) and Alzheimer’s disease (61.26±21.69 μg/dL)&#x0D; groups compared to the control (76.96±30.99 μg/dL) (p=0.001). Lymphocyte numbers were lower in type 2 diabetes mellitus (1.94±0.79&#x0D; count.10³) and Alzheimer’s disease (1.84±0.68 count.10³) groups compared to the control (2.25±1.03 count.10³) (p=0.032). Monocytelymphocyte&#x0D; ratio were significantly higher in type 2 diabetes mellitus (0.3±0.18) and Alzheimer’s disease (0.28±0.11) groups compared&#x0D; to the control (0.24±0.1) (p=0.039).&#x0D; Conclusion: The high monocyte-lymphocyte ratio can be considered as an indicator of systemic inflammation in Alzheimer's disease&#x0D; and type 2 diabetes mellitus. In conclusion, serum iron levels, lymphocyte numbers and monocyte-lymphocyte ratio as inflammation&#x0D; markers can be useful for the early diagnosis of type 2 diabetes mellitus and Alzheimer’s disease

Association Between Executive Dysfunction-Related Activities of Daily Living Disability and Clinical Dementia Rating Domain Patterns in Patients With Vascular Dementia and Age-Matched Patients With Alzheimer's Dementia.

Although the Clinical Dementia Rating (CDR) scale was originally developed to stage Alzheimer's dementia (AD), it is now used globally for various types of dementia. The aim of this study was to investigate the characteristic pattern of CDR domains and its association with neuropsychological findings and activities of daily living (ADL) in patients with vascular dementia (VaD) and patients with AD. We recruited very mild to mild VaD and AD patients who were age-matched among the first visitors to a dementia clinic. All subjects underwent a standardized clinical interview, physical and neurological examinations, and laboratory tests, including brain magnetic resonance imaging, according to the protocol of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease assessment battery. A total of 105 pairs of VaD and AD patients participated in this study. Although the adjusted scores on Korean version of the Mini-Mental State Examination were similar between the two groups, the VaD patients performed better on the Boston Naming Test, Word List Memory, Word List Recall, Word List Recognition, and Constructional Recall Test. However, the scores on global CDR, CDR sum of boxes, and ADL-related CDR domains were higher in VaD patients than in AD patients (p<0.001). The VaD patients also showed poor performances on the Disability Assessment for Dementia Scale, Frontal Assessment Battery, Executive Clock Drawing Task, and Stroop tests. Despite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

The relationship between executive dysfunction‐associated activities of daily living (ADL) and the pattern of Clinical Dementia Rating (CDR) in patients with vascular dementia and age‐matched patients with Alzheimer’s disease

AbstractBackgroundClinical dementia rating (CDR) scale was originally developed to stage the severity of Alzheimer’s dementia (AD) but is now used globally regardless of types of dementia. This study aims to investigate the relationship between the characteristic pattern of CDR domains, neuropsychological findings, and activities of daily living (ADL) in patients with vascular dementia (VaD), compared with age‐matched patients with AD.MethodVery mild to mild VaD and AD patients matched for age were recruited among the first visitors to a dementia clinic. All subjects were administered a standardized clinical interview, physical and neurological examinations, and laboratory tests including the brain MRI according to the protocol of the Korean version of the CERAD assessment battery.ResultOne hundred and five pairs of VaD and AD patients participated in this study. Although the adjusted scores on MMSE were similar between two groups and the performances on Boston naming, word list memory, word list recall, word list recognition, constructional recall test were better in VaD patients, the scores on global CDR, CDR sum of box (SOB), and ADL‐related CDR domains were higher in VaD patients than in AD patients (p&lt;0.001). The poor performances on disability assessment for dementia scale, frontal assessment battery, executive clock drawing task, and Stroop tests were observed in VaD patients.ConclusionDespite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Building a neuropsychiatric testing database for veterans with mild cognitive impairment and Alzheimer’s disease with unstructured electronic health records

AbstractBackgroundInformation on clinical decision making and disease severity assessments for mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) typically only exists in medical notes. In this study, we present the methodology of constructing a database from unstructured electronic health records (EHR), which enables enriched population studies when combined with structured administrative databases.MethodA multidisciplinary team with expertise in neurology, epidemiology, biology, and health informatics designed and created the relational database. The database was established with three tables for patient demographics, neurocognitive and neuropsychiatric test results, and clinical judgment of AD severity. Patient cohorts were identified by searching keywords ("Alz*” or “Mild Cognitive Impairment”) from electronic clinical notes and excluding false positives using expert‐designed rules. The most frequently used six neuropsychiatric tests (MMSE, MoCA, SLUMS, Mini‐cog, BNT, BVRT) and their corresponding testing results were extracted in addition to clinicians’ judgment on disease severity. The test scores were extracted using a rule‐based natural language processing (NLP) system.ResultA patient cohort with MCI (N = 74,444) or probable AD (N = 141,816) was identified in the VA database for the fiscal year of 2019 (Table 1), with 18,173 patients having both MCI and AD diagnosis among their clinical notes of the year. A total of 1,529,897 neuropsychiatric testing scores were extracted from the patients’ clinical notes across all years, with 388,253 MMSE scores, 614,400 MoCA scores, 462,646 SLUMS scores, 18,868 Mini‐cog scores, 45,259 BNT scores, and 471 BVRT scores. A total of 57,879 (77.75%) MCI patients and 82,656 (58.28%) AD patients had at least one test score extracted. A total of 18,939 (13.35%) AD patients had at least one documented severity categorization made by a clinician.ConclusionWe established a database of neuropsychiatric testing scores for patients with MCI or AD based on electronic medical notes from the VA healthcare system, aided by NLP tools. Our approach demonstrated a scalable pipeline to integrate with structured EHR in support of enriched population level analysis in AD.

Ex vivo identification of transcriptional regulation landscape and potential therapeutic targets against oxidative stress using Alzheimer’s disease patient‐derived dermal fibroblast: findings from BICWALZS cohort

AbstractBackgroundReactive oxygen species (ROS) is considered as a central pathophysiology for neurodegeneration in Alzheimer’s disease (AD). Many studies using in vitro cell line or in vivo mouse model have shown the possible association between ROS defense mechanisms and cellular damage. However, that connection was not elucidated well in AD patient‐derived cell or brain organoids. In this study, we aimed to identify transcriptional regulation landscape and potential therapeutic targets against oxidative stress using AD dementia patient‐derived dermal fibroblastMethodsFor the purposes of ex vivo research, we performed skin biopsy and stabilized dermal fibroblasts in vitro. Total of 20 AD dementia patients and 22 cognitively normal older adults were assessed. All of AD dementia patients were amyloid positive on PET imaging, APOE e4 carrier, and cognition was imparied. On the contrary, all of cognitively normal older adults were amyloid negative on PET imaging, and APOE e4 non‐carrier. We applied H2O2 (600 uM) to dermal fibroblast for 24 hours as an oxidant agent to promote oxidative stress. After that, to identify transcriptional regulation landscape against oxidative stress, RNA sequencing was performed.ResultsTotal of 406 transcripts (up = 61, down = 345) were commonly differentially expressed in both of AD dementia and cognitively normal older adults derived dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to cell division, cell cycle, and DNA repair. Interestingly, 133 transcripts (up = 41, down = 92) were only differentially expressed in AD dementia dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to DNA duplex unwinding, cell division, and DNA replication. Total of 147 transcripts (up = 67, down = 80) were only differentially expressed in cognitively normal older adults dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to negative regulation of cell proliferation, notch signaling pathway, and NMDA glutamate receptor signaling pathway.ConclusionWe identified transcriptional regulation landscape by ROS‐H2O2 in AD dementia and cognitively normal older adults dermal fibroblast. Further bioinformatic analysis with computational tools and validation experiments will be performed to find potential therapeutic targets against oxidative stress.

Ex vivo identification of transcriptional regulation landscape and potential therapeutic targets against ER stress using Alzheimer’s disease patient‐derived dermal fibroblast: findings from BICWALZS cohort

AbstractBackgroundEndoplasmic reticulum (ER) stress is considered as a central pathophysiology for neurodegeneration in Alzheimer’s disease (AD). Many studies using in vitro cell line or in vivo mouse model have shown the possible association between ER stress and neurodegeneration. However, that connection was not elucidated well in AD patient‐derived cell or brain organoids. In this study, we aimed to identify transcriptional regulation landscape and potential therapeutic targets against ER stress using AD dementia patient‐derived dermal fibroblast.MethodFor the purposes of ex vivo research, we performed skin biopsy and stabilized dermal fibroblasts in vitro. Total of 20 AD dementia patients and 22 cognitively normal older adults were assessed. All of AD dementia patients were amyloid positive on PET imaging, APOE e4 carrier, and cognition was imparied. On the contrary, all of cognitively normal older adults were amyloid negative on PET imaging, and APOE e4 non‐carrier. We applied thabsigargin (10 nM) to dermal fibroblast for 24 hours to promote ER stress. After that, to identify transcriptional regulation landscape against ER stress, RNA sequencing was performed.ResultTotal of 252 transcripts (up = 162, down = 90) were commonly differentially expressed in both of AD dementia and cognitively normal older adults derived dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to protein folding in ER, response to ER stress, and ERAD pathway. Interestingly, 80 transcripts (up = 33, down = 47) were only differentially expressed in AD dementia dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to cell division, miotic cell cycle, and microtubule‐based movement. Total of 60 transcripts (up = 41, down = 19) were only differentially expressed in cognitively normal older adults dermal fibroblast by ER stress‐thabsigargin. These transcripts were enriched in GO categories related to cholesterol biosynthesis process, DNA replication checkpoint, and cAMP‐mediated signaling.ConclusionWe identified transcriptional regulation landscape by ER stress‐thabsigargin in AD dementia and cognitively normal older adults dermal fibroblast. Further bioinformatic analysis with computational tools and validation experiments will be performed to find potential therapeutic targets against ER stress.

Clustering of neuropsychiatric symptoms across time in Alzheimer’s disease and Mild Cognitive Impairment

AbstractBackgroundNeuropsychiatric symptoms are behavioural manifestations highly prevalent along the Alzheimer’s disease (AD) continuum, including at the stage of Mild Cognitive Impairment (MCI). Although various projects have investigated the factors that underpin these symptoms, the most stable clustering pattern is still matter for debate; furthermore, to our knowledge, no study has investigated, longitudinally, how clusters might change due to development of AD pathology. Therefore, our objective is to investigate neuropsychiatric clusters over time, in a large sample of MCI and AD dementia patients.MethodsSamples were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu), using data from the Neuropsychiatric Inventory (NPI), from the baseline assessment visit, followed up yearly until data recorded at month 72. The samples included MCI and AD dementia patients (based on ADNI’s inclusion criteria), presenting with at least one neuropsychiatric symptom at the time‐point selected. Using SPSS (Version 28), we performed a series of exploratory principal components analyses (PCA), Varimax rotation, and principal axis factor analyses (FA), comparing Promax and Direct Oblimin rotations.ResultsThe best‐fitting structure was interpreted at each time‐point, based on: Eigenvalues&gt;1, items’ loadings&gt;0.4, scree plot patterns, minimum 40% of variance explained by the model, and independence of factors. Results from both PCA and FA indicated that a unique structure could not be identified, as factors were not stable over time; however, some symptoms tended to load on the same factors across most measurements (i.e. delusions with hallucinations; agitation with depression, anxiety and irritability; to a lesser extent elation with disinhibition; apathy with aberrant motor behaviour, sleep disturbances and appetite disorder).ConclusionsThe available evidence reveals that factors underlying the neuropsychiatric symptoms in a sample of AD and MCI patients are not consistent across the time‐points. However, some symptoms tend to co‐occur across time, with implications, for example, that an investigation into one of those symptoms should consider the presence of the other; furthermore, as clear theoretically driven factors are not distinctively identified at every time‐point, this illustrates the potential importance of sample selection (e.g., disease stage, and/or heterogeneity) on studies of neuropsychiatric symptoms.

Plasma SNAP‐25 as a potential Alzheimer’s disease biomarker

AbstractBackgroundSynaptic degeneration and dysfunction are hallmarks of several neurodegenerative diseases, including Alzheimer’s disease (AD). Several studies have shown that the presynaptic protein, synaptosomal‐associated‐protein‐25 (SNAP‐25), is increased in the cerebrospinal fluid (CSF) of AD patients. In the era of ultra‐sensitive immunoassays, the quantification of SNAP‐25 concentration in blood could provide an easily accessible measure of synaptic integrity in AD.MethodIn this pilot study, we investigated 42 participants (n = 23 cognitively unimpaired [CU]; n = 19 MCI or AD dementia patients [CI]) from Geneva University Hospital. A total of 27 participants underwent amyloid positron emission tomography (PET) scans and 14 underwent tau PET scans within 1 year. Global cognition was assessed with Mini Mental State Examination (MMSE). Mann‐Whitney tests were used to assess differences in plasma SNAP25 levels between diagnostic, amyloid (A+/‐) and tau (T+/‐) classification. Furthermore, we used Pearson correlations to assess the association between SNAP25, amyloid centiloid, Tau SUVr and MMSE.ResultThe mean age was 66.9 years +/‐ 7.6 years and 57% were female. SNAP‐25 was significantly increased in CI patients (0.87 pg/mL ±/‐ 0.19) compared to CU participants (0.59 pg/mL ±/‐ 0.11; p&gt;0.001). SNAP‐25 levels were also significantly increased in A+ (0.89 pg/mL ±/‐ 0.18) and T+ (0.92 pg/mL ±/‐ 0.19) individuals compared to A‐ (0.65 pg/mL ±/‐ 0.09; p&lt;0.001) and T‐ (0.717 pg/mL ±/‐ 0.07; p = 0.041). Moreover, we observed a significant correlation between the SNAP‐25 levels and amyloid centiloid (p = 0.016, rho = 0.48), while the correlation was not significant between SNAP‐25 and tau SUVr (p = 0.146, rho = 0.41). Finally, we observed a significant correlation between SNAP‐25 levels and MMSE score (p = 0.033, rho = ‐0.35).ConclusionThe novel plasma single molecular array (Simoa) can accurately quantify SNAP‐25 in blood plasma. In a pilot study, we observed significantly elevated plasma SNAP‐25 levels in cognitively impaired individuals and amyloid and tau positive individuals. Our findings suggest that SNAP‐25 is a potential biomarker indexing synaptic loss in AD. Further results will extend to a memory clinic cohort of &gt;350 participants to assess its diagnostic and prognostic power and relationship to amyloid, tau, MRI and CSF biomarkers.

Cortical thickness is influenced by bilingual language dominance in typical and pathological cognitive aging

AbstractBackgroundPrior research in clinical and non‐clinical populations demonstrates that speaking more than one language can modify gray matter structure (e.g., DeLuca et al., 2020; Torres et al., 2022). However, existing work has largely classified bilingualism dichotomously, diminishing the ability to establish associations between bilingual factors (e.g., language dominance) and regional cortical thickness (CT).MethodWe examined cross‐sectional differences in CT across a large, ethnically diverse sample of bilingual and monolingual older adults from the Health and Aging Brain Study: Health Disparities cohort (n = 1,605; O’Bryant et al., 2021). Differences in CT between language dominance subgroups across three levels of diagnostic phase (cognitively unimpaired, mild cognitive impairment (MCI), and Alzheimer’s dementia (AD)) were evaluated using linear‐mixed effects models. Participants were characterized as English‐dominant or Spanish‐dominant speakers according to responses on language interview questions and the Short Acculturation Scale for Hispanics (Marin et al., 1987).ResultAssociations between CT and language dominance differed across diagnostic phase (Tukey‐adjusted ps &lt;0.05). In the cognitively unimpaired group, English‐dominant speakers exhibited greater CT than Spanish‐dominant speakers in in regions‐of‐interest (ROIs) related to auditory processing (Heschl’s gyrus), semantic processing (temporal pole), and executive functioning (frontal pole). Spanish‐dominant speakers exhibited greater CT than English‐dominant speakers in two ROIs supporting motor (precentral) and spatial processing (entorhinal). These CT differences were attenuated in the MCI phase. Here, English‐dominant speakers exhibited greater CT than Spanish‐dominant patients in the frontal pole (executive processing). Spanish‐dominant patients did not exhibit greater CT than English‐dominant patients. Notably, this pattern of group differences was reversed in AD patients. Here, Spanish‐dominant patients exhibited greater CT than English‐dominant patients in ROIs in Alzheimer’s disease‐related regions (parahippocampal and entorhinal).ConclusionOur results indicate associations between language dominance and regional CT, with distinct patterns by diagnostic phase. Whereas English‐dominant bilinguals demonstrated greater regional CT relative to Spanish‐dominant bilinguals in the cognitively unimpaired and MCI phase, Spanish‐dominant bilinguals had greater CT in disease‐related regions in the AD phase. The presence of greater CT in Spanish‐dominant bilingual AD patients is suggestive of resistance to pathological progression. Future research examining longitudinal patterns of neural decline in larger samples is needed.

Cholinesterase inhibitors are associated with large reductions in hospitalization for cardiovascular events and mortality in patients with Alzheimer’s dementia and heart failure

AbstractIntroductionCholinesterase inhibitors (ChEIs) are approved for treatment of Alzheimer’s dementia (AD). ChEIs inhibit the enzyme acetylcholinesterase, increasing the duration of action of acetylcholine in the central and peripheral nervous systems. ChEIs are known to be anti‐inflammatory and to have negative chronotropic effects. Observational studies by us and other groups have indeed shown an association with use of ChEIs in AD with lower risk of death and cardiovascular events (CVD) including myocardial infarction, heart failure (HF), and stroke. We next wanted to investigate whether ChEI treatment in AD patients with HF is associated with reduced risk for mortality and for hospitalization due to CVD.MethodsData from the Swedish registry for dementia disorders, SveDem,was linked to the Patient‐, Prescribed Drug‐ and Cause of death registries. In a propensity score (PS) matched cohort of patients with AD and HF, the association between ChEI use and all‐cause death or hospitalization due to CVD was examined with Cox proportional hazards models.ResultsThe PS matched cohort included 455 patients with HF prior to the AD diagnosis with ChEI and 455 non‐ChEI users. During a median follow‐up time of 2.14 years, 549 deaths occurred. Compared to non‐users, ChEI use was associated with 21% lower risk of death (adjusted HR 0.79; 0.66‐0.96). Galantamine and donepezil (0.64; CI 0.47‐0.87 and 0.80; CI 0.64‐0.98) but not rivastigmine (0.96; CI 0.73‐1.28) were associated with lower risk of death. Any ChEI use was associated with a 47% (CI 0.38‐0.75) reduction in risk of hospitalization due to HF and a 52% reduction (CI 0.32‐072) among donepezil‐users.ConclusionsThis study supports previous reports that treatment with ChEIs in AD is associated with reduced mortality risk. We here show that this association is also found in patients with HF and AD but with differential effects among the ChEIs. Further studies are needed to elucidate the mechanisms. The study also showed a substantial reduction in hospitalization due to CVD. Our results highlight the impact of cardiovascular comorbidities in AD which need to be considered in clinical trials as would the impact of the baseline treatment with ChEIs in new anti‐dementia drug trials.

Dynamical irreversibility, high‐order interactions, and whole‐brain modeling of gamma oscillations in neurodegeneration

AbstractBackgroundAbnormal gamma oscillations (γ) have been systematically reported in preclinical animal models of Alzheimer’s disease (AD) and human AD patients. However, little is known about the underlying mechanisms, non‐linear dynamics, and high‐order interactions of γ in dementia.MethodTo bridge this gap, we combined EEG and fMRI with three novel approaches to offer a comprehensive pathophysiological characterization of γ oscillations: We assessed the irreversibility of large‐scale brain dynamics to provide a precise signature capable of distinguishing AD at the global, local and network levels and at different oscillatory regimes (study 1). A high‐order functional connectivity (HOFC) multivariate information theory approach capturing interactions between 3 or more regions across spatiotemporal scales was compared with standard connectivity metrics for dementia characterization (study 2). A whole‐brain semi‐empirical model with a perturbational approach combined EEG, structural connectivity, and atrophy to explain the disrupted high‐order interactions observed in AD (study 3).ResultsStudy 1: AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels at γ and other oscillations. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from controls. Study 2: EEG‐HOFC revealed hypoconnectivity in γ between frontal, limbic, and sensory regions in AD, and large effect sizes, compared to standard pairwise metrics, proving a more accurate and parsimonious characterization of AD and frontotemporal dementia (FTD) patients. Study 3: whole‐brain modeling showed that a combined mechanism involving reduced structural integration (DTI) and hypo‐excitability (altered excitation/inhibition balance) triggered the altered high‐order interaction γ dynamics observed in AD and FTD. A perturbational approach identified physiopathological regions (SFG, MTG, precuneus) deviating the trajectories from disease to a healthy brain state.ConclusionThe present results offer new evidence regarding the pathophysiological link, mechanistic processes, and non‐linear whole‐brain dynamics between altered resting‐state γ rhythms and the characterization of AD and FTD, opening new avenues for dementia research at different levels.