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

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