Journal of Alzheimer's Disease - Volume 97, issue 2

Authors: Mahzarnia, Ali | Lutz, Michael W. | Badea, Alexandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies. Objective: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype. Methods: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of …the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways. Results: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers. Conclusions: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2’s role in AD cognition and demonstrated ITGA5’s significant role in mediating the AD pathology-cognition connection. Show more

Keywords: Alzheimer’s disease, continuous GSLRT, likelihood ratio-derived test statistics, RNA-seq, VEGF

DOI: 10.3233/JAD-230934

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 635-648, 2024

Authors: Morgenstern, Lewis B. | Briceño, Emily M. | Mehdipanah, Roshanak | Chang, Wen | Lewandowski-Romps, Lisa | Gonzales, Xavier F. | Levine, Deborah A. | Langa, Kenneth M. | Garcia, Nelda | Khan, Noreen | Zahuranec, Darin B. | Heeringa, Steven G.

Article Type: Research Article

Abstract: Background: Little information is available on the prevalence of cognitive impairment in Mexican American persons. Objective: To determine the prevalence of mild cognitive impairment (MCI) and dementia in those 65 years and older among Mexican American and non-Hispanic white individuals in a community. Methods: This was a population-based cohort study in Nueces County, Texas, USA. Participants were recruited using a random housing sample. The Harmonized Cognitive Assessment (HCAP) participant and informant protocol was performed after Montreal Cognitive Assessment (MoCA) screening. An algorithm was used to sort participants into diagnostic categories: no cognitive impairment, …MCI, or dementia. Logistic regression determined the association of ethnicity with MCI and dementia controlling for age, gender, and education. Results: 1,901 participants completed the MoCA and 547 the HCAP. Mexican Americans were younger and had less educational attainment than non-Hispanic whites. Overall, dementia prevalence was 11.6% (95% CI 9.2–14.0) and MCI prevalence was 21.2% (95% CI 17.5–24.8). After adjusting for age, gender, and education level, there was no significant ethnic difference in the odds of dementia or MCI. Those with ≤11 compared with ≥16 years of education had much higher dementia [OR = 4.9 (95% CI 2.2–11.1)] and MCI risk [OR = 3.5 (95% CI 1.6–7.5)]. Conclusions: Dementia and MCI prevalence were high in both Mexican American and non-Hispanic white populations. Mexican American persons had double the odds of mild cognitive impairment and this was attenuated when age and educational attainment were considered. Educational attainment was a potent predictor of cognitive impairment. Show more

Keywords: Alzheimer’s disease, community, dementia, disparities, education, epidemiology, health equity, Hispanic, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-230729

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 649-658, 2024

Authors: Kosel, Filip | Hartley, Mackenzie Rae | Franklin, Tamara Brook

Article Type: Research Article

Abstract: Background: Neuroimaging studies investigating the behavioral and psychological symptoms of dementia (BPSD)— such as apathy, anxiety, and depression— have linked some of these symptoms with altered neural activity. However, inconsistencies in operational definitions and rating scales, limited scope of assessments, and poor temporal resolution of imaging techniques have hampered human studies. Many transgenic (Tg) mouse models of Alzheimer’s disease (AD) exhibit BPSD-like behaviors concomitant with AD-related neuropathology, allowing examination of how neural activity may relate to BPSD-like behaviors with high temporal and spatial resolution. Objective: To examine task-dependent neural activity in the medial prefrontal cortex (mPFC) of AD-model …mice in response to social and non-social olfactory stimuli. Methods: We previously demonstrated age-related decreases in social investigation in Tg 5xFAD females, and this reduced social investigation is evident in Tg 5xFAD females and males by 6 months of age. In the present study, we examine local field potential (LFP) in the mPFC of awake, behaving 5xFAD females and males at 6 months of age during exposure to social and non-social odor stimuli in a novel olfactometer. Results: Our results indicate that Tg 5xFAD mice exhibit aberrant baseline and task-dependent LFP activity in the mPFC— including higher relative delta (1–4 Hz) band power and lower relative power in higher bands, and overall stronger phase-amplitude coupling— compared to wild-type controls. Conclusions: These results are consistent with previous human and animal studies examining emotional processing, anxiety, fear behaviors, and stress responses, and suggest that Tg 5xFAD mice may exhibit altered arousal or anxiety. Show more

Keywords: Alzheimer’s disease, anxiety, arousal, behavioral and psychological symptoms of dementia, local field potentials, olfaction, phase-amplitude coupling, social odors, 5xFAD mice

DOI: 10.3233/JAD-230858

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 659-677, 2024

Authors: Park, Minah | Jang, Sung-In | Hurh, Kyungduk | Park, Eun-Cheol | Kim, Seung Hoon

Article Type: Research Article

Abstract: Background: Among the older adults, hearing impairment is a common problem and may contribute to dementia. Objective: Therefore, we aimed to examine the association between hearing impairment and the risk of dementia among older adults in South Korea. Methods: Using the Korean National Health Insurance Service-Senior Cohort from 2005 to 2019, we collected data of 44,728 patients. Hearing impairment was determined using the national disability registry. Propensity score matching (1:1) was performed to match patients with and without hearing impairment (case: 22,364, control: 22,364). A Cox proportional hazards regression model was built to analyze the association …between hearing impairment and dementia. Results: Patients with hearing impairment had a higher risk of dementia than those without hearing impairment (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.23–1.34). Assessing the degree of disability, both severe (HR = 1.25, 95% CI = 1.16–1.35) and mild conditions (HR = 1.29, 95% CI = 1.23–1.35) had an increased risk of dementia, respectively. Conclusions: Older patients with hearing impairment exhibit an increased risk of dementia, thereby warranting a new approach to dementia care among these patients regardless of the degree of hearing impairment. Show more

Keywords: Alzheimer’s disease, dementia, hearing impairment, hearing loss

DOI: 10.3233/JAD-230816

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 679-686, 2024

Authors: Morin, Peter | Aguilar, Byron J. | Li, Xuyang | Chen, Jinying | Berlowitz, Dan | Zhang, Raymond | Tahami Monfared, Amir Abbas | Zhang, Quanwu | Xia, Weiming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the “window of time” within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. Objective: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). Methods: This retrospective analysis (2010–2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. …AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. Results: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2–4 years, whether assessed by MMSE, MoCA, or SLUMS. Conclusion: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2–4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD. Show more

Keywords: Alzheimer’s disease, amyloid, anti-amyloid therapy, cognitive test, dementia, mild cognitive impairment, mini-mental state examination, montreal cognitive assessment, saint louis university mental status examination, veterans

DOI: 10.3233/JAD-230850

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 687-695, 2024

Authors: Prada Crespo, David | Montejo Carrasco, Pedro | Díaz-Mardomingo, Carmen | Villalba-Mora, Elena | Montenegro-Peña, Mercedes

Article Type: Research Article

Abstract: Background: Loneliness and social isolation are considered public health problems among older individuals. In addition, both increase the risk of developing cognitive impairment and dementia. The Social Loneliness construct has been proposed to refer to these harmful social interaction-related factors. Objective: To define the risk factors of Social Loneliness in individuals with mild cognitive impairment (MCI) and to analyze cognitive, emotional, and functional differences according to the participant’s degree of Social Loneliness. Methods: Through convenience sampling, 105 participants over 60 diagnosed with MCI were selected. The evaluation consisted of anamnesis and a comprehensive …neuropsychological examination. The ESTE-II questionnaire was used to assess Social Loneliness and its three factors: perceived social support, social participation, and use of communication technologies. Personality was measured with the NEO-FFI questionnaire. Results: The predictors of the Social Loneliness factors were as follows; 1) perceived social support (R2  = 0.33): Neuroticism (β= 0.353), depression (β= 0.205), and perceived health (β= 0.133); 2) social participation (R2  = 0.24): Conscientiousness (β= –0.344) and Extraversion (β= –0.263); 3) use of communication technologies (R2  = 0.44): age (β= 0.409), type of cohabitation (β= 0.331), cognitive reserve (β= –0.303), and Conscientiousness (β= –0.247); all p  < 0.05. The participants with a higher degree of Social Loneliness showed more depressive symptoms (R2  = 0.133), more memory complaints (R2  = 0.086), worse perceived health (R2  = 0.147), lower attentional performance/processing speed (R2  = 0.094), and more naming difficulties (R2  = 0.132); all p  < 0.05. Conclusions: This research represents an advance in detecting individuals with MCI and an increased risk of developing Social Loneliness, which influences the configuration of the clinical profile of MCI. Show more

Keywords: Aging, Alzheimer's disease, dementia, loneliness, mild cognitive impairment, risk factors, social isolation

DOI: 10.3233/JAD-230901

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 697-714, 2024

Authors: Torkpoor, Rozita | Frolich, Kristin | Londos, Elisabet | Nielsen, T. Rune

Article Type: Research Article

Abstract: Background: Cognitive assessment for foreign-born individuals is suboptimal. The Multicultural Cognitive Examination (MCE) was developed for use in culturally, linguistically and educationally diverse populations. The MCE includes the Rowland Universal Dementia Assessment Scale (RUDAS) and performs assessment of memory, verbal fluency, and visuospatial function. Objective: To compare the psychometric properties of the Swedish version of the Multicultural Cognitive Examination (MCE-S) with the Swedish versions of the RUDAS (RUDAS-S), the Mini-Mental State Examination (MMSE-SR), and the Clock Drawing Test (CDT), and to explore the ability of the MCE-S test to differentiate patients with and without dementia in a multicultural …population. Methods: 117 outpatients at four memory clinics were tested using the MCE-S to complement the routine cognitive assessment. Results: Significant differences between patients with and without dementia were observed for all MCE-S components. There were significant differences between foreign-born and Swedish-born patients in the MMSE-SR, but not in the MCE-S or the RUDAS-S. The MCE-S, had good diagnostic performance for detecting dementia (AUC, 0.82), and was at least as good as the RUDAS-S alone (AUC, 0.79). The MCE-S also distinguished Alzheimer’s disease (AD) from non-AD dementia. Contrary to expectations, the MCE-S was also at least as good as the MMSE-SR among the Swedish-born patients. Conclusions: The MCE-S is adequate for detecting dementia in both foreign-born and Swedish-born populations. Based on the cultural diversity of general society, adapted cognitive tests that can be used for everyone are practical and beneficial for both patients and health-care professionals. Further studies are needed within primary care. Show more

Keywords: Alzheimer’s disease, assessment, cognition, dementia, ethnic minorities, immigrants, multicultural cognitive examination

DOI: 10.3233/JAD-230998

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 715-726, 2024

Authors: Chen, Meimei | Wang, Fengzhen | Lei, Huangwei | Yang, Zhaoyang | Li, Candong

Article Type: Research Article

Abstract: Background: The taxus chinensis fruit (TCF) shows promises in treatment of aging-related diseases such as Alzheimer’s disease (AD). However, its related constituents and targets against AD have not been deciphered. Objective: This study was to uncover constituents and targets of TCF extracts against AD. Methods: An integrated approach including ultrasound extractions and constituent identification of TCF by UPLC-QE-MS/MS, target identification of constituents and AD by R data-mining from Pubchem, Drugbank and GEO databases, network construction, molecular docking and the ROC curve analysis was carried out. Results: We identified 250 compounds in TCF extracts, and …obtained 3,231 known constituent targets and 5,326 differential expression genes of AD, and 988 intersection genes. Through the network construction and KEGG pathway analysis, 19 chemicals, 31 targets, and 11 biological pathways were obtained as core compounds, targets and pathways of TCF extracts against AD. Among these constituents, luteolin, oleic acid, gallic acid, baicalein, naringenin, lovastatin and rutin had obvious anti-AD effect. Molecular docking results further confirmed above results. The ROC AUC values of about 87% of these core targets of TCF extracts was greater than 0.5 in the two GEO chips of AD, especially 10 targets with ROC AUC values greater than 0.7, such as BCL2, CASP7, NFKBIA, HMOX1, CDK2, LDLR, RELA, and CCL2, which mainly referred to neuron apoptosis, response to oxidative stress and inflammation, fibroblast proliferation, etc. Conclusions: The TCF extracts have diverse active compounds that can act on the diagnostic genes of AD, which deserve further in-depth study. Show more

Keywords: Alzheimer’s disease, GEO gene chips, molecular docking, network construction, ROC curve analysis, UPLC-QE-MS/MS

DOI: 10.3233/JAD-231066

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 727-740, 2024

Authors: Mazzola, Paolo | Zanetti, Mariella | Ferraguzzi, Gaia | Villa, Maria Letizia | Sandrini, Maria Cristina | Fumagalli, Marco | Volpi, Maurizio | Caggiu, Giulia | Monzio Compagnoni, Matteo | Mecocci, Patrizia | Bellelli, Giuseppe

Article Type: Research Article

Abstract: Background: Il Paese Ritrovato is an Italian nursing home founded in 2018, it is based on the Alzheimer village model and admits people with mild-to-moderate dementia. Objective: Describe the impact of the SARS-CoV-2 pandemic on people living at Il Paese Ritrovato through a Comprehensive Geriatric Assessment (CGA) regularly administered prior to and during the pandemic. Methods: We explored the effects of a person-centered approach. We assessed 64 subjects (enrolled and followed between June 2018 and December 2020), who underwent at least 18 months of observation prior to the pandemic. Each subject was evaluated using …a CGA on admission time (T0 ) and at defined time-points: T6 , T12 , T18 . One last CGA evaluation was performed during the SARS-CoV-2 pandemic (TCovid-19 ). Temporal trends during T0 –T18 , and differences between T18 and TCovid-19 were calculated. Results: The mean age was 82 years with a prevalence for females (77.0%) and Alzheimer’s disease diagnosis (60%). Psychiatric and behavioral disorders were the most common conditions (80%). We utilized a nonpharmacological approach aimed at promoting the residents’ overall wellbeing and observed satisfactory performance during the first 18 months. In comparison with the pre-pandemic period, TCovid-19 enlightened +11.7% use of antidepressants and a decline of Mini-Mental State Examination mean values (not statistically significant), while engagement in activities dropped. Conclusions: The pandemic may have disrupted the existing model of care, but at the same time, it confirmed that the Il Paese Ritrovato approach, which encompasses symptoms improvement and multicomponent support, is in fact beneficial. Show more

Keywords: Alzheimer’s disease, Alzheimer’s village, comprehensive geriatric assessment, italy, pandemic, SARS-CoV-2

DOI: 10.3233/JAD-230229

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 741-752, 2024

Authors: Safieh, Mirna | Liraz, Ori | Ovadia, Maayan | Michaelson, Danny

Article Type: Research Article

Abstract: Background: Apolipoprotein E4 (APOE4 ) is the most prevalent genetic risk factor of Alzheimer’s disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR). Objective: To examine the effects of APOE genotype on receptors protein levels and compartmentalization. Methods: Primary mouse neurons were prepared from APOE3 …or APOE4 targeted replacement mice, or APOE -KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors’ colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors. Results: Our results revealed lower receptors’ levels in APOE4 , specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes. Conclusions: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes. Show more

Keywords: ABCA1, Alzheimer’s disease, APOE4 pathology, APOER2, Apolipoprotein E4, insulin receptors, LRP1, lipidation, receptor recycling, VEGFR

DOI: 10.3233/JAD-230514

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 753-775, 2024