Journal of Alzheimer's Disease - Volume 88, issue 4

Authors: Agüera-Ortiz, Luis | Babulal, Ganesh M. | Bruneau, Marie-Andrée | Creese, Byron | D’Antonio, Fabrizia | Fischer, Corinne E. | Gatchel, Jennifer R. | Ismail, Zahinoor | Kumar, Sanjeev | McGeown, William J. | Mortby, Moyra E. | Nuñez, Nicolas A. | de Oliveira, Fabricio F. | Pereiro, Arturo X. | Ravona-Springer, Ramit | Rouse, Hillary J. | Wang, Huali | Lanctôt, Krista L.

Article Type: Review Article

Abstract: Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present …proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials. Show more

Keywords: Clinical trials, dementia, delusions, hallucinations, investigational therapies, psychotic disorders

DOI: 10.3233/JAD-215483

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1203-1228, 2022

Authors: Turnbull, Adam | Kaplan, Robert M. | Adeli, Ehsan | Lin, Feng V.

Article Type: Review Article

Abstract: Brain aging leads to difficulties in functional independence. Mitigating these difficulties can benefit from technology that predicts, monitors, and modifies brain aging. Translational research prioritizes solutions that can be causally linked to specific pathophysiologies at the same time as demonstrating improvements in impactful real-world outcome measures. This poses a challenge for brain aging technology that needs to address the tension between mechanism-driven precision and clinical relevance. In the current opinion, by synthesizing emerging mechanistic, translational, and clinical research-related frameworks, and our own development of technology-driven brain aging research, we suggest incorporating the appreciation of four desiderata (causality, informativeness, transferability, and …fairness) of explainability into early-stage research that designs and tests brain aging technology. We apply a series of work on electrocardiography-based “peripheral” neuroplasticity markers from our work as an illustration of our proposed approach. We believe this novel approach will promote the development and adoption of brain aging technology that links and addresses brain pathophysiology and functional independence in the field of translational research. Show more

Keywords: Artificial intelligence, brain aging, explainability, technology, translational research

DOI: 10.3233/JAD-220441

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1229-1239, 2022

Authors: Plantone, Domenico | Pardini, Matteo | Locci, Sara | Nobili, Flavio | De Stefano, Nicola

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-β (Aβ) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature …subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of “inflammaging”, which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aβ in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aβ and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications. Show more

Keywords: Aging, Alzheimer’s disease, amyloid beta-peptides, B-lymphocytes, vaccination

DOI: 10.3233/JAD-220261

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1241-1262, 2022

Authors: Li, Hui | Su, Wenlong | Dang, Hui | Han, Kaiyue | Lu, Haitao | Yue, Shouwei | Zhang, Hao

Article Type: Systematic Review

Abstract: Background: The prevalence of mild cognitive impairment (MCI) continues to increase due to population aging. Exercise has been a supporting health strategy that may elicit beneficial effects on cognitive function and prevent dementia. Objective: This study aimed to examine the effects of aerobic, resistance, and multimodal exercise training on cognition in adults aged > 60 years with MCI. Methods: We searched the Cochrane Library, PubMed, and Embase databases and ClinicalTrials.gov (https://clinicaltrials.gov ) up to November 2021, with no language restrictions. We included all published randomized controlled trials (RCTs) comparing the effect of exercise programs on cognitive function …with any other active intervention or no intervention in participants with MCI aged > 60 years. Results: Twelve RCTs were included in this review. Meta-analysis results revealed significant improvements in resistance training on measures of executive function (p  < 0.05) and attention (p  < 0.05); no significant differences were observed between aerobic exercise and controls on any of the cognitive comparisons. Conclusion: Exercise training had a small beneficial effect on executive function and attention in older adults with MCI. Larger studies are required to examine the effects of exercise and the possible moderators. Show more

Keywords: Aged, exercise, meta-analysis, mild cognitive impairment, systematic review

DOI: 10.3233/JAD-220243

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1263-1278, 2022

Authors: Krance, Saffire H. | Wu, Che-Yuan | Chan, Alison C.Y. | Kwong, Stephanie | Song, Bing Xin | Xiong, Lisa Y. | Ouk, Michael | Chen, Ming Hui | Zhang, Jane | Yung, Adrian | Stanley, Meagan | Herrmann, Nathan | Lanctôt, Krista L. | Swardfager, Walter

Article Type: Systematic Review

Abstract: Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer’s disease (AD); however, findings thus far have been inconsistent. Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. Results: Of 2,471 …unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD /NHC  = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2  = 72.8%; LAMP-2: NAD /NHC  = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2  = 78.7%) and intra-lysosomal proteins (GM2A: NAD /NHC  = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2  = 87.7%; CTSB: NAD /NHC  = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2  = 28.5%; CTSZ: NAD /NHC  = 535/820, SMD [95% CI] = –0.160 [–0.305, –0.015], I2  = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD /NHC  = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2  = 27.4%; FLOT1: NAD /NHC  = 41/45, SMD [95% CI] = –0.489 [–0.919, –0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD /NHC  = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2  = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. Conclusion: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD. Show more

Keywords: Alzheimer’s disease, autophagy, biomarkers, dementia, endosomes, lysosomes, meta-analysis, proteins, systematic review

DOI: 10.3233/JAD-220360

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1279-1292, 2022

Authors: Mohamad Asfia, Siti Khadijah Binti | Bucholc, Jessica | McCaffrey, Nikki | Mihalopoulos, Cathrine | Muldowney, Anne | Engel, Lidia

Article Type: Systematic Review

Abstract: Background: There is currently a lack of a comprehensive review identifying the broad scope of factors that impact quality of life (QoL) of informal carers of people with dementia in order to validate existing measures and inform the provision of support services for carers of people with dementia that impact QoL domains important to them. Objective: To explore and identify QoL impacts on informal carers from providing care to people with dementia. Methods: A systematic review was conducted across four databases: EMBASE, CINAHL, PsychINFO, and Medline. Eligible studies consisted of published, peer-reviewed, qualitative studies focusing on …lived experiences of informal carers of people with dementia. Non-English studies and quantitative studies were excluded. Screening of included studies was conducted independently by three reviewers. A “best-fit” framework synthesis was used to combine the qualitative data, applying deductive and inductive analysis techniques. Quality assessment was conducted using the Critical Appraisal Skills Programme. Results: Of the 4,251 articles identified, 59 articles were included. Five main themes pertaining to QoL aspects were identified that included coping (emotion-coping and problem-coping), relationship with the person with dementia (sense of loss and change in relationship), support (formal support and informal support), interference with life (control over caring situation, and freedom and independence), and health (physical health, emotional and mental health, and social health). Conclusion: This study identified domains of QoL that are impacted by providing informal care to people living with dementia, offering a conceptual framework for instrument validation and development as well as guidance for service provision. Show more

Keywords: Caregivers, dementia, qualitative research, quality of life, review

DOI: 10.3233/JAD-220219

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1293-1309, 2022

Authors: Luo, Anling | Ning, Pingping | Lu, Haitao | Huang, Hongyan | Shen, Qiuyan | Zhang, Dan | Xu, Fang | Yang, Li | Xu, Yanming

Article Type: Systematic Review

Abstract: Background: As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer’s disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results. Objective: This study aimed to evaluate the association between metformin and the risk of developing AD. Methods: We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between …AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models. Results: After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88–1.56, p  = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24–2.37, p  = 0.001). Conclusion: The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, meta-analysis, metformin

DOI: 10.3233/JAD-220180

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1311-1323, 2022

Authors: Almulla, Abbas F. | Supasitthumrong, Thitiporn | Amrapala, Arisara | Tunvirachaisakul, Chavit | Jaleel, Al-Karrar Kais Abdul | Oxenkrug, Gregory | Al-Hakeim, Hussein K. | Maes, Michael

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway. Objective: To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients. Methods: We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible …articles which involved 738 patients and 665 healthy controls. Results: Our results revealed a significant difference (p  = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = –0.520, 95% CI: –0.738; –0.302, p  < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood. Conclusion: AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD. Show more

Keywords: Biomarkers, inflammation, kynurenine, neuro-immune, oxidative stress, psychiatry

DOI: 10.3233/JAD-220295

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1325-1339, 2022

Authors: Papaioannou, Themis | Voinescu, Alexandra | Petrini, Karin | Stanton Fraser, Danaë

Article Type: Systematic Review

Abstract: Background: Mild cognitive impairment (MCI) and dementia result in cognitive decline which can negatively impact everyday functional abilities and quality of life. Virtual reality (VR) interventions could benefit the cognitive abilities of people with MCI and dementia, but evidence is inconclusive. Objective: To investigate the efficacy of VR training on global and domain-specific cognition, activities of daily living and quality of life. To explore the influence of priori moderators (e.g., immersion type, training type) on the effects of VR training. Adverse effects of VR training were also considered. Methods: A systematic literature search was conducted on …all major databases for randomized control trial studies. Two separate meta-analyses were performed on studies with people with MCI and dementia. Results: Sixteen studies with people with MCI and four studies with people with dementia were included in each meta-analysis. Results showed moderate to large effects of VR training on global cognition, attention, memory, and construction and motor performance in people with MCI. Immersion and training type were found to be significant moderators of the effect of VR training on global cognition. For people with dementia, results showed moderate to large improvements after VR training on global cognition, memory, and executive function, but a subgroup analysis was not possible. Conclusion: Our findings suggest that VR training is an effective treatment for both people with MCI and dementia. These results contribute to the establishment of practical guidelines for VR interventions for patients with cognitive decline. Show more

Keywords: Cognition, cognitive rehabilitation, cognitive training, dementia, mild cognitive impairment, virtual reality

DOI: 10.3233/JAD-210672

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1341-1370, 2022

Authors: Han, Sang-Won | Park, Young Ho | Jang, Eun Sun | Nho, Kwangsik | Kim, SangYun

Article Type: Short Communication

Abstract: To investigate an association of serum liver enzymes with Alzheimer’s disease (AD) diagnosis and cognitive performance, we performed logistic and linear regression analyses in 781 patients with AD and 405 cognitively normal subjects. We found that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels had significant positive associations with cognitive performance and were significantly decreased in AD patients. The alkaline phosphatase level and AST to ALT ratio were significantly negatively associated with cognitive performance and were significantly increased in AD patients. This suggests that these liver enzymes might be implicated in the pathogenesis of AD.

Keywords: Alzheimer’s disease, cognition, liver enzymes, neuropsychological assessment

DOI: 10.3233/JAD-220343

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1371-1376, 2022

Authors: Goldberg, Sarah M. | Zhao, Yanji | Cheng, Yu | Weinstein, Andrea M. | Gujral, Swathi | Berman, Sarah B. | Sweet, Robert A. | Butters, Meryl A. | Lopez, Oscar L. | Snitz, Beth E.

Article Type: Research Article

Abstract: Background: This memory-clinic study joins efforts to study earliest clinical signs and symptoms of Alzheimer’s disease and related dementias: subjective reports and objective neuropsychological test performance. Objective: The memory-clinic denoted two clinical “grey zones”: 1) subjective cognitive decline (SCD; n  = 107) with normal objective test scores, and 2) isolated low test scores (ILTS; n  = 74) without subjective complaints to observe risk for future decline. Methods: Initial and annual follow-up clinical research evaluations and consensus diagnosis were used to evaluate baseline characteristics and clinical progression over 2.7 years, compared to normal controls (NC; n  = 117). …Results: The ILTS group was on average older than the NC and SCD groups. They had a higher proportion of people identifying as belonging to a minoritized racial group. The SCD group had significantly more years of education than the ILTS group. Both ILTS and SCD groups had increased risk of progression to mild cognitive impairment. Older age, minoritized racial identity, and baseline cognitive classification were risk factors for progression. Conclusion: The two baseline risk groups look different from each other, especially with respect to demographic correlates, but both groups predict faster progression than controls, over and above demographic differences. Varied presentations of early risk are important to recognize and may advance cognitive health equity in aging. Show more

Keywords: Cognitive decline, mild cognitive impairment, neurocognitive tests, risk factors

DOI: 10.3233/JAD-215607

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1377-1384, 2022

Authors: Rubin-Norowitz, Mariel | Lipton, Richard B. | Petersen, Kellen | Ezzati, Ali

Article Type: Research Article

Abstract: Background: Depression is a late-life risk factor for cognitive decline. Evidence suggests an association between Alzheimer’s disease (AD) associated pathologic changes and depressive symptoms. Objective: To investigate the influence of AT(N) biomarker profile (amyloid-β [A], p-tau [T], and neurodegeneration [N]) and gender on cross-sectional associations between subclinical depressive symptoms and cognitive function among older adults without dementia. Methods: Participants included 868 individuals without dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Depressive symptoms were measured using the Geriatric Depression Scale (GDS). ADNI neuropsychological composite scores assessed memory and executive function (EF). PET, cerebrospinal fluid, and MRI …modalities classified the study sample into biomarker profiles: normal biomarkers (A–T–N–), AD continuum (A+T±N±), and suspect non-AD pathology (SNAP; A–T±N–or A–T–N±). Multivariate regression models were used to investigate associations between GDS and cognitive domains. Results: GDS was negatively associated with memory (β= –0.156, p  < 0.001) and EF (β= –0.147, p  < 0.001) in the whole sample. When classified by biomarker profile, GDS was negatively associated with memory and EF in AD continuum (memory: β= –0.174, p  < 0.001; EF: β= –0.129 p  = 0.003) and SNAP (memory: β= –0.172, p  = 0.005; EF: β= –0.197, p  = 0.001) subgroups. When stratified by sex, GDS was negatively associated with memory (β= –0.227, p  < 0.001) and EF (β= –0.205, p  < 0.001) in men only. Conclusion: The association between subclinical depressive symptoms and cognitive function is highly influenced by the AT(N) biomarker profile. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, cognition, depressive symptoms, neurodegeneration, tau

DOI: 10.3233/JAD-215665

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1385-1395, 2022

Authors: Vyhnalek, Martin | Jester, Dylan J. | Andel, Ross | Horakova, Hana | Nikolai, Tomas | Laczó, Jan | Matuskova, Veronika | Cechova, Katerina | Sheardova, Katerina | Hort, Jakub

Article Type: Research Article

Abstract: Background: Memory tests using controlled encoding and cued recall paradigm (CECR) have been shown to identify prodromal Alzheimer’s disease (AD), but information about the effectiveness of CECR compared to other memory tests in predicting clinical progression is missing. Objective: The aim was to examine the predictive ability of a memory test based on the CECR paradigm in comparison to other memory/non-memory tests for conversion to dementia in patients with amnestic mild cognitive impairment (aMCI). Methods: 270 aMCI patients from the clinical-based Czech Brain Aging Study underwent a comprehensive neuropsychological assessment including the Enhanced Cued Recall test …(ECR), a memory test with CECR, two verbal memory tests without controlled encoding: the Auditory Verbal Learning Test (AVLT) and Logical memory test (LM), a visuospatial memory test: the Rey-Osterrieth Complex Figure test, and cognitive testing based on the Uniform Data Set battery. The patients were followed prospectively. Conversion to dementia as a function of cognitive performance was examined using Cox proportional hazard models. Results: 144 (53%) patients converted to dementia. Most converters (89%) developed dementia due to AD or mixed (AD and vascular) dementia. Comparing the four memory tests, the delayed recall scores on AVLT and LM best predicted conversion to dementia. Adjusted hazard ratios (HR) of immediate recall scores on ECR, AVLT, and LM were similar to the HR of categorical verbal fluency. Conclusion: Using the CECR memory paradigm in assessment of aMCI patients has no superiority over verbal and non-verbal memory tests without cued recall in predicting conversion to dementia. Show more

Keywords: Alzheimer’s disease, memory, mild cognitive impairment, verbal fluency

DOI: 10.3233/JAD-215364

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1397-1409, 2022

Authors: Toups, Kat | Hathaway, Ann | Gordon, Deborah | Chung, Henrianna | Raji, Cyrus | Boyd, Alan | Hill, Benjamin D. | Hausman-Cohen, Sharon | Attarha, Mouna | Chwa, Won Jong | Jarrett, Michael | Bredesen, Dale E.

Article Type: Research Article

Abstract: Background: Effective therapeutics for Alzheimer’s disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. Objective: To determine whether a precision medicine approach to Alzheimer’s disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. …Methods: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t  = 0, 3, 6, and 9 months. Results: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer’s Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. Conclusion: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted. Show more

Keywords: Clinical trial, mild cognitive impairment, MRI volumetrics, neurodegeneration, systems medicine

DOI: 10.3233/JAD-215707

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1411-1421, 2022

Authors: Tsujimoto, Masashi | Suzuki, Keisuke | Saji, Naoki | Sakurai, Takashi | Ito, Kengo | Toba, Kenji

Article Type: Research Article

Abstract: Background: With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan. Objective: To establish a large cohort for use in clinical trials and research in Japan. Methods: This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment [MCI], and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression. …Results: There were 1450 registered patients (649 men, 801 women; mean age, 77.92±6.70 years; mean Mini-Mental State Examination [MMSE] score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio [OR] = 11.085, 95% confidence interval [CI]:1.619–75.913, p  = 0.014), low MMSE score (OR = 0.835, 95% CI: 0.761–0.917, p  < 0.001), high Geriatric Depression Scale score (OR = 1.093, 95% CI: 1.005–1.189, p  = 0.038), and low body mass index (OR = 0.895, 95% CI: 0.829–0.967, p  = 0.005) at enrollment were significant factors for conversion. Conclusion: The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, humans, longitudinal studies, preventive medicine, registries

DOI: 10.3233/JAD-220039

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1423-1433, 2022

Authors: Zhang, Xiaoyu | Cong, Ruyi | Geng, Tao | Zhang, Jinxia | Liu, Di | Tian, Qiuyue | Meng, Xiaoni | Song, Manshu | Wu, Lijuan | Zheng, Deqiang | Wang, Wei | Wang, Baoguo | Wang, Youxin

Article Type: Research Article

Abstract: Background: Previous prospective studies highlighted aberrant immunoglobulin G (IgG) N-glycosylation as a risk factor for dementia [such as Alzheimer’s disease (AD) and vascular dementia (VaD)]. It is unclear whether this association is causal or explained by confounding or reverse causation. Objective: The aim is to examine the association of genetically predicted IgG N-glycosylation with dementia using 2-sample Mendelian randomization (MR). Methods: Independent genetic variants for IgG N-glycosylation traits were selected as instrument variables from published genome-wide association studies (GWAS) among individuals of European ancestry. We extracted their corresponding summary statistics from large-scale clinically diagnosed AD GWAS …dataset and FinnGen biobank VaD GWAS dataset. The inverse variance weighted (IVW) was performed to calculate the effect estimates. Meanwhile, multiple sensitivity analyses were used to assess horizontal pleiotropy and outliers. Results: There were no associations of genetically predicted IgG N-glycosylation traits with the risk of AD and VaD using the IVW method (all Bonferroni corrected p  > 0.0013). These estimates of four additional sensitivity analyses methods were consistent with the IVW estimates in terms of direction and magnitude. Additionally, the MR-PRESSO global test and the intercept of MR-Egger regression indicated no evidence of horizontal pleiotropy. Meanwhile, the heterogeneity test showed no significant heterogeneity using the Cochran Q statistic. The leave-one-out sensitivity analyses also did not detect any significant change. Conclusion: Our MR study did not support evidence for the hypothesis that IgG N-glycosylation level may be causally associated with the risk of dementia. Show more

Keywords: Alzheimer’s disease, IgG N-glycosylation, mendelian randomization, vascular dementia

DOI: 10.3233/JAD-220074

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1435-1441, 2022

Authors: Zhu, Mei Hong | Jogdand, Aditi H. | Jang, Jinyoung | Nagella, Sai C. | Das, Brati | Milosevic, Milena M. | Yan, Riqiang | Antic, Srdjan D.

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline. Objective: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings. Methods: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes). Results: Expression of GEVI did not disrupt AD model formation of …amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting “hyperexcitability” prior to the formation of plaques. Conclusion: Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition. Show more

Keywords: Alzheimer’s disease, amyloid plaque, APP/PS1, excitability, synaptic dysfunction

DOI: 10.3233/JAD-220249

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1443-1458, 2022

Authors: Wojdała, Anna Lidia | Chiasserini, Davide | Bellomo, Giovanni | Paciotti, Silvia | Gaetani, Lorenzo | Paoletti, Federico Paolini | Parnetti, Lucilla

Article Type: Research Article

Abstract: Background: Phosphatidylethanolamine binding protein 1 (PEBP1) is a multifunctional protein, mainly known for its specific binding of phosphatidylethanolamine and the ability to suppress the Raf1-MAPK pathway. Its potential role as an Alzheimer’s disease (AD) biomarker has been proposed in several studies. However, evaluation of its discriminative value in clinical cohorts is missing. Objective: We aimed to develop a new immunoassay for the measurement of PEBP1 in cerebrospinal fluid (CSF) and assess the possible role of this protein as AD biomarker. Methods: We developed a sandwich enzyme-linked immunosorbent assay (ELISA) for detection of PEBP1 in CSF …and performed a technical and a clinical validation on two well-characterized cohorts. The first cohort included 14 mild cognitive impairment due to AD (MCI-AD) and 11 other neurological diseases (OND) patients. The second, larger cohort, included 25 MCI-AD, 29 AD dementia (AD-dem), and 21 OND patients. Results: PEBP1 is highly sensitive to pre-analytical conditions, especially to prolonged storage at room temperature or 4°C. Analysis of the first cohort showed a trend of an increase of PEBP1 level in MCI-AD patients versus OND subjects. Analysis of the second cohort did not show significant differences among diagnostic groups. Weak, positive correlation was found between CSF PEBP1 and t-tau, p-tau, and Aβ40 in the AD-dem group. Conclusion: A novel ELISA for the detection of PEBP1 in CSF was developed. Further research is needed to assess the potential of PEBP1 in AD diagnostics. The observed dependence of the PEBP1 signal on operating procedures encourages its potential application as CSF quality control. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, ELISA, PEBP1

DOI: 10.3233/JAD-220323

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1459-1468, 2022

Authors: Luo, Shuyue | Dong, Xiangjun | Guo, Shipeng | Wang, Qunxian | Dai, Xi | Jiang, Yanshuang | Zhu, Weiyi | Zhou, Weihui | Song, Weihong

Article Type: Research Article

Abstract: Background: Interleukin-10 (IL-10) is a classic anti-inflammatory cytokine that exerts its effects via the receptor complexes IL-10RA and IL-10RB. Loss of IL-10RB results in many diseases. Moreover, IL-10RB is closely associated with neuronal survival and synaptic formation. However, the regulation of IL-10RB gene expression remains elusive. Objective: To investigate whether the expression of IL-10RB gene is increased in brain of Alzheimer’s disease (AD) and its transcriptional regulation. Methods: We examined the gene expression of AD patient brain from public database and detected the protein expression of AD model mouse brain by western …blot. We constructed a variety of reporter gene plasmids with different lengths or mutation sites, tested the promoter activity and defined the functional region of the promoter with the luciferase reporter assay. The protein-DNA binding between transcription factors and the promoter was analyzed using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Results: We found that the IL-10RB is elevated in the brain of AD patient and AD model mice. The minimal promoter of the IL-10RB gene is located in the –90 to +51 bp region (relative to the transcriptional start site) and is sufficient for high-level expression of the IL-10RB gene. Transcription factors Sp8 and Sp9 bind to the IL-10RB promoter in vitro . The overexpression or knockdown of Sp8 and Sp9 affected the IL-10RB promoter activity and its gene expression. Conclusion: Our study functionally characterized the promoter of the IL-10RB gene and demonstrated that Sp8 and Sp9 regulated its expression. Show more

Keywords: Gene expression, IL-10RB, Sp8, Sp9, transcriptional regulation

DOI: 10.3233/JAD-220321

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1469-1485, 2022

Authors: He, Xue-Ying | Dobkin, Carl | Brown, W.Ted | Yang, Song-Yu

Article Type: Research Article

Abstract: Background: Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aβ-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17β-HSD10. Objective: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals. Methods: 6xHis-tagged 17β-HSD10 was prepared and characterized by well-established experimental procedures. Results: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17β-HSD10, but the …kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports. Conclusion: Brain 17β-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD. Show more

Keywords: ABAD/ERAB, Alzheimer’s disease, infantile neurodegeneration, kinetic analysis of multifunctional proteins, research integrity

DOI: 10.3233/JAD-220481

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1487-1497, 2022

Authors: Bleakley, Amy | Maloney, Erin K. | Harkins, Kristin | Nelson, Maria N. | Akpek, Eda | Langbaum, Jessica B.

Article Type: Research Article

Abstract: Background: There is a lack of racial, ethnic, and sex diversity in recruitment research registries and Alzheimer’s disease (AD) research studies and trials. Theory-based recruitment messages may provide an opportunity to increase study participant diversity in AD research studies and trials. Objective: To identify behavioral, normative, and control beliefs that are associated with joining an AD-focused recruitment registry among historically underrepresented groups. Method: Using a Reasoned Action Approach, we conducted 60 semi-structured phone interviews in 2020 among White, Black, and Hispanic adults ages 49–79 years in Philadelphia, PA. Underlying beliefs were elicited for the target behavior …of “signing up to be on a registry for brain health research studies in the next month.” Percentages based on counts are reported for the overall sample and by race and ethnicity and sex. Results: Participants were most concerned that if they were to sign up for a registry, they would be asked to participate in experimental studies. Advancing science to help others was a commonly reported positive belief about signing up. Participants’ children and friends/neighbors were important from a normative perspective. Barriers to enrollment focused on logistical concerns and inconvenient sign-up processes, including using a computer. Results show generally few racial and ethnic or sex group differences. Conclusion: The elicited beliefs from underrepresented groups offer a basis for understanding the behavior of signing up for research registries. However, there were few differences between the groups. Implications for outreach and recruitment are discussed. Show more

Keywords: Alzheimer’s disease, attitudes, health behavior, health communication, research participant recruitment

DOI: 10.3233/JAD-220196

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1499-1509, 2022

Authors: Rahja, Miia | Air, Tracy | Ahern, Susannah | Ward, Stephanie A. | Caughey, Gillian E. | Sluggett, Janet K. | Cations, Monica | Lin, Xiaoping | Wallis, Kasey | Crotty, Maria | Inacio, Maria C.

Article Type: Research Article

Abstract: Background: Studies related to clinical quality indicators (CQIs) in dementia have focused on hospitalizations, medication management, and safety. Less attention has been paid to indicators related to primary and secondary care. Objective: To evaluate the incidence of primary and secondary care CQIs for Australians with dementia using government-subsidized aged care. The examined CQIs were: comprehensive medication reviews, 75+ health assessments, comprehensive geriatric assessments, chronic disease management plans, general practitioner (GP) mental health treatment plans, and psychiatrist attendances. Methods: Retrospective cohort study (2011–2016) of 255,458 individuals. National trend analyses estimated incidence rates and 95% confidence intervals (CI) …using Poisson or negative binomial regression. Associations were assessed using backward stepwise multivariate Poisson or negative binomial regression model, as appropriate. Funnel plots examined geographic and permanent residential aged care (PRAC) facility variation. Results: CQI incidence increased in all CQIs but medication reviews. For the overall cohort, 75+ health assessments increased from 1.07/1000 person-days to 1.16/1000 person-days (adjusted incidence rate ratio (aIRR) = 1.03, 95% CI 1.02–1.03).Comprehensive geriatric assessments increased from 0.24 to 0.37/1000 person-days (aIRR = 1.12, 95% CI 1.10–1.14). GP mental health treatment plans increased from 0.04 to 0.07/1000 person-days (aIRR = 1.13, 95% CI 1.12–1.15). Psychiatric attendances increased from 0.09 to 0.11/1000 person-days (aIRR = 1.05, 95% CI 1.03–1.07). Being female, older, having fewer comorbidities, and living outside a major city were associated with lower likelihood of using the services. Large geographical and PRAC facility variation was observed (0–92%). Conclusion: Better use of primary and secondary care services to address needs of individuals with dementia is urgently needed. Show more

Keywords: Dementia, health care, health services for the aged, primary health care, quality indicators, secondary care

DOI: 10.3233/JAD-220336

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1511-1522, 2022

Authors: Sun, Wenhao | Wu, Qiuyan | Chen, Huifeng | Yu, Lechang | Yin, Jie | Liu, Fang | Tian, Rui | Song, Bingbing | Qu, Bingqian | Xing, Mengya | Zhang, Nan

Article Type: Research Article

Abstract: Background: The Hong Kong Brief Cognitive Test (HKBC), a brief instrument designed to screen for cognitive impairment in older adults, has been validated in Cantonese-speaking populations and has shown better performance than the Mini-Mental State Examination (MMSE) in detecting both mild and major neurocognitive disorder (NCD). Objective: This study aimed to validate the HKBC for detecting patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) in a Mandarin-speaking Chinese population. Methods: Two hundred forty-eight patients with aMCI, 67 patients with mild AD and 306 healthy controls (HCs) were recruited for this study and completed …both the HKBC and the MMSE. The performance of the HKBC and MMSE in distinguishing patients with aMCI from HCs and distinguishing patients with AD from patients with aMCI was compared in the whole population and in age- and education-stratified subgroups. Results: The optimal HKBC cutoff score for distinguishing patients with aMCI from HCs was 23, and the optimal cutoff score for distinguishing patients with AD from patients with aMCI was 17. The HKBC significantly outperformed the MMSE at differentiating patients with aMCI from HCs in the whole population (z  = 12.38, p  < 0.01) and all subgroups stratified by age or education. Regarding the discrimination of patients with AD from patients with aMCI, the HKBC showed better performance than the MMSE in the oldest subgroup (z  = 2.18, p  = 0.03). Conclusion: The HKBC is a sensitive and specific screening tool for detecting aMCI and AD in the Chinese population across age groups and educational levels. Show more

Keywords: Alzheimer’s disease, cognitive test, mild cognitive impairment, Mini-Mental State Examination

DOI: 10.3233/JAD-220417

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1523-1532, 2022

Authors: Motazedi, Ehsan | Cheng, Weiqiu | Thomassen, Jesper Q. | Frei, Oleksandr | Rongve, Arvid | Athanasiu, Lavinia | Bahrami, Shahram | Shadrin, Alexey | Ulstein, Ingun | Stordal, Eystein | Brækhus, Anne | Saltvedt, Ingvild | Sando, Sigrid B. | O’Connell, Kevin S. | Hindley, Guy | van der Meer, Dennis | Bergh, Sverre | Nordestgaard, Børge G. | Tybjærg-Hansen, Anne | Bråthen, Geir | Pihlstrøm, Lasse | Djurovic, Srdjan | Frikke-Schmidt, Ruth | Fladby, Tormod | Aarsland, Dag | Selbæk, Geir | Seibert, Tyler M. | Dale, Anders M. | Fan, Chun C. | Andreassen, Ole A.

Article Type: Research Article

Abstract: Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian …DemGene cohort (n  = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n  = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n  = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations. Show more

Keywords: Age at onset, Alzheimer’s disease, Nordic ancestry, polygenic hazard score

DOI: 10.3233/JAD-220174

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1533-1544, 2022

Authors: Boujelbane, Mohamed Ali | Trabelsi, Khaled | Boukhris, Omar | Kacem, Faten Hadj | Ammar, Achraf | Charfi, Ichrak | Turki, Mouna | Charfeddine, Salma | Bouaziz, Bassem | Hakim, Ahmed | Frikha, Hamdi | Chabchoub, Mohamed Amine | Chtourou, Hamdi | Glenn, Jordan M. | Myers, Jennifer Rae

Article Type: Research Article

Abstract: Background: There has been increasing evidence and support for the use of digital technology in the cognitive health field. Despite the growing use of innovative digital technology to assess cognitive function, such technology remains scarce in Arabic countries, particularly in Tunisia. Objective: To investigate the effectiveness of a digitally delivered cognitive assessment battery in differentiating varying degrees of cognitive function in older Tunisian adults. Methods: One hundred fifty-five Tunisian older adults (age: 62.24±7.52 years) were assigned to one of four groups: healthy controls (HC), at-risk (AR), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Participants completed …a translated version of the Neurotrack digital cognitive battery. Results: The AD group performed significantly lower on the associative learning (p  = 0.01) and associative memory assessments (p  = 0.002), than the HC and AR groups. The AD group also performed worse on the inhibition measure (p  = 0.008) than the HC, AR, and MCI groups. For recognition memory, the was a significant difference between all four groups (p  < 0.0005), with AD having the lowest scores followed by the MCI, AR, and HC groups, respectively. There were no significant differences observed on attention, executive function and processing speed performance between the four groups (p  > 0.05). Conclusion: The use of digital technology appears to be a viable solution to current cognitive assessment challenges for assessing cognitive function in a Tunisian population. These findings provide further support for the use of digital technology in cognitive assessment, particularly in understudied populations. Show more

Keywords: Aging, cognitive decline, dementia, digital technology, eye-tracking movement

DOI: 10.3233/JAD-220398

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1545-1552, 2022

Authors: Howard, Erica | Ballinger, Samantha | Kinney, Nikolas G. | Balgenorth, Yvonne | Ehrhardt, Annabess | Phillips, Jeffrey S. | Irwin, David J. | Grossman, Murray | Cousins, Katheryn A.Q.

Article Type: Research Article

Abstract: Background: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS. Objective: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD). Methods: Fifty-six patients (LBSD = 35; PSP = 21) …completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman’s and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls. Results: PSP had worse complex numbers performance than LBSD (F  = 6.06, p  = 0.02) but similar basic numbers performance (F  = 0.38, p  > 0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p  = 0.01) but not JOLO (rho = 0.23, p  > 0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance. Conclusion: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy. Show more

Keywords: Cognitive decline, executive function, frontal lobe, neurodegenerative diseases, Parkinsonian disorders, progressive supranuclear palsy

DOI: 10.3233/JAD-215327

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1553-1566, 2022

Authors: Chia, Sook Yoong | Vipin, Ashwati | Ng, Kok Pin | Tu, Haitao | Bommakanti, Ananth | Wang, Brian Zhiyang | Tan, Yi Jayne | Zailan, Fatin Zahra | Ng, Adeline Su Lyn | Ling, Shuo-Chien | Okamura, Katsutomo | Tan, Eng-King | Kandiah, Nagaendran | Zeng, Li

Article Type: Research Article

Abstract: Background: There is an urgent need for noninvasive, cost-effective biomarkers for Alzheimer’s disease (AD), such as blood-based biomarkers. They will not only support the clinical diagnosis of dementia but also allow for timely pharmacological and nonpharmacological interventions and evaluations. Objective: To identify and validate a novel blood-based microRNA biomarker for dementia of the Alzheimer’s type (DAT). Methods: We conducted microRNA sequencing using peripheral blood mononuclear cells isolated from a discovery cohort and validated the identified miRNAs in an independent cohort and AD postmortem tissues. miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted. We …also performed bioinformatics and cell-based assay to identify miRNA target genes. Results: We found that miR-150-5p expression was significantly upregulated in DAT compared to mild cognitive impairment and healthy subjects. Upregulation of miR-150-5p was observed in AD hippocampus. We further found that higher miR-150-5p levels were correlated with the clinical measures of DAT, including lower global cognitive scores, lower CSF Aβ42 , and higher CSF total tau. Interestingly, we observed that higher miR-150-5p levels were associated with MRI brain volumes within the default mode and executive control networks, two key networks implicated in AD. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signaling pathway, including programmed cell death 4 (PDCD4 ). We found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both the transcriptional and protein levels Conclusion: Our findings demonstrated that miR-150-5p is a promising clinical blood-based biomarker for DAT Show more

Keywords: Alzheimer’s dementia, biomarker, cerebrospinal fluid, MRI, microRNA

DOI: 10.3233/JAD-220116

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1567-1584, 2022

Authors: Nabirotchkin, Serguei | Bouaziz, Jan | Glibert, Fabrice | Mandel, Jonas | Foucquier, Julie | Hajj, Rodolphe | Callizot, Noëlle | Cholet, Nathalie | Guedj, Mickaël | Cohen, Daniel

Article Type: Research Article

Abstract: Background: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. Objective: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations …of repurposed drugs for treatment of common human diseases. Methods: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. Results: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. Conclusion: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer’s disease. Show more

Keywords: Drug combination, drug repurposing, genetics, networks, neurodegeneration, pathways, systems biology

DOI: 10.3233/JAD-220120

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1585-1603, 2022

Authors: Camino, Julieta | Khondoker, Mizanur | Trucco, Ana Paula | Backhouse, Tamara | Kishita, Naoko | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: The identification and understanding of the discrepancy between caregivers’ reports of people with dementia’s (PwD) performance of activities of daily living (ADLs) and observed performance, could clarify what kind of support a PwD effectively needs when completing tasks. Strategies used by caregivers have not been included in the investigation of this discrepancy. Objective: To (1) investigate if caregivers’ report of PwD’s ADL performance are consistent with PwD’s observed performance; (2) explore if caregiver management styles, depression, and anxiety, contribute to this discrepancy. Methods: PwD (n  = 64) were assessed with standardized performance-based (Assessment of Motor and …Process Skills, AMPS) and informant-based (Disability Assessment for Dementia, DAD) ADL assessments. Caregivers completed depression (PHQ-9), anxiety (GAD-7), and dementia management style (DMSS: criticism, active-management, and encouragement) questionnaires. Cohen’s kappa determined agreement/disagreement in ADL performance. To investigate the potential discrepancy between the DAD and AMPS, a continuous variable was generated: comparative ADL score. Multiple linear regression analysis explored whether caregivers’ management styles, depression or anxiety could explain the ADL discrepancy. Results: Poor level of agreement between observed and reported ADL performance [k  = –0.025 (95% CI –0.123 –0.073)] was identified, with most caregivers underestimating ADL performance. The combined model explained 18% (R2  = 0.18, F (5,55)   = 2.52, p ≤0.05) of the variance of the comparative ADL score . Active-management (β= –0.037, t  (60)   = –3.363, p  = 0.001) and encouragement (β= 0.025, t  (60)   = 2.018, p  = 0.05) styles made the largest and statistically significant contribution to the model. Conclusion: Encouragement style could be advised for caregivers who underestimate ADL performance, while active management style for those who overestimate it. Findings have scope to increase caregivers’ abilities to support PwD activity engagement in daily life. Show more

Keywords: Activities of daily living, caregiver management styles, anxiety, depression

DOI: 10.3233/JAD-220155

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1605-1614, 2022

Authors: Ramanan, Vijay K. | Heckman, Michael G. | Przybelski, Scott A. | Lesnick, Timothy G. | Lowe, Val J. | Graff-Radford, Jonathan | Mielke, M. | Jack Jr. , Clifford R. | Knopman, David S. | Petersen, Ronald C. | Ross, Owen A. | Vemuri, Prashanthi

Article Type: Research Article

Abstract: Background: Brain accumulation of amyloid-β is a hallmark event in Alzheimer’s disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. Objective: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer’s Disease …Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. Results: Known AD risk variants in APOE , PICALM , CR1 , and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p  = 1.51×10–50 ) and ADNI (p  = 3.21×10–64 ). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. Conclusion: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity. Show more

Keywords: Alzheimer’s disease, amyloid, Apolipoprotein E, polygenic risk scores, positron emission tomography

DOI: 10.3233/JAD-220164

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1615-1625, 2022

Authors: Krishnadas, Natasha | Huang, Kun | Schultz, Stephanie A. | Doré, Vincent | Bourgeat, Pierrick | Goh, Anita M.Y. | Lamb, Fiona | Bozinovski, Svetlana | Burnham, Samantha C. | Robertson, Joanne S. | Laws, Simon M. | Maruff, Paul | Masters, Colin L. | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18 F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Methods: Tau 18 F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated …as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. Results: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen’s kappa values of 0.89 and 0.86 respectively). Tracer retention in a “hook”-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. Conclusion: Tau distribution patterns can be visually identified using 18 F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition. Show more

Keywords: Alzheimer’s disease, cognition, 18F-MK6240, patterns, positron emission tomography, tau

DOI: 10.3233/JAD-215558

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1627-1637, 2022

Authors: Xue, Chuanwei | Tang, Yi | Wang, Changming | Yang, Haibo | Li, Liang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has been confirmed as an influencing factor of visual impairment, but potential concomitant effects on visual and cognitive performance are not well understood. Objective: To provide a new method for early screening of Alzheimer’s disease and further explore the theoretical mechanism of the decline of whole visual and cognitive performance in AD. Methods: We studied 60 individuals without dementia as normal control (NC), 74 individuals with subjective cognitive decline (SCD), 60 individuals with amnesia mild cognitive impairment (aMCI), and 75 patients with AD on a battery of tests designed to measure multiple …aspects of basic and higher-order visual perception and cognition. All subjects performed on same visual and cognitive test batteries. Results: The results showed both of four groups, with the stimulus-presentation time being longer, the visual-search performance improved, and both the eye interest-area first fixation duration and the interest-area-fixation count increased. Particularly under the noise-masking condition, the AD group performed the worst at stimulus-presentation times between 300 and 900 ms. The aMCI group, but not the SCD group, performed worse than the NC group at the stimulus-presentation time of either 300 or 500 ms. The interest-area-fixation count was higher in all the patient groups than that in the NC group, and distinguishable between participants with AD and those with SCD or aMCI. Conclusion: The visual-search performance combined with eye-movement tracking under the noise-masking condition can be used for distinguishing AD from normal aging, SCD, and aMCI. Show more

Keywords: Alzheimer’s disease, attention allocation, cognitive load, eye movement tracking, visual search

DOI: 10.3233/JAD-220209

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1639-1650, 2022

Authors: Terracciano, Antonio | Piras, Maria Rita | Sutin, Angelina R. | Delitala, Alessandro | Curreli, Nicolò Camillo | Balaci, Lenuta | Marongiu, Michele | Zhu, Xianghe | Aschwanden, Damaris | Luchetti, Martina | Oppong, Richard | Schlessinger, David | Cucca, Francesco | Launer, Lenore J. | Fiorillo, Edoardo

Article Type: Research Article

Abstract: Background: Few studies have examined the associations between personality facets and dementia risk and rarely included individuals from rural settings or with low education. Objective: To examine the association between personality and the risk of cognitive impairment. Methods: Participants (N = 1,668; age 50 to 94 at baseline; 56.4% women; 86.5% less than high school diploma) were from a rural region of Sardinia (Italy) who completed the Revised NEO Personality Inventory (NEO-PI-R) during the first wave (2001–2004) and the Mini-Mental State Examination (MMSE) at waves two to five (2005–2021). Cox regression was used to test personality and covariates …as predictors of cognitive impairment based on MMSE education-adjusted cutoffs. Results: During the up to 18-year follow-up (M = 10.38; SD = 4.76), 187 individuals (11.2%) scored as cognitively impaired. Participants with higher neuroticism (particularly the depression facet [HR = 1.22, 95% CI = 1.06–1.40]), and lower agreeableness (particularly the modesty facet [HR = 0.83, 95% CI = 0.71–0.97]) and lower conscientiousness (particularly the dutifulness facet [HR = 0.78, 95% CI = 0.67–0.92]) were at higher risk of cognitive impairment. Lower warmth ([HR = 0.75, 95% CI = 0.65–0.87], facet of extraversion) and ideas ([HR = 0.76, 95% CI = 0.65–0.89], facet of openness) were also associated with increased risk of impairment. These associations were virtually unchanged in models that accounted for other risk factors, including smoking, depression, obesity, hypertension, diabetes, and apolipoprotein E (APOE ) ɛ4 carrier status. Across the five domains, sex and the APOE variant did not moderate the associations. Conclusion: In a sample with demographic characteristics underrepresented in dementia research, this study identifies personality domains and facets most relevant to the risk of cognitive impairment. Show more

Keywords: Cognition, dementia, longitudinal study, personality, risk factors

DOI: 10.3233/JAD-220400

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1651-1661, 2022

Authors: Polcher, Alexandra | Wolfsgruber, Steffen | Peters, Oliver | Frölich, Lutz | Wiltfang, Jens | Kornhuber, Johannes | Hüll, Michael | Rüther, Eckart | Lewczuk, Piotr | Maier, Wolfgang | Jessen, Frank | Wagner, Michael

Article Type: Research Article

Abstract: Background: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. Objective: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimer’s disease (AD). Methods: Memory clinic patients without dementia (N  = 558; mean age = 66; up to 3 years of follow-up; n  = 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were …retrospectively applied: 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF Aβ42 /tau-ratio indicative of AD. Results: The four definitions overlapped considerably, classified 35–58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39–46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy. Conclusion: he operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials. Show more

Keywords: Alzheimer’s disease, biomarker, cognition, conversion, dementia, diagnosis, DSM-5 mild NCD, mild cognitive impairment, prognosis

DOI: 10.3233/JAD-215548

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1663-1678, 2022