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

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