Journal of Alzheimer's Disease - Volume 75, issue 1

Authors: Horvath, Alexandra | Salman, Zeinab | Quinlan, Patrick | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer’s disease (AD) patients had vascular comorbidities. Objective and Methods: A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. Results: After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I …and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005–3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10–4.48). In the total study population (n  = 76) as well in the AD group (n  = 40), serum IGF-I correlated negatively with CSF Aβ1-42 , and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. Conclusion: In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia. Show more

Keywords: Alzheimer’s disease, cerebral vascular pathology, cerebrospinal fluid, CSF AD biomarkers, IGF-I, serum

DOI: 10.3233/JAD-190921

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 289-298, 2020

Authors: Ou, Ya-Nan | Zhu, Jun-Xia | Hou, Xiao-He | Shen, Xue-Ning | Xu, Wei | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The role of infectious agents in the development of Alzheimer’s disease (AD) has long been debated, however, uncertainties still persist. Objective: We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Methods: Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Results: Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. …Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81–10.67; I2  = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04–7.75; I2  = 0%, Epstein-Barr virus (OR:1.45, 95% CI = 1.00–2.08; I2  = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02–1.75; I2  = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15–1.74; I2  = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. Conclusion: These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future. Show more

Keywords: Alzheimer’s disease, Chlamydia pneumoniae, Herpesviridae, infectious, meta-analysis

DOI: 10.3233/JAD-191337

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 299-309, 2020

Authors: Cheng, Yan | Ahmed, Ali | Zamrini, Edward | Tsuang, Debby W. | Sheriff, Helen M. | Zeng-Treitler, Qing

Article Type: Research Article

Abstract: Background: Racial disparity in the epidemiology of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) has been reported. However, less is known about this disparity among Veterans. Objective: To estimate the racial disparity in AD/ADRD among the Veterans. Methods: Of the 5,413,418 Veterans≥65 years receiving care at the Veterans Health Administration (1999–2016), 4,045,269 were free of prevalent AD/ADRD, schizophrenia, or bipolar disorder at baseline. Of these, 432,469 were African American. Race was self-identified and incident AD/ADRD during 20 (median 6.7) years of follow-up was ascertained using International Classification of Diseases codes. Results: Patients had a …mean age of 70.4 (±6.6) years and 97.8% were men. Age-sex-adjusted incidence of AD/ADRD per 1,000 person-year was 19.3 and 10.8 for African American and white Veterans, respectively (age-sex-adjusted hazard ratio associated with African American race, 1.77; 95% confidence interval, 1.75–1.79; p  < 0.0001). This association remained essentially unchanged after multivariable adjustment (hazard ratio, 1.67; 95% confidence interval, 1.65–1.69; p  < 0.0001). Among the key baseline characteristics that were significant predictors of AD/ADRD in both races, stroke was a significantly stronger predictor among African Americans, and Hispanic ethnicity and depression among whites (p-value for all interaction,<0.0001). Conclusion: The findings of a higher incidence of AD/ADRD among African American Veterans is consistent with the findings in the general population reported in the literature, although the overall incidence appears to be lower than that in the general population. Future studies need to examine this disparity in incidence as well as the between-race heterogeneity in AD/ADRD risk. Show more

Keywords: dementia, health status disparities, incidence, race factors

DOI: 10.3233/JAD-191188

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 311-320, 2020

Authors: Schedin-Weiss, Sophia | Nilsson, Per | Sandebring-Matton, Anna | Axenhus, Michael | Sekiguchi, Misaki | Saito, Takashi | Winblad, Bengt | Saido, Takaomi | Tjernberg, Lars O.

Article Type: Research Article

Abstract: Background: The 42 amino acids long amyloid-β peptide, Aβ42 , may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer’s disease (AD) brain. However, the underlying molecular mechanisms remain to be established. Objective: To find early Aβ42 -induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, AppNL -F , expressing high levels of Aβ42 without AβPP overexpression artifacts. Methods: Hippocampus and cortex were analyzed separately by using 18 O-labelling mass spectrometry to reveal alterations in protein levels. Pathway …analysis of proteomics data was used to identify altered biological functions. Immunohistochemistry was used to further investigate a significant key regulatory protein. Results: Around 100 proteins were differently expressed in AppNL -F mice at each time point (3, 6, 9, and 18 months of age) as compared to wild type mice. Strikingly, already at 3 months of age—long before Aβ plaque development and memory impairment—several pathways, including long-term potentiation and synaptic plasticity, were downregulated, and neuritogenesis was increased. Huntingtin (HTT) was identified as an upstream regulator, i.e., a key protein affecting the levels of several proteins. Increased levels of HTT in hippocampus of AppNL -F mice was supported by immunofluorescence microscopy. Conclusion: Notably, the proteome was significantly altered already at 3 months of age, 6 months before the development of plaques. Differentially expressed proteins varied over time, indicating that increased Aβ42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory. Show more

Keywords: Alzheimer’s disease, amyloid-β, App knock-in mouse model, ingenuity pathway analysis, proteomics

DOI: 10.3233/JAD-200028

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 321-335, 2020

Authors: Hunter, Sally | Hokkanen, Suvi R.K. | Keage, Hannah A.D. | Fleming, Jane | Minett, Thais | Polvikoski, Tuomo | Allinson, Kieren | Brayne, Carol | the Cambridge City over 75s Cohort collaboration

Article Type: Research Article

Abstract: Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation …state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia. Show more

Keywords: Aging, dementia, hippocampus, phosphorylation, population study, TAR-DNA binding protein of 43 kDa

DOI: 10.3233/JAD-191093

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 337-350, 2020

Article Type: Correction

DOI: 10.3233/JAD-209002

Citation: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 361-361, 2020