Journal of Alzheimer's Disease - Volume 84, issue 3

Authors: Kim, Heeyoung | Jun, Sungmin | Kim, Bum Soo | Kim, In-Joo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The association between dementia and serum adiponectin has been evaluated in many studies; however, conclusions remain mixed. Objective: We investigated the cross-sectional associations of adiponectin with cognitive function and Alzheimer’s disease (AD) biomarkers and whether serum adiponectin levels can predict cognitive outcomes. Methods: This study included 496 participants from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI1) with available serum adiponectin levels at baseline and ≥65 years of age. Subjects were stratified based on sex and apolipoprotein ɛ 4 (APOE4 ) carrier status to determine associations between adiponectin and cognitive function. The linear mixed model was …used to analyze associations between adiponectin level and cognitive outcome in amnestic mild cognitive impairment (aMCI) patients. Results: Serum adiponectin levels were higher in aMCI and AD than in CN subjects among APOE4 non-carrier males (adiponectin in CN, aMCI, and AD: 0.54±0.24, 0.74±0.25, and 0.85±0.25, respectively, p  < 0.001). In this group, serum adiponectin levels were associated with age (p  = 0.001), ADAS13 (p  < 0.001), memory function (p  < 0.001), executive function (p  < 0.001), total tau (p  < 0.001), and phosphorylated tau (p  < 0.001) measures in cerebrospinal fluid (CSF). Higher adiponectin level was not associated with cognitive outcome in aMCI patients in the linear mixed model analysis over 5.3±2.6 years of mean follow-up. Conclusion: Serum adiponectin level was associated with cognitive function and CSF AD biomarkers among APOE4 non-carrier males. However, serum adiponectin level was not associated with longitudinal cognitive function outcome in aMCI. Show more

Keywords: Adiponectin, Alzheimer’s disease, apolipoprotein E4, mild cognitive impairment, tau proteins

DOI: 10.3233/JAD-210722

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1163-1172, 2021

Authors: Rutten, Jeanine J.S. | van Kooten, Janine | van Loon, Anouk M. | van Buul, Laura W. | Joling, Karlijn J. | Smalbrugge, Martin | Hertogh, Cees M.P.M.

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has led to high mortality rates in nursing homes (NHs) in Europe. For adequate risk management and good prognostications, it is essential to identify mortality risk factors. Objective: This study aimed to determine whether previously identified risk factors for 30-day mortality in Dutch NH residents with COVID-19 are unique to COVID-19. Methods: In this cohort study, we included 1,294 NH residents with COVID-19 (cases) and 17,999 NH residents without COVID-19 (controls, from the pre-COVID-19 period). We used descriptive statistics and Cox proportional hazard models to compare mortality rates in residents with and …without COVID-19, categorized by risk factors. Results: Cases had a more than 18 times higher hazard of death within 30 days compared to controls (HR 18, 95%CI: 16–20). For residents with COVID-19, being male, having dementia, and having Parkinson’s disease (PD) were all associated with a higher 30-day mortality (HR 1.8 versus 1.3 versus 1.7). Being male was also associated with a higher mortality (HR 1.7) in the control group, whereas having dementia and PD were not. COVID-19 symptomatology was very similar for residents with and without dementia or PD, except for delirium and malaise which was more frequent in residents with dementia. Conclusion: Dementia and PD were significant additional risk factors for mortality in Dutch NH residents with COVID-19, whereas male gender was not unique to residents with COVID-19. The frailty of PD and dementia in NH residents with COVID-19 are relevant to consider in prognostication, communication, and care planning with residents and their families. Show more

Keywords: Coronavirus, dementia, long-term care facilities, Parkinson’s disease, SARS-CoV-2

DOI: 10.3233/JAD-210319

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1173-1181, 2021

Authors: Oh, Chorong

Article Type: Research Article

Abstract: Background: A person’s gait performance requires the integration of sensorimotor and cognitive systems. Therefore, a person’s gait may be influenced by concurrent cognitive load such as simultaneous talking. Although it has been known that gait performance of people with Alzheimer’s dementia (AD) is compromised when they attempt a dual-task walking task, it is unclear if using a dual-task gait performance during an AD assessment yields higher diagnostic accuracy. Objective: This study was designed to compare the predictive power for AD of dual-task gait performance in an AD assessment to that of single-task gait performance. Methods: Participants …(14 with AD and 15 healthy controls) walked across the GAITRite© Portable Walkway mat under three different cognitive load conditions: no simultaneous cognitive load, walking while counting numbers by ones, and walking while completing category naming. Results: Multiple logistic regression revealed that the gait performance under a dual-task condition (i.e., concurrent counting or category naming) increased the proportion of variance explained by the FAP, SL, and DST, of the incidence of AD. Conclusion: Dual-task walking and talking may be a more effective diagnostic feature than single-task walking in a comprehensive AD diagnostic assessment. Show more

Keywords: Alzheimer’s disease, dementia, diagnosis, dual-task, gait, screening

DOI: 10.3233/JAD-210690

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1183-1192, 2021

Authors: Hofmann, Carolin | Sander, Annika | Wang, Xing Xing | Buerge, Martina | Jungwirth, Bettina | Borgstedt, Laura | Kreuzer, Matthias | Kopp, Claudia | Schorpp, Kenji | Hadian, Kamyar | Wotjak, Carsten T. | Ebert, Tim | Ruitenberg, Maarten | Parsons, Christopher G. | Rammes, Gerhard

Article Type: Research Article

Abstract: Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer’s disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. Objective: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Methods: Oligomerization of Aβ1–42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due …to anesthetics and Aβ1–42 , Aβ1–40 , pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Results: Whereas isoflurane and sevoflurane did not affect Aβ1–42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ1–42 -induced spine density attenuation. In the presence of Aβ1–40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ1–42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. Conclusion: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ1–42 aggregation, LTP, and spine density. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, amyloid plaques, general anesthesia, isoflurane, sevoflurane, synaptic plasticity, xenon

DOI: 10.3233/JAD-201185

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1193-1218, 2021

Authors: Lazarou, Ioulietta | Moraitou, Despina | Papatheodorou, Marianna | Vavouras, Isaak | Lokantidou, Chrysanthi | Agogiatou, Christina | Gialaoutzis, Moses | Nikolopoulos, Spiros | Stavropoulos, Thanos G. | Kompatsiaris, Ioannis | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The Memory Alteration Test (M@T) is a verbal episodic and semantic memory screening test able to detect subjective cognitive decline (SCD) and Mild Cognitive Impairment (MCI). Objective: To adapt M@T, creating a Greek version of the Memory Alteration Test (M@T-GR), and to validate M@T-GR compared to the Mini-Mental State Examination (MMSE), and Subjective Cognitive Decline- Questionnaire (SCD-Q) MyCog and TheirCog. Methods: 232 people over 55 years old participated in the study and they were classified as healthy controls (HC, n  = 65), SCD (n  = 78), or MCI (n  = 89). Results: The ANCOVA showed that …the M@T-GR’s total score was significantly different in HC and SCD (I-J = 2.26, p  = 0.032), HC and MCI (I-J = 6.16, p  < 0.0001), and SCD compared to MCI (I-J = 3.90, p  < 0.0001). In particular, a cut-off score of 46.50 points had an 81%sensitivity and 61%specificity for discriminating HC from SCD (AUC = 0.76, p  < 0.0001), while a cut-off score of 45.50 had a sensitivity of 92%and a specificity of 73%for discriminating MCI (AUC = 0.88, p  < 0.0001), and a cut-off score of 45.50 points had a sensitivity of 63%and a specificity of 73%for discriminating SCD from those with MCI (AUC = 0.69, p  < 0.0021). Exploratory factor analysis indicated that there was one factor explaining 38.46%of the total variance. Internal consistency was adequate (α= 0.75), while convergent validity was found between M@T-GR and MMSE (r  = 0.37, p  < 0.0001) and SCD-Q TheirCog (r  = –0.32, p  < 0.0001). Conclusion: The M@T-GR is a good to fair screening tool with adequate discriminant validity for administration in people with SCD and MCI in Greece. Show more

Keywords: Alzheimer’s disease, diagnosis, memory alteration test, mild cognitive impairment, neuropsychological test, subjective cognitive decline

DOI: 10.3233/JAD-210558

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1219-1232, 2021

Authors: Nakahata, Naoko | Nakamura, Takumi | Kawarabayashi, Takeshi | Seino, Yusuke | Ichii, Sadanobu | Ikeda, Yoshio | Amari, Masakuni | Takatama, Masamitsu | Murashita, Koichi | Ihara, Kazunari | Itoh, Ken | Nakaji, Shigeyuki | Shoji, Mikio

Article Type: Research Article

Abstract: Background: The Iwaki Health Promotion Project (IHPP) is a community-based study for the prevention of lifestyle-related diseases and improvement of quality of life. Objective: Between 2014 and 2017, a total of 4,442 Iwaki town residents from 19 to 93 years of age participated in annual surveys to clarify the natural course of age-related cognitive decline and mild cognitive impairment (MCI). Methods: Modified OLD and SED-11Q questionnaires, MMSE, Logical Memory II, educational history, and APOE genotypes were examined at the first screening. MCI and dementia were diagnosed at the second examination by detailed …neurological examination, CDR, and MRI, and followed for 3 years. Spline regression analyses based on a linear mixed model was adopted for statistical analysis. Results: MMSE scores declined with age from 55 to 64 years. There was also interaction between levels of education and ages. At the second examination, 56 MCI and 5 dementia patients were identified. None of the MCI cases progressed to dementia during the 3 years. During follow-up examinations, 13 cases showed improved MMSE scores (0.95 point/year), 5 remained stable, and 7 deteriorated (–0.83 point/year). Five cases showed improved CDR-SOB scores (–0.28 point/year), 9 remained stable, and 6 deteriorated (0.3 point/year). Conclusion: IHPP revealed that age- and education-related cognitive decline began and advanced from 55 years of age. The prevalence of MCI and dementia was estimated to be 5.9%in the Iwaki town cohort over 60 yeas of age. About 30%of MCI cases showed progression of cognitive decline. Show more

Keywords: Age-related cognitive decline, APOE ɛ4, dementia, education, Iwaki Health Promotion Project, mild cognitive impairment

DOI: 10.3233/JAD-210699

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1233-1245, 2021

Authors: Stargatt, Jennifer | Bhar, Sunil | Petrovich, Tanya | Bhowmik, Jahar | Sykes, David | Burns, Kelly

Article Type: Research Article

Abstract: Background: There is support for the effectiveness of virtual reality (VR) technology in dementia education. However, it is not yet known if VR is a useful tool for improving empathy and understanding of dementia care environments among dementia care workers. Objective: This study compared learning outcomes of VR versus non-VR (control) workshops for dementia care workers of different ages and English-speaking backgrounds. Methods: Dementia care workers enrolled in workshops on dementia care principles. Once participants were enrolled, workshops were assigned at random to deliver non-VR or VR-based education. Participants (N  = 114, 91.8%female, mean age = 46.4; SD  = 13.2; …n  = 60VR condition , 54control condition ) completed self-report measures of empathy towards people living with dementia, understanding of dementia care environments, dementia knowledge, and attitudes towards dementia at pre- and post-workshop. Results: Significant pre-post main effects were observed for empathy, understanding of dementia care environments, and attitudes. Interaction effects were not found; improvements in outcomes were similar between conditions. However, interaction effects were observed for subgroups. Empathy improved significantly more in the VR condition for older participants. Understanding of dementia care environments improved more in the VR condition for younger and non-English-speaking background participants. Conclusion: Using VR may not augment teaching outcomes for all learners. VR may differentially assist leaners of different ages and English-speaking backgrounds. More research is needed to understand for which variables and for whom VR is a useful teaching tool. Show more

Keywords: Dementia, education, environment, health facility environment, nursing care, simulation training, virtual reality

DOI: 10.3233/JAD-210723

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1247-1257, 2021

Authors: Silhan, David | Pashkovska, Olga | Bartos, Ales | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) visual scales of brain atrophy are important for differential diagnosis of dementias in routine clinical practice. Atrophy patterns in early- and late-onset Alzheimer’s disease (AD) can be different according to some studies. Objective: Our goal was to assess brain atrophy patterns in early- and late-onset AD using our recently developed simple MRI visual scales and evaluate their reliability. Methods: We used Hippocampo-horn percentage (Hip-hop) and Parietal Atrophy Score (PAS) to compare mediotemporal and parietal atrophy on brain MRI among 4 groups: 26 patients with early-onset AD, 21 younger cognitively normal persons, …32 patients with late-onset AD, and 36 older cognitively normal persons. Two raters scored all brain MRI to assess reliability of the Hip-hop and PAS. Brain MRIs were obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The patients with early-onset AD had significantly more pronounced mediotemporal and also parietal atrophy bilaterally compared to the controls (both p  < 0.01). The patients with late-onset AD had significantly more pronounced only mediotemporal atrophy bilaterally compared to the controls (p  < 0.000001), but parietal lobes were the same. Intra-rater and inter-rater reliability of both visual scales Hip-hop and PAS were almost perfect in all cases (weighted-kappa value ranged from 0.90 to 0.99). Conclusion: While mediotemporal atrophy detected using Hip-hop is universal across the whole AD age spectrum, parietal atrophy detected using PAS is worth rating only in early-onset AD. Hip-hop and PAS are very reliable MRI visual scales. Show more

Keywords: Early-onset Alzheimer’s disease, hippocampo-horn percentage, late-onset Alzheimer’s disease, mediotemporal atrophy, parietal atrophy score, parietal atrophy, reliability

DOI: 10.3233/JAD-210372

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1259-1266, 2021

Authors: Casanova, Ramon | Gaussoin, Sarah A. | Wallace, Robert | Baker, Laura D. | Chen, Jiu-Chiuan | Manson, JoAnn E. | Henderson, Victor W. | Sachs, Bonnie C. | Justice, Jamie N. | Whitsel, Eric A. | Hayden, Kathleen M. | Rapp, Stephen R.

Article Type: Research Article

Abstract: Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. Objective: We used data from the longitudinal Women’s Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at …least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score < 31. Random Forests was used to rank the predictors of preserved cognitive function. Results: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76–0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels. Conclusion: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors. Show more

Keywords: Cognitive preservation, machine learning, random forests, WHIMS, women

DOI: 10.3233/JAD-210621

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1267-1278, 2021

Authors: Liu, Yi | Li, Zhuoyuan | Jiang, Xueyan | Du, Wenying | Wang, Xiaoqi | Sheng, Can | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Evidence suggests that subjective cognitive decline (SCD) individuals with worry have a higher risk of cognitive decline. However, how SCD-related worry influences the functional brain network is still unknown. Objective: In this study, we aimed to explore the differences in functional brain networks between SCD subjects with and without worry. Methods: A total of 228 participants were enrolled from the Sino Longitudinal Study on Cognitive Decline (SILCODE), including 39 normal control (NC) subjects, 117 SCD subjects with worry, and 72 SCD subjects without worry. All subjects completed neuropsychological assessments, APOE genotyping, and resting-state functional …magnetic resonance imaging (rs-fMRI). Graph theory was applied for functional brain network analysis based on both the whole brain and default mode network (DMN). Parameters including the clustering coefficient, shortest path length, local efficiency, and global efficiency were calculated. Two-sample T -tests and chi-square tests were used to analyze differences between two groups. In addition, a false discovery rate-corrected post hoc test was applied. Results: Our analysis showed that compared to the SCD without worry group, SCD with worry group had significantly increased functional connectivity and shortest path length (p  = 0.002) and a decreased clustering coefficient (p  = 0.013), global efficiency (p  = 0.001), and local efficiency (p  < 0.001). The above results appeared in both the whole brain and DMN. Conclusion: There were significant differences in functional brain networks between SCD individuals with and without worry. We speculated that worry might result in alterations of the functional brain network for SCD individuals and then result in a higher risk of cognitive decline. Show more

Keywords: Functional connectivity, functional MRI, graph theory, subjective cognitive decline, worry

DOI: 10.3233/JAD-215156

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1279-1289, 2021

Authors: Aranđelović, Jovana | Santrač, Anja | Batinić, Bojan | Todorović, Lidija | Ahmed Khan, Md Zubair | Rashid, Farjana | Poe, Michael M. | Obradović, Aleksandar | Cook, James M. | Savić, Miroslav M.

Article Type: Research Article

Abstract: Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. …Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising. Show more

Keywords: 5xFAD, α5 GABAA receptors, Alzheimer’s disease, emotionality, motor function, motivation, negative allosteric modulation, positive allosteric modulation

DOI: 10.3233/JAD-215079

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1291-1302, 2021

Authors: Imahori, Yume | Vetrano, Davide L. | Ljungman, Petter | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Markers of altered cardiac function might predict cognitive decline and dementia. Objective: This systematic review aims to review the literature that examines the associations of various electrocardiogram (ECG) markers with cognitive decline and dementia in middle-aged and elderly populations. Methods: We searched PubMed, Embase, and Web of Science through 1 July 2020 for literature and conducted a systematic literature review. We included studies examining the associations of ECG markers (e.g., left ventricular hypertrophy [LVH], spatial QRS-T angle, and QT prolongation) with cognitive function and dementia in adult populations regardless of study setting and design, but …excluded studies examining atrial fibrillation and heart rate variability. Results: Fourteen community-based cross-sectional and longitudinal studies were identified. ECG markers were investigated in association with dementia in four prospective studies, and with cognitive decline in ten prospective studies. ECG-assessed LVH was associated with dementia in one study while five heterogeneous prospective studies yielded inconsistent associations with cognitive decline. Regarding ventricular repolarization markers, spatial QRS-T angle was associated with cognitive decline in one study while another study found no association between QT prolongation and cognitive decline. High resting heart rate was associated with both dementia and cognitive decline in one study but not associated with dementia in another study. P-wave abnormality was significantly associated with incident dementia and cognitive decline in one prospective study. Conclusion: Some ECG markers were associated with incident dementia and cognitive decline. However, limited number of heterogeneous studies did not allow us to make firm conclusions. Further studies are needed. Show more

Keywords: Cognitive decline, dementia, electrocardiogram, epidemiology, systematic literature review

DOI: 10.3233/JAD-210606

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1303-1322, 2021

Authors: Liu, Hongliang | Lutz, Michael | Luo, Sheng | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer’s disease (AD). Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the …ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, SE = 0.061, p  = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, SE = 0.037, p  = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PiB-PET and AV45-PET), but decreased hippocampus and entorhinal cortex volumes (p  < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ42 (beta = 0.056, SE = 0.026, p  = 0.036). Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI. Show more

Keywords: Alzheimer’s disease, longitudinal analysis, mild cognitive impairment, neuroimaging, polygenic risk score, survival analysis

DOI: 10.3233/JAD-210700

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1323-1335, 2021

Authors: Jung, Youjin | Viviano, Raymond P. | van Rooden, Sanneke | van der Grond, Jeroen | Rombouts, Serge A.R.B. | Damoiseaux, Jessica S.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) show a robust relationship with arterial pressure as well as objective and subjective cognitive functioning. In addition, APO E ɛ4 carriership may influence how arterial pressure affects cognitive functioning. Objective: To determine the role of region-specific WMH burden and APOE ɛ4 carriership on the relationship between mean arterial pressure (MAP) and cognitive function as well as subjective cognitive decline (SCD). Methods: The sample consisted of 87 cognitively unimpaired middle-aged to older adults aged 50–85. We measured WMH volume for the whole brain, anterior thalamic radiation (ATR), forceps minor, and superior …longitudinal fasciculus (SLF). We examined whether WMH burden mediated the relationship between MAP and cognition (i.e., TMT-A score for processing speed; Stroop performance for executive function) as well as SCD (i.e., Frequency of Forgetting (FoF)), and whether APOE ɛ4 carriership moderated that mediation. Results: WMH burden within SLF mediated the effect of MAP on Stroop performance. Both whole brain and ATR WMH burden mediated the effect of MAP on FoF score. In the MAP–WMH–Stroop relationship, the mediation effect of SLF WMH and the effect of MAP on SLF WMH were significant only in APOE ɛ4 carriers. In the MAP–WMH–FoF relationship, the effect of MAP on whole brain WMH burden was significant only in ɛ4 carriers. Conclusion: WMH burden and APOE genotype explain the link between blood pressure and cognitive function and may enable a more accurate assessment of the effect of high blood pressure on cognitive decline and risk for dementia. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E4, blood pressure, dementia, executive function, subjective cognitive decline, white matter hyperintensities

DOI: 10.3233/JAD-210695

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1337-1350, 2021

Authors: Hu, Di | Liu, Chuning | Xia, Kai | Abramowitz, Amy | Wu, Guorong | and Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Background: With the rapid development of neurobiology and neuroimaging technologies, mounting evidence shows that Alzheimer’s disease (AD) is caused by the build-up of two abnormal proteins, amyloid-β plaques (A) and neurofibrillary tangles (T). Over time, these AD-related neuropathological burdens begin to spread throughout the brain, which results in the characteristic progression of symptoms in AD. Objective: Although tremendous efforts have been made to link biological indicators to the progression of AD, limited attention has been paid to investigate the multi-factorial role of socioeconomic status (SES) in the prevalence or incidence of AD. There is high demand to explore …the synergetic effect of sex and SES factors in moderating the neurodegeneration process caused by the accumulation of A and T biomarkers. Methods: We carry out a meta-data analysis on the longitudinal neuroimaging data, clinical outcomes, genotypes, and demographic data in Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu ). Results: Our major findings include 1) education and occupation show resilience effects at the angular gyrus, superior parietal lobule, lateral occipital-temporal sulcus, and posterior transverse collateral sulcus where we found significant slowdown of neurodegeneration due to higher education level or more advanced occupation rank; 2) A and T biomarkers manifest different spatial patterns of brain resilience; 3) BDNF (brain-derived neurotrophic factor) single nucleotide polymorphism (SNP) rs10835211 shows strong association to the identified resilience effect; 4) the identified resilience effect is associated with the clinical manifestation in memory, learning, and organization performance. Conclusion: Several brain regions manifest resilience from SES to A and T biomarkers. BDNF SNPs have a potential association with the resilience effect from SES. In addition, cognitive measures of learning and memory demonstrate the resilience effect. Show more

Keywords: Alzheimer’s disease, cognitive reserve, computational proxy, neurodegeneration

DOI: 10.3233/JAD-215160

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1351-1362, 2021

Authors: Lindgren, Emma | Sörenson, Josephine | Wattmo, Carina | Kåreholt, Ingemar | Nägga, Katarina

Article Type: Research Article

Abstract: Background: With a growing elderly population worldwide, the prevalence of dementia is rapidly increasing. Studies from high income countries have shown that belonging to a minority ethnic group increases the risk of health disadvantages. Objective: The aim of the present registry-based study was to identify potential differences in diagnostics, treatment, and care of individuals with dementia focusing on foreign-born in Sweden and the impact of country level socioeconomic position (SEP). Methods: The study was based on a large dataset from the Swedish Dementia Registry (SveDem) and the Swedish Tax Agency’s population registry. Data on demographic variables, …cognitive tests, clinical assessments, medication, diagnosis, and interventions initiated at diagnosis were collected. Country level SEP was determined by country of birth as classified by World Bank Country and Lending groups. Results: Of 57,982 patients with dementia registered in SveDem, 7,171 (12.4%) were foreign-born. The foreign-born were significantly younger at diagnosis (p  < 0.001), had a lower MMSE score (p  < 0.001), lower odds of receiving a specific dementia diagnosis (p  < 0.001), lower use of acetylcholinesterase inhibitors (p  < 0.001), and overall a higher use of neuroleptics compared with the Swedish-born group. The lower SEP, the greater differences to Swedish-born were seen in many of the examined variables. Conclusion: There were significant differences in dementia diagnostics, treatment, and care between foreign-born and Swedish-born, a lower SEP indicating greater differences. Further research should focus on various socioeconomic aspects and health care outcomes for a more profound analysis of equity in dementia care. Show more

Keywords: Dementia care, differences, immigrant, minority ethnic group, qualitative registry, socioeconomic position

DOI: 10.3233/JAD-210734

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1363-1371, 2021

Authors: Newby, Danielle | Winchester, Laura | Sproviero, William | Fernandes, Marco | Wang, Dai | Kormilitzin, Andrey | Launer, Lenore J. | Nevado-Holgado, Alejo J.

Article Type: Research Article

Abstract: Background: Mid-life hypertension is an established risk factor for cognitive impairment and dementia and related to greater brain atrophy and poorer cognitive performance. Previous studies often have small sample sizes from older populations that lack utilizing multiple measures to define hypertension such as blood pressure, self-report information, and medication use; furthermore, the impact of the duration of hypertension is less extensively studied. Objective: To investigate the relationship between hypertension defined using multiple measures and length of hypertension with brain measure and cognition. Methods: Using participants from the UK Biobank MRI visit with blood pressure measurements (n … = 31,513), we examined the cross-sectional relationships between hypertension and duration of hypertension with brain volumes and cognitive tests using generalized linear models adjusted for confounding. Results: Compared with normotensives, hypertensive participants had smaller brain volumes, larger white matter hyperintensities (WMH), and poorer performance on cognitive tests. For total brain, total grey, and hippocampal volumes, those with greatest duration of hypertension had the smallest brain volumes and the largest WMH, ventricular cerebrospinal fluid volumes. For other subcortical and white matter microstructural regions, there was no clear relationship. There were no significant associations between duration of hypertension and cognitive tests. Conclusion: Our results show hypertension is associated with poorer brain and cognitive health however, the impact of duration since diagnosis warrants further investigation. This work adds further insights by using multiple measures defining hypertension and analysis on duration of hypertension which is a substantial advance on prior analyses—particularly those in UK Biobank which present otherwise similar analyses on smaller subsets. Show more

Keywords: Cardiovascular, cognitive decline, dementia, epidemiology, hypertension

DOI: 10.3233/JAD-210512

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1373-1389, 2021