Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

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, delusions, dementia, hallucinations, investigational therapies, psychotic disorders

DOI: 10.3233/JAD-215483

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 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. Pre-press, no. Pre-press, pp. 1-8, 2022

Article Type: Correction

DOI: 10.3233/JAD-229007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 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. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Vyhnalek, Martin | Jester, Dylan J. | Andel, Ross | Markova, 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. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-6, 2022

Authors: Rubin-Norowitz, Mariel | Lipton, Richard B. | Petersen, Kellen | Ezzati, Ali | for the Alzheimer’s Disease Neuroimaging Initiative

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. Pre-press, no. Pre-press, pp. 1-11, 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 Aβ 40 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. Pre-press, no. Pre-press, pp. 1-10, 2022