Journal of Alzheimer's Disease - Volume 89, issue 1

Authors: Clark, Kaylyn | Leung, Yuk Yee | Lee, Wan-Ping | Voight, Benjamin | Wang, Li-San

Article Type: Review Article

Abstract: The success of genome-wide association studies (GWAS) completed in the last 15 years has reinforced a key fact: polygenic architecture makes a substantial contribution to variation of susceptibility to complex disease, including Alzheimer’s disease. One straight-forward way to capture this architecture and predict which individuals in a population are most at risk is to calculate a polygenic risk score (PRS). This score aggregates the risk conferred across multiple genetic variants, ultimately representing an individual’s predicted genetic susceptibility for a disease. PRS have received increasing attention after having been successfully used in complex traits. This has brought with it renewed attention …on new methods which improve the accuracy of risk prediction. While these applications are initially informative, their utility is far from equitable: the majority of PRS models use samples heavily if not entirely of individuals of European descent. This basic approach opens concerns of health equity if applied inaccurately to other population groups, or health disparity if we fail to use them at all. In this review we will examine the methods of calculating PRS and some of their previous uses in disease prediction. We also advocate for, with supporting scientific evidence, inclusion of data from diverse populations in these existing and future studies of population risk via PRS. Show more

Keywords: Alzheimer’s disease, diversity, genome-wide association studies, polygenic risk score, statistical genetics

DOI: 10.3233/JAD-220025

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 1-12, 2022

Authors: Leitão, Mariana | Saúde, Alexandra | Bouça-Machado, Raquel | Ferreira, Joaquim J.

Article Type: Systematic Review

Abstract: Background: In addition to cognitive changes, motor impairments have been observed in patients with dementia and are present early in the disease, even at the preclinical stage. Although it is difficult to assess motor function in this population, it is critical for monitoring disease progression and determining the efficacy of therapeutic interventions. However, the best measurement tools for assessing motor function in dementia patients have yet to be determined. Objective: We aimed to summarize and critically evaluate the measurement tools used to assess motor function indementia. Methods: A systematic review was conducted using the databases CENTRAL, …MEDLINE, Embase, and PEDro from their inception to June 2021 to identify all experimental studies conducted in patients with dementia and that included an assessment of motor function. Two reviewers independently screened citations, extracted data, and assessed clinimetric properties. Results: We included 200 studies that assess motor function in dementia patients. Motor function was assessed using a total of 84 different measurement tools. Only nine (12%) were used in over ten studies. The Timed-Up-and-Go test, 6MWT, Berg Balance Scale, and the Short Physical Performance Battery are all suggested. Conclusion: Currently, a wide variety of measurement instruments are used to assess motor performance in people with dementia, most instruments were not designed for this population and have not been validated for this use. We propose the development of an assessment protocol tailored to the different disease stages. We also recommend that future research continues to develop technological devices that can assist with this task. Show more

Keywords: Alzheimer’s disease, dementia, measurement instruments, motor assessment, outcome measures, systematic review

DOI: 10.3233/JAD-220151

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 13-24, 2022

Authors: Sandhu, Gurveen Kaur | Zailan, Fatin Zahra | Vipin, Ashwati | Ann, Soo See | Kumar, Dilip | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Short Communication

Abstract: Oligomeric amyloid-β (OAβ), an upstream driver of Alzheimer’s disease (AD) neuropathology, correlates with poor cognitive performance and brain volume reduction. Its effect on cognitive performance measured by the language neutral Visual Cognitive Assessment Test (VCAT) remains to be evaluated. We studied the correlation of plasma OAβ with VCAT scores and grey matter volume (GMV) in a Southeast Asian cohort with mild cognitive impairment. Higher plasma OAβ significantly correlated with lower; cognitive scores (VCAT, Mini-Mental State Examination) and GMV/intracranial volume ratio. Such findings reveal the clinical utility of plasma OAβ as a promising biomarker and support validation through longitudinal studies.

Keywords: Alzheimer’s disease, cognitive assessment, cross sectional study, grey matter volume, mild cognitive impairment, Mini-Mental State Examination, multimer detection system, oligomeric amyloid-beta, plasma biomarkers, Visual Cognitive Assessment Test

DOI: 10.3233/JAD-220484

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 25-29, 2022

Authors: Yang, Yulin | Swinnerton, Kaitlin | Portacolone, Elena | Allen, Isabel Elaine | Torres, Jacqueline M. | Duchowny, Kate

Article Type: Short Communication

Abstract: We compared the prevalence of reporting difficulty with basic and instrumental activities of daily living without help received for persons with cognitive impairment living alone versus those living with others. We used data on 13,782 community-dwelling participants aged 55+ with cognitive impairment in the Health and Retirement Study (2000–2016). Models were stratified by gender and race/ethnicity. Among cognitively impaired older adults, those living alone were more likely to report difficulty without help received than those living with others. Results were similar by gender and race/ethnicity. Providers and policymakers might focus their efforts on ensuring the adequate provision of home and …community-based services for older adults living alone with cognitive impairment. Show more

Keywords: Aging in place, cognitive impairment, disability, living arrangement, racial/ethnic disparity

DOI: 10.3233/JAD-220172

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 31-37, 2022

Authors: Vlegels, Naomi | Ossenkoppele, Rik | van der Flier, Wiesje M. | Koek, Huiberdina L. | Reijmer, Yael D. | Wisse, Laura EM | Biessels, Geert Jan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer’s Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, …T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy. Show more

Keywords: Alzheimer’s disease, amyloid-β, diffusion tensor imaging, medial temporal lobe, neurodegeneration, PET, white matter integrity

DOI: 10.3233/JAD-220024

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 39-49, 2022

Authors: Carnemolla, Sarah E. | Kumfor, Fiona | Liang, Cheng Tao | Foxe, David | Ahmed, Rebekah M. | Piguet, Olivier

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. Objective: To measure OB volume in FTD and AD patients longitudinally using MRI. Methods: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n  = 55), semantic dementia (n  = 34), progressive non-fluent aphasia (n  = 30), AD (n  = 50), and …healthy age-matched controls (n  = 55) at their first visit to a dementia research clinic (‘baseline’). Imaging data in patients 12-months later were analyzed where available (n  = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions (‘olfactory network’) were obtained via surface-based morphometry. Results: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10–25% volume reduction) in all dementia groups with disease progression. Conclusion: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, magnetic resonance imaging, neurodegeneration, olfaction, olfactory bulb

DOI: 10.3233/JAD-220080

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 51-66, 2022

Authors: Xue, Feng | Gao, Luyan | Chen, TingTing | Chen, Hongyuan | Zhang, Haihua | Wang, Tao | Han, Zhifa | Gao, Shan | Wang, Longcai | Hu, Yang | Tang, Jiangwei | Huang, Lei | Liu, Guiyou | Zhang, Yan

Article Type: Research Article

Abstract: Background: Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson’s disease (PD) risk, and INPP5D was an Alzheimer’s disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. Objective: We aim to investigate the roles of rs117896735 in AD. Methods: First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the …expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F . Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. Results: We found that 1) rs117896735 A allele was associated with the increased risk of AD with OR = 1.15, 95% CI 1.005–1.315, p  = 0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. Conclusion: Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD. Show more

Keywords: Alzheimer’s disease, eQTLs, genome-wide association study, INPP5F, Parkinson’s disease

DOI: 10.3233/JAD-220086

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 67-77, 2022

Authors: Zhou, Kai | Wu, Peng

Article Type: Research Article

Abstract: Background: The question that whether the presence of osteoarthritis (OA) can modify the effects of apolipoprotein E4 (APOE4 ) genotype on longitudinal change in cognitive performance among non-demented older people remains unclear. Objective: To examine whether the association of APOE4 genotype with change in verbal episodic memory over time is modified by the presence of OA among non-demented older people. Methods: Longitudinal data from 1,400 non-demented older people were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. The sample included 466 healthy individuals and 934 mild cognitive impairment. The effects of the OA×APOE4 genotype …interaction term on longitudinal change in cognitive performance were examined using linear mixed-effects regression models. Global cognition was assessed by the Mini-Mental State Examination score and Clinical Dementia Rating–Sum of Boxes. Verbal episodic memory was evaluated by the Rey Auditory Verbal Learning Test (RAVLT) immediate recall and delayed recall score. Results: We found that OA interacted with APOE4 genotype to influence longitudinal change in verbal episodic memory (as assessed by RAVLT immediate recall score) but not global cognition. Specifically, the OA–/APOE4+ group had a steeper decline in RAVLT immediate recall score compared with the OA+/APOE4+ group. However, there was no difference in RAVLT immediate recall score between OA–/APOE4 –and OA+/APOE4 –individuals. Conclusion: Our study suggested that the association of APOE4 genotype with change in RAVLT immediate recall score over time is modified by the presence of OA at earliest stages of the disease. Show more

Keywords: APOE , Alzheimer’ disease, cognitive decline, mild cognitive impairment, osteoarthritis

DOI: 10.3233/JAD-220138

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 79-86, 2022

Authors: Aschwanden, Damaris | Sutin, Angelina R. | Ledermann, Thomas | Luchetti, Martina | Stephan, Yannick | Sesker, Amanda A. | Zhu, Xianghe | Terracciano, Antonio

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is related to personality functioning and risk of subsequent objective cognitive impairment. Objective: The aim of this study was to examine whether lower neuroticism and higher conscientiousness—resilient personality traits—protect against conversion from SCD to objective cognitive impairment in two longitudinal community-based cohorts. Methods: Data from the Health and Retirement Study (N = 1,741, Mean age = 68.64 years, Follow-up mean = 7.34 years) and the National Health and Aging Trends Survey (N = 258, Mean age = 79.34 years, Follow-up mean = 4.31 years) were analyzed using Cox regression analysis, controlling for sociodemographic covariates, symptoms of anxiety and depression, and apolipoprotein ɛ4. …Results: The pooled results showed that lower neuroticism and higher conscientiousness were associated with decreased risk of conversion from SCD to objective cognitive impairment. Conclusion: Among individuals with SCD, those with a resilient personality may have more cognitive and psychological reserve to maintain cognitive functioning and delay conversion to objective cognitive impairment. The findings further contribute to a better understanding of personality along the cognitive continuum: The observed effect sizes were smaller than those reported in cognitively normal individuals but larger than in individuals with mild cognitive impairment. Personality could provide useful information to identify individuals with SCD who may develop objective cognitive impairment—namely those who hold a vulnerable personality (higher neuroticism, lower conscientiousness). Show more

Keywords: Conscientiousness, neuroticism, progression to cognitive impairment, resilient personality, subjective cognitive decline

DOI: 10.3233/JAD-220319

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 87-105, 2022

Authors: Man, Viet Hoang | Lin, Da | He, Xibing | Gao, Jie | Wang, Junmei

Article Type: Research Article

Abstract: Background: Tau assembly produces soluble oligomers and insoluble neurofibrillary tangles, which are neurotoxic to the brain and associated with Alzheimer’s and Parkinson’s diseases. Therefore, preventing tau aggregation is a promising therapy for those neurodegenerative disorders. Objective: The aim of this study was to develop a joint computational/cell-based oligomerization protocol for screening inhibitors of tau assembly. Methods: Virtual oligomerization inhibition (VOI) experiment using molecular dynamics simulation was performed to screen potential oligomerization inhibitors of PHF6 hexapeptide. Tau seeding assay, which is directly related to the outcome of therapeutic intervention, was carried out to confirm a ligand’s ability …in inhibiting tau assembly formation. Results: Our protocol was tested on two known compounds, EGCG and Blarcamesine. EGCG inhibited both the aggregation of PHF6 peptide in VOI and tau assembly in tau seeding assay, while Blarcamesine was not a good inhibitor at the two tasks. We also pointed out that good binding affinity to tau aggregates is needed, but not sufficient for a ligand to become a good inhibitor of tau oligomerization. Conclusion: VOI goes beyond traditional computational inhibitor screening of amyloid aggregation by directly examining the inhibitory ability of a ligand to tau oligomerization. Comparing with the traditional biochemical assays, tau seeding activities in cells is a better indicator for the outcome of a therapeutic intervention. Our hybrid protocol has been successfully validated. It can effectively and efficiently identify the inhibitors of amyloid oligomerization/aggregation processes, thus, facilitate to the drug development of tau-related neurodegenerative diseases. Show more

Keywords: Aggregation, EGCG, MD simulation, oligomerization, PHF6, tau protein

DOI: 10.3233/JAD-220450

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 107-119, 2022

Authors: Liu, Qianqian | Liu, Hui | Zhang, Sizhe | Yang, Qijie | Shen, Lu | Jiao, Bin

Article Type: Research Article

Abstract: Background: Several studies have shown increased levels of cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) in patients with Alzheimer’s disease (AD). However, results have been inconsistent thus far. Objective: We conducted meta-analyses summarizing the associations of CSF SNAP-25 levels with AD to assess the utility of SNAP-25 as a novel biomarker for AD. Methods: We conducted a meta-analysis of differences in CSF SNAP-25 levels in patients with AD or mild cognitive impairment (MCI) and in cognitively healthy controls (HC). We calculated pooled correlation coefficients comparing SNAP-25 levels and total tau (T-tau) or hyperphosphorylated tau (P-tau) in …CSF. Results: Eight studies enrolling 1,162 individuals (423 AD, 275 MCI, 464 HC) were included for quantitative analysis. Patients with AD (ratio of means [RoM] = 1.50, 95% confidence interval [CI]: 1.30,1.74) and MCI (RoM = 1.45, 95% CI: 1.12,1.87) had increased levels of CSF SNAP-25 as compared to HC. The difference in CSF SNAP-25 levels when comparing AD and MCI (RoM = 1.05, 95% CI: 0.96,1.14) was not statistically significant but showed a trend toward significance. Statistically significant correlations were found when comparing CSF SNAP-25 with CSF T-tau (Spearman correlation coefficient, ρ =0.78; ρ =0.66; ρ =0.69, respectively) and P-tau (ρ =0.77; ρ =0.70; ρ =0.62, respectively) levels in patients with AD, MCI, and HC. Conclusion: Increased CSF SNAP-25 levels differentiated patients with AD or MCI from controls, suggesting the utility of this biomarker in the early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, CSF biomarkers, meta-analysis, mild cognitive impairment, synaptosomal-associated protein 25

DOI: 10.3233/JAD-215696

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 121-132, 2022

Authors: Pezzoli, Stefania | Manca, Riccardo | Cagnin, Annachiara | Venneri, Annalena

Article Type: Research Article

Abstract: Background: Hallucinations in Alzheimer’s disease (AD) have been linked to more severe cognitive and functional decline. However, research on visual hallucinations (VH), the most common type of hallucinations in AD, is limited. Objective: To investigate the cognitive and cerebral macrostructural and metabolic features associated with VH in AD. Methods: Twenty-four AD patients with VH, 24 with no VH (NVH), and 24 cognitively normal (CN) matched controls were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Differences in regional gray matter (GM) volumes and cognitive performance were investigated with whole brain voxel-based morphometry analyses of MRI …structural brain scans, and analyses of neuropsychological tests. Glucose metabolic changes were explored in a sub-sample of patients who had FDG-PET scans available. Results: More severe visuoconstructive and attentional deficits were found in AD VH compared with NVH. GM atrophy and hypometabolism were detected in occipital and temporal areas in VH patients in comparison with CN. On the other hand, NVH patients had atrophy and hypometabolism mainly in temporal areas. No differences in GM volume and glucose metabolism were found in the direct comparison between AD VH and NVH. Conclusion: In addition to the pattern of brain abnormalities typical of AD, occipital alterations were observed in patients with VH compared with CN. More severe visuoconstructive and attentional deficits were found in AD VH when directly compared with NVH, and might contribute to the emergence of VH in AD. Show more

Keywords: Alzheimer’s disease, attention, FDG-PET, MRI, neuropsychology, visual hallucinations, visuoconstruction

DOI: 10.3233/JAD-215107

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 133-149, 2022

Authors: Wezeman, Sandra L. | Uleman, Jeroen F. | Scarmeas, Nikolaos | Kosmidis, Mary H. | Dardiotis, Efthimios | Peeters, G.M.E.E. (Geeske) | Olde Rikkert, Marcel G.M.

Article Type: Research Article

Abstract: Background: Recent global meta-analyses show that 40% of dementia cases can be attributed to twelve modifiable risk factors. Objective: To investigate how health promotion strategies may differ in specific populations, this study estimated population attributable fractions (PAFs) of these risk factors for dementia in cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) in United States and Greek cohorts. Methods: We re-analyzed data from the National Alzheimer’s Coordinating Centre (NACC, n  = 16,147, mean age 75.2±6.9 years, 59.0% female) and the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD, n  = 1,141, mean age 72.9±5.0 years, …58.0% female). PAFs for the total samples and CN and MCI subgroups were calculated based on hazard ratios for the risk of dementia and risk factor prevalence in NACC (9 risk factors) and HELIAD (10 risk factors). Results: In NACC, 2,630 participants developed MCI (25.1%) and 3,333 developed dementia (20.7%) during a mean follow-up of 4.9±3.5 years. Weighted overall PAFs were 19.4% in the total sample, 15.9% in the CN subgroup, and 3.3% in the MCI subgroup. In HELIAD, 131 participants developed MCI (11.2%) and 68 developed dementia (5.9%) during an average follow-up of 3.1±0.86 years. Weighted overall PAFs were 65.5% in the total sample, 65.8% in the CN subgroup and 64.6% in the MCI subgroup. Conclusion: Translation of global meta-analysis data on modifiable risk factors should be carefully carried out per population. The PAFs of risk factors differ substantially across populations, directing health policy making to tailored risk factor modification plans. Show more

Keywords: Dementia, mild cognitive impairment, prevention, risk factors

DOI: 10.3233/JAD-215386

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 151-162, 2022

Authors: Fan, Yaohua | Liu, Wen | Chen, Si | Li, Mengzhu | Zhao, Lijun | Wu, Chunxiao | Liu, Helu | Zhu, Meiling

Article Type: Research Article

Abstract: Background: The relationship between serum folate status and cognitive functions is still controversial. Objective: To evaluate the association between serum tetrahydrofolate and cognitive functions. Methods: A total of 3,132 participants (60–80 years old) from the 2011–2014 NHANES were included in this cross-sectional study. The primary outcome measure was cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), …and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions. Results: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p  < 0.05). In GAM, the inflection points were 1.1, 2.8, and 2.8 nmol/L tetrahydrofolate, determined by a two-piece wise linear regression model of AF, DSST, and global cognitive score, respectively. Also, in GAM, there were no non-linear relationship between serum tetrahydrofolate and low cognitive functions, as determined by CERAD-WL or CERAD-DR. The results of subgroup analyses found that serum tetrahydrofolate levels and reduced cognitive functions as determined by AF had significant interactions for age and body mass index. The association between high serum tetrahydrofolate level and reduced cognitive functions as determined using DSST, CERAD-WL, CERAD-DR, or global cognitive score had no interaction with the associations between cognition and gender, or age, or so on. Conclusion: High serum tetrahydrofolate level is associated with significantly reduced cognitive function. Show more

Keywords: Analysis of non-linear relationship, cognitive functions, dementia, multiple logistic regression, NHANES, serum tetrahydrofolate

DOI: 10.3233/JAD-220058

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 163-179, 2022

Authors: Miotto, Eliane Correa | Brucki, Sonia Maria Dozzi | Cerqueira, Carlos T. | Bazán, Paulo R. | Silva, Geise Aline de Almeida | Martin, Maria da Graça M. | da Silveira, Paula Squarzoni | Faria, Daniele de Paula | Coutinho, Artur Martins | Buchpiguel, Carlos Alberto | Busatto Filho, Geraldo | Nitrini, Ricardo

Article Type: Research Article

Abstract: Background: Previous studies of hippocampal function and volume related to episodic memory deficits in patients with amnestic mild cognitive impairment (aMCI) have produced mixed results including increased or decreased activity and volume. However, most of them have not included biomarkers, such as amyloid-β (Aβ) deposition which is the hallmark for early identification of the Alzheimer’s disease continuum. Objective: We investigated the role of Aβ deposition, functional hippocampal activity and structural volume in aMCI patients and healthy elderly controls (HC) using a new functional MRI (fMRI) ecological episodic memory task. Methods: Forty-six older adults were included, among …them Aβ PET PIB positive (PIB+) aMCI (N = 17), Aβ PET PIB negative (PIB–) aMCI (N = 15), and HC (N = 14). Hippocampal volume and function were analyzed using Freesurfer v6.0 and FSL for news headlines episodic memory fMRI task, and logistic regression for group classification in conjunction with episodic memory task and traditional neuropsychological tests. Results: The aMCI PIB+ and PIB–patients showed significantly worse performance in relation to HC in most traditional neuropsychological tests and within group difference only on story recall and the ecological episodic memory fMRI task delayed recall. The classification model reached a significant accuracy (78%) and the classification pattern characterizing the PIB+ included decreased left hippocampal function and volume, increased right hippocampal function and volume, and worse episodic memory performance differing from PIB–which showed increased left hippocampus volume. Conclusion: The main findings showed differential neural correlates, hippocampal volume and function during episodic memory in aMCI patients with the presence of Aβ deposition. Show more

Keywords: Amyloid-beta, episodic memory, functional magnetic resonance, hippocampal volume, mild cognitive impairment

DOI: 10.3233/JAD-220100

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 181-192, 2022

Authors: Timsina, Jigyasha | Gomez-Fonseca, Duber | Wang, Lihua | Do, Anh | Western, Dan | Alvarez, Ignacio | Aguilar, Miquel | Pastor, Pau | Henson, Rachel L. | Herries, Elizabeth | Xiong, Chengjie | Schindler, Suzanne E. | Fagan, Anne M. | Bateman, Randall J. | Farlow, Martin | Morris, John C. | Perrin, Richard J. | Moulder, Krista | Hassenstab, Jason | Vöglein, Jonathan | Chhatwal, Jasmeer | Mori, Hiroshi | Sung, Yun Ju | Cruchaga, Carlos

Article Type: Research Article

Abstract: Background: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. Objective: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer’s disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. Methods: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine …measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson’s correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. Results: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r  > 0.9). sTREM2 had a fair correlation (r  > 0.6), whereas SNAP-25 showed weak correlation (r  = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. Conclusion: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. Show more

Keywords: Alzheimer’s disease, assays, cerebrospinal fluid biomarkers, correlation, SOMAscan

DOI: 10.3233/JAD-220399

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 193-207, 2022

Authors: Drenthen, Gerhard S. | Backes, Walter H. | Freeze, Whitney M. | Jacobs, Heidi I.L. | Verheggen, Inge C.M. | van Boxtel, Martin P.J. | Hoff, Erik I. | Verhey, Frans R. | Jansen, Jacobus F.A.

Article Type: Research Article

Abstract: Background: Though mediotemporal lobe volume changes are well-known features of Alzheimer’s disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN). Objective: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club. Methods: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n  = 37; mild cognitive impairment, n  = 41; …Alzheimer-type dementia, n  = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression. Results: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume. Conclusion: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy. Show more

Keywords: Cognition, cortex, hub, magnetic resonance imaging, memory, network analysis

DOI: 10.3233/JAD-220175

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 209-217, 2022

Authors: Song, Cheng | Li, Feng | Wang, Liu-Yu | Shi, Yu-Quan | Shen, Zhen-Hai

Article Type: Research Article

Abstract: Background: National and international experts have been attempting to find diagnostic tools for the early identification of symptoms to facilitate early identification and intervention of the disease. Objective: Detection of urine Alzheimer-associated neuronal thread protein (AD7c-NTP) and serum 25-hydroxyvitamin D (25(OH)D) in the diagnosis of Alzheimer’s disease (AD). Methods: Subjects aged >50 years who underwent a physical examination at the Taihu Sanatorium of Jiangsu Province, had no clinical evidence of AD-related issues, and had normal Mini-Mental State Exam and Montreal Cognitive Assessment scores were enrolled in the present study. There were 35 males and 15 females, …who were aged 51–91 years. Urine AD7c-NTP levels and serum 25(OH)D concentrations were measured. Results: The Pearson correlation analysis revealed that the urine AD7c-NTP levels in these subjects were negatively correlated with the serum 25(OH)D concentrations (r  = –0.460, p  < 0.001). Conclusion: Combined with previous studies, it was considered that cognitive function might be the only link for the correlation between AD7c-NTP and 25(OH)D. This finding might provide a starting point to investigate the potential value of the interaction between urine AD7c-NTP and serum 25(OH)D in chronic diseases. Further large-scale studies are needed to validate the results of the present study. Show more

Keywords: AD7c-NTP, Alzheimer’s disease, correlation analysis, serum 25-hydroxyvitamin D, urine Alzheimer-associated neuronal thread protein

DOI: 10.3233/JAD-220165

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 219-222, 2022

Authors: Baradaran, Hediyeh | Peloso, Gina M. | Polak, Joseph F. | Killiany, Ronald J. | Ghosh, Saptaparni | DeCarli, Charles S. | Thibault, Emma G. | Sperling, Reisa A. | Johnson, Keith A. | Beiser, Alexa | Romero, Jose R. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. Objective: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11 C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. Methods: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on …average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer’s disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. Results: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p  = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p  = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. Conclusion: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology. Show more

Keywords: Alzheimer’s disease, amyloid, carotid atherosclerosis, carotid ultrasound

DOI: 10.3233/JAD-215679

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 223-232, 2022

Authors: Kamath, Vidyulata | Senjem, Matthew L. | Spychalla, Anthony J. | Chen, Honglei | Palta, Priya | Mosley, Thomas H. | Windham, B. Gwen | Griswold, Michael | Knopman, David S. | Gottesman, Rebecca F. | Jack Jr, Clifford R. | Sharrett, A. Richey | Schneider, Andrea L.C.

Article Type: Research Article

Abstract: Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor …identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume (p  < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD. Show more

Keywords: Alzheimer’s disease, chemosensory, hyposmia, olfaction, smell

DOI: 10.3233/JAD-220228

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 233-245, 2022

Authors: Macpherson, Helen | Brownell, Sarah | Harris, Elizabeth | Duckham, Rachel L. | O’Connell, Stella | Meyer, Barbara J. | Mirzaee, Sam | Daly, Robin M.

Article Type: Research Article

Abstract: Background: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline. Objective: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes). Methods: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 …participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n  = 73), or a control condition (n  = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A. Results: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26–1.19), p  = 0.001]. Conclusion: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass. Show more

Keywords: Cognition, dietary proteins, exercise, fatty acids, omega-3, vitamin D, white matter hyperintensities, white matter lesions

DOI: 10.3233/JAD-220234

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 247-263, 2022

Authors: Heal, Mackenzie | McFall, G. Peggy | Vergote, David | Jhamandas, Jack H. | Westaway, David | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: A promising risk loci for sporadic Alzheimer’s disease (AD), Bridging Integrator 1 (BIN1 ), is thought to operate through the tau pathology pathway. Objective: We examine BIN1 risk for a moderating role with vascular health (pulse pressure; PP) and sex in predictions of episodic memory trajectories in asymptomatic aging adults. Methods: The sample included 623 participants (Baseline Mean age = 70.1; 66.8% female) covering a 44-year longitudinal band (53–97 years). With an established memory latent variable arrayed as individualized trajectories, we applied Mplus 8.5 to determine the best fitting longitudinal growth model. Main analyses were …conducted in three sequential phases to investigate: 1) memory trajectory prediction by PP, 2) moderation by BIN1 genetic risk, and 3) stratification by sex. Results: We first confirmed that good vascular health (lower PP) was associated with higher memory level and shallower decline and males were more severely affected by worsening PP in both memory performance and longitudinal decline. Second, the PP prediction of memory trajectories was significant for BIN1 C/C and C/T carriers but not for persons with the highest AD risk (T/T homozygotes). Third, when further stratified by sex, the BIN1 moderation of memory prediction by PP was selective for females. Conclusion: We observed a novel interaction whereby BIN1 (linked with tauopathy in AD) and sex sequentially moderated a benchmark PP prediction of differential memory decline in asymptomatic aging. This multi-modal biomarker interaction approach, disaggregated by sex, can be an effective method for enhancing precision of AD genetic risk assessment. Show more

Keywords: Bridging integrator 1, memory trajectories, pulse pressure, sex differences, Victoria Longitudinal Study

DOI: 10.3233/JAD-220334

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 265-281, 2022

Authors: Huffels, Christiaan F.M. | van Dijk, Roland E. | Karst, Henk | Meye, Frank J. | Hol, Elly M. | Middeldorp, Jinte

Article Type: Research Article

Abstract: Background: Aging is characterized by systemic alterations and forms an important risk factor for Alzheimer’s disease (AD). Recently, it has been indicated that blood-borne factors present in the systemic milieu contribute to the aging process. Exposing young mice to aged blood plasma results in impaired neurogenesis and synaptic plasticity in the dentate gyrus, as well as impaired cognition. Vice versa, treating aged mice with young blood plasma rescues impairments associated with aging. Objective: Whether blood-borne factors are sufficient to drive impairments outside the dentate gyrus, how they impact neurophysiology, and how the functional outcome compares to impairments found …in mouse models for AD is still unclear. Methods: Here, we treated adult mice with blood plasma from aged mice and assessed neurophysiological parameters in the hippocampal CA1. Results: Mice treated with aged blood plasma show significantly impaired levels of long-term potentiation (LTP), similar to those present in APP/PS1 mice. These impaired levels of LTP in plasma-treated mice are associated with alterations in basic properties of glutamatergic transmission and the enhanced activity of voltage-gated Ca2+ channels. Conclusion: Together, the data presented in this study show that blood-borne factors are sufficient to drive neurophysiological impairments in the hippocampal CA1. Show more

Keywords: Aging, Alzheimer’s disease, calcium, calcium channels, hippocampus, neuronal plasticity, plasma

DOI: 10.3233/JAD-220337

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 283-297, 2022

Authors: Cerami, Chiara | Perdixi, Elena | Meli, Claudia | Marcone, Alessandra | Zamboni, Michele | Iannaccone, Sandro | Dodich, Alessandra

Article Type: Research Article

Abstract: Background: The Frontal Behavioral Inventory (FBI) is a questionnaire designed to quantify behavioral changes in frontotemporal dementia (FTD). Literature showed heterogeneous FBI profiles in FTD versus Alzheimer’s disease (AD) with variable occurrence of positive and negative symptoms. Objective: In this study, we constructed a short FBI version (i.e., mini-FBI) with the aim to provide clinicians with a brief tool for the identification of early behavioral changes in behavioral variant of FTD (bvFTD), also facilitating the differential diagnosis with AD. Methods: 40 bvFTD and 33 AD patients were enrolled. FBI items were selected based on internal consistency …and exploratory factor analysis. Convergent validity of mini-FBI was also assessed. A behavioral index (i.e., B-index) representing the balance between positive and negative mini-FBI symptoms was computed in order to analyze its distribution in bvFTD through a cluster analysis and to compare performance among patient groups. Results: The final version of the mini-FBI included 12 items, showing a significant convergent validity with the Neuropsychiatric Inventory scores (rp  = 0.61, p  < 0.001). Cluster analysis split patients in four clusters. bvFTD were included in three different clusters characterized by prevalent positive symptoms, both positive and negative symptoms, or prevalent negative behavioral alterations, similar to a subset of AD patients. A fourth cluster included only AD patients showing no positive symptoms. Conclusion: The mini-FBI is a valuable easily administrable questionnaire able to early identify symptoms effectively contributing to the bvFTD behavioral syndrome, aiding clinician in diagnosis and management. Show more

Keywords: Accuracy, Alzheimer’s disease, behavioral disorders, behavioral variant of frontotemporal dementia, diagnosis, frontal syndrome, frontotemporal dementia

DOI: 10.3233/JAD-220173

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 299-308, 2022

Authors: Luo, Wendy | Pryzbyl, Katherine J. | Bigio, Eileen H. | Weintraub, Sandra | Mesulam, M.-Marsel | Redei, Eva E.

Article Type: Research Article

Abstract: Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer’s disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference. Objective: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2 ), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD. Methods: Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior …cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD. Results: Transcript levels of the antioxidant enzymes catalase (CAT ) and superoxide dismutase 1 (SOD1 ), as well as IGF2 and its receptor (IGF2R ) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa ) and PAQR8 (mPR β), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2 ) and mPR β are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R. Conclusion: Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD. Show more

Keywords: Antioxidant enzymes, depression, insulin like growth factor 2, membrane progesterone receptor, molecular vulnerability, sex/gender differences

DOI: 10.3233/JAD-220574

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 309-321, 2022

Authors: Yen, Fu-Shun | Wei, James Cheng-Chung | Yip, Hei-Tung | Hwu, Chii-Min | Hsu, Chih-Cheng

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2D) and hypertension (HTN) are well-known modifiable risk factors for dementia, but their intricate attributes accounting for dementia development has not been clearly delineated. Objective: We conducted this study to investigate and compare the effects of T2D and HTN on dementia risk. Methods: We screened data of matched pairs of patients with T2D or HTN between January 1, 2000 and December 31, 2017 from Taiwan’s National Health Insurance Research Database. Fine and Gray’s subdistribution hazard models were used for calculating the risk of dementia. Results: Patients with T2D and subsequent …HTN were associated with significantly higher risks of all-cause dementia (aHR 1.51, 95% CI 1.25–1.83) and vascular dementia (aHR 2.30, 95% CI 1.71–3.13) compared with those without subsequent HTN. Patients with HTN and subsequent T2D were associated with significantly higher risks of all-cause dementia (aHR 1.15, 95% CI 1.08–1.21), vascular dementia (aHR 1.25, 95% CI 1.62–1.34), and other dementia (aHR 1.31, 95% CI 1.03–1.66) compared with those without subsequent HTN. The subgroups of male and female patients, age of 50–69 and 70–90 years with subsequent comorbidity were associated with significantly higher risks of all-cause dementia and vascular dementia than those without subsequent comorbidity. Conclusion: This nationwide cohort study demonstrated that patients with T2D and subsequent HTN had association with higher risks of all-cause dementia and vascular dementia, and those with HTN and subsequent T2D were associated with higher risks of all-cause dementia, vascular dementia, and other dementia. Show more

Keywords: All-cause dementia, Alzheimer’s disease, other dementia, vascular dementia

DOI: 10.3233/JAD-220207

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 323-333, 2022

Authors: Zhang, Yangyang | Yang, Yin | Hu, Zhengtao | Zhu, Manyi | Qin, Shuangying | Yu, Pengpeng | Li, Bo | Xu, Jitian | Ondrejcak, Tomas | Klyubin, Igor | Rowan, Michael J. | Hu, Neng-Wei

Article Type: Research Article

Abstract: Background: Cognitive decline in Alzheimer’s disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood. Objective: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus. Methods: …In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting. Results: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats. Conclusion: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging. Show more

Keywords: Aging, Alzheimer’s disease, integrated stress response, long-term depression, tau phosphorylation

DOI: 10.3233/JAD-220351

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 335-350, 2022

Authors: Wang, Steven | Gustafson, Sara | Deckelman, Celia | Sampene, Emmanuel | Daggett, Sarah | Loosen, Julia | Robison, Raele | Pulia, Michael S. | Knigge, Molly | Thibeault, Susan | Gilmore-Bykovskyi, Andrea | Kind, Amy | Rogus-Pulia, Nicole

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) patients who are hospitalized often develop oropharyngeal dysphagia, increasing risk for adverse outcomes, such as aspiration pneumonia. However, prevalence estimates of dysphagia are highly variable and often based on patient report or clinical testing rather than visualization of the swallow. Objective: The aims of this study were to determine prevalence and severity of dysphagia among inpatients with ADRD referred for swallowing evaluation. Methods: Electronic health record (EHR) abstraction of ADRD diagnosis and presence and severity of clinically-determined dysphagia on bedside swallow evaluation (BSE) and videofluoroscopic swallow study (VFSS). …Results: 16% (n  = 268) had an ADRD diagnosis or were taking dementia-specific medication based on the EHR. 75% (n  = 202) were diagnosed with dysphagia on the BSE. 60% subsequently underwent VFSS (n  = 122) with dysphagia confirmation in 92% (n  = 112). ADRD inpatients were significantly more likely to be diagnosed with dysphagia based on the BSE (p  < 0.0001) than those without ADRD. Additionally, dysphagia on the VFSS was more severe in the ADRD group (p  < 0.03). Discussion: ADRD individuals may be vulnerable to developing or worsening dysphagia during hospitalization. Results underscore the importance of evaluating swallowing function in hospitalized patients with ADRD in order to facilitate targeted intervention. Show more

Keywords: Alzheimer’s disease and related dementias, oropharyngeal dysphagia, swallow, videofluoroscopic

DOI: 10.3233/JAD-220402

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 351-358, 2022

Authors: Klein, Philip Charles Gerard | Huygens, Simone | Handels, Ron | Wester, Valérie | Kanters, Tim Andre

Article Type: Research Article

Abstract: Background: Disease modifying treatments (DMTs) currently under development for Alzheimer’s disease, have the potential to prevent or postpone institutionalization and more expensive care and might delay institutionalization of persons with dementia. Objective: The current study estimates costs of living in a nursing home for persons with dementia in the Netherlands to help inform economic evaluations of future DMTs. Methods: Data were collected during semi-structured interviews with healthcare professionals and from the financial administration of a healthcare organization with several nursing homes. Personnel costs were calculated using a bottom-up approach by valuing the time estimates. Non-personnel costs …were calculated using information from the financial administration of the healthcare organization. Results: Total costs of a person with dementia per 24 hours, including both care staff and other healthcare providers, were € 151 for small-scale living wards and € 147 for independent living wards. Non-personnel costs were € 37 per day. Conclusion: This study provides Dutch estimates for total healthcare costs per day for institutionalized persons with dementia. These cost estimates can be used in cost-effectiveness analyses for future DMTs in dementia. Show more

Keywords: Dementia, health care economics and organizations, health resources, nursing homes

DOI: 10.3233/JAD-220416

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 359-366, 2022

Authors: Zhang, Dan-Dan | Ou, Ya-Nan | Fu, Yan | Wang, Zhi-Bo | Huang, Liang-Yu | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: A negative association between cancer and Alzheimer’s disease (AD) was revealed. Objective: We aimed to further explore the dementia risk among cancer survivors and then among cancer survivors who received cancer treatment in subsequent subgroup analyses. Methods: Databases of PubMed, Embase, and Cochrane Library were systematically searched from inception to April 1, 2021, following PRISMA and MOOSE guidelines. Relative risks (RR) of dementia were pooled by a random-effects model stratifying the data by potential confounding factors to explore the heterogeneity. This study is registered with PROSPERO, number CRD42021250654. Results: A total of 36 …studies were included in this meta-analysis, of which 16 studies were about the risk of dementia in cancer survivors, and 20 studies were about the risk of dementia in survivors who accepted cancer treatment. The pooled RR reached 0.89 ([95% CI = 0.82–0.97], I2  = 97.9%) for dementia and 0.89 ([0.83–0.95], I2  = 92.6%) for AD in cancer survivors compared with non-cancer controls. Notably, both dementia risk and AD risk significantly decreased in survivors of colon, leukemia, small intestine, and thyroid cancers (RR ranged from 0.64 to 0.92). Furthermore, prostate cancer patients treated with androgen deprivation therapy exhibited a significantly increased risk of dementia (RR:1.18 [1.09–1.27], I2  = 89.5%) and AD (RR:1.17 [1.08–1.25], I2  = 81.3%), with evidence of between-study heterogeneity. Conclusion: Currently, available evidence suggests that the risk of dementia among cancer survivors is decreased. However, large-scale prospective cohort studies are warranted to further prove the association. Show more

Keywords: Alzheimer’s disease, cancer, cancer treatment, dementia, meta-analysis

DOI: 10.3233/JAD-220436

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 367-380, 2022

Authors: Saito, Satoshi | Yamashiro, Takayuki | Yamauchi, Miho | Yamamoto, Yumi | Noguchi, Michio | Tomita, Tsutomu | Kawakami, Daisuke | Shikata, Masamitsu | Tanaka, Tomotaka | Ihara, Masafumi

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy is a cerebrovascular disease directly implicated in Alzheimer’s disease pathogenesis through amyloid-β deposition. Growing evidence has shown a pivotal role of chronic neuroinflammation both in cerebral amyloid angiopathy and Alzheimer’s disease. Objective: The aim of this study was to investigate whether circulating levels of the complement 3, a crucial component of the innate immune system, are increased in patients with cerebral amyloid angiopathy. Methods: Serum complement 3 levels were retrospectively measured by a sandwich enzyme-linked immunosorbent assay in a single-center cohort of patients with mild cognitive impairment. The diagnosis of cerebral amyloid …angiopathy was based on the modified Boston criteria. Logistic regression analysis was performed to identify the predictive factors for cerebral amyloid angiopathy. Results: We analyzed 55 mild cognitive impairment patients (mean age [standard deviation]: 76.3 [6.8] years; 33 [60% ] men). Complement 3 levels were significantly increased in cerebral amyloid angiopathy patients (n  = 16) compared with those without cerebral amyloid angiopathy (n  = 39) (median [interquartile range]: 0.43 [0.34–0.65] versus 0.35 [0.25–0.45], respectively; p  = 0.040). Univariate and multivariate logistic regression analysis revealed that increased complement 3 levels were significantly associated with cerebral amyloid angiopathy. After selection of the best predictive model using stepwise selection, complement 3 was preserved as a significant independent predictive factor for cerebral amyloid angiopathy (odds ratio per 0.1 unit/mL increase [95% confidence interval]: 1.407 [1.042–1.899]; p  = 0.026). Conclusion: Complement activation may play a pivotal role in cerebral amyloid angiopathy. Complement 3 may be a novel diagnostic biomarker for cerebral amyloid angiopathy. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral amyloid angiopathy, complement 3, inflammation

DOI: 10.3233/JAD-220494

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 381-387, 2022

Authors: Ceresetti, Romain | Rouch, Isabelle | Laurent, Bernard | Getenet, Jean-Claude | Pommier, Morgane | de Chalvron, Stéphanie | Chainay, Hanna | Borg, Céline

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative pathology that disrupts processing of facial expressions of emotion. The impairment was demonstrated for negative emotions in tasks of matching, discriminating, and labeling facial expressions but no study has included the expression of pain in its protocol. Objective: The objective was to study the processing of emotional facial expressions in AD with a particular interest in pain expression. Methods: Twenty-seven controls, 15 mild AD patients, and 15 moderate AD patients had to perform four emotional tasks: identification of facial expressions, matching pain expressions, discriminating the intensity of pain expressions, …and judging pain intensity. Results: Some emotions were less efficiently recognized by AD patients compared to controls (p  < 0.001), specifically fear from the mild stage (p  < 0.05), pain and disgust from the moderate stage (p  < 0.05 and p  < 0.001 respectively). The Exploratory Factor Analysis showed that recognition of pain and recognition of other discreet emotions were underpinned by two different latent factors. Performances on pain expression matching task and pain intensity discrimination task did not differ by group. (p  = 0.334 and p  = 0.787 respectively). Finally, moderate AD patients judged the pain less intensively than the Control group for both, moderate, and severe pain intensity (p  < 0.001). Conclusion: Our data suggest that AD disrupts the recognition of pain expression along with recognition of fear and disgust. Additionally, AD patients seem to underestimate pain intensity compared to controls. The self-rated pain scales should be adapted to the pain processing deficit of AD patients. Show more

Keywords: Alzheimer’s disease, facial expression, identification of pain, pain intensity, painful faces

DOI: 10.3233/JAD-220236

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 389-398, 2022