Journal of Alzheimer's Disease - Volume 93, issue 4

Authors: Li, Yujiao | Chang, Jun | Chen, Xi | Liu, Jianwei | Zhao, Lan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive degenerative disease of the nervous system (CNS) with an insidious onset. Clinically, it is characterized by a full range of dementia manifestations including memory impairment, aphasia, loss of speech, loss of use, loss of recognition, impairment of visuospatial skills, and impairment of executive function, as well as changes in personality and behavior. The exact cause of AD has not yet been identified. Nevertheless, modern research indicates that genetic factors contribute to 70% of human’s risk of AD. Apolipoprotein (APOE ) accounts for up to 90% of the genetic predisposition. APOE is a crucial …gene that cannot be overstated. In addition, innate immunity plays a significant role in the etiology and treatment of AD. Understanding the different subtypes of APOE and their interconnections is of paramount importance. APOE and innate immunity, along with their relationship to AD, are primary research motivators for in-depth research and clinical trials. The exploration of novel technologies has led to an increasing trend in the study of AD at the cellular and molecular levels and continues to make more breakthroughs and progress. As of today, there is no effective treatment available for AD around the world. This paper aims to summarize and analyze the role of APOE and innate immunity, as well as development trends in recent years. It is anticipated that APOE and innate immunity will provide a breakthrough for humans to hinder AD progression in the near future. Show more

Keywords: Alzheimer’s disease, apolipoprotein, genetic factors, innate immunity, progression

DOI: 10.3233/JAD-230179

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1195-1210, 2023

Authors: Moyaert, Paulien | Beun, Soetkin | Achten, Eric | Clement, Patricia

Article Type: Systematic Review

Abstract: Background: Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated. Objective: In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine. Results: Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. …These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment. Conclusion: AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data. Show more

Keywords: Acetylcholinesterase inhibitors, alzheimer’s disease, biological variation, diagnosis, perfusion

DOI: 10.3233/JAD-221125

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1211-1221, 2023

Authors: Qu, Yi | Zhuang, Lin | Zhang, Huiying | Liu, Chang | Wang, Xiaonan

Article Type: Systematic Review

Abstract: Background: Depression is one of the most common symptoms in patients with dementia. Objective: This meta-analysis aimed to evaluate the effect of light therapy on depression associated with dementia by using a single scale. Methods: Published studies based on the terms including “Dementia”, “depression”, and “Phototherapy” were searched. Web of Science, PubMed, Embase, CiNii, CNKI, Wanfang Database, and China Biology Medicine disc were adopted to collect randomized controlled studies or cross-controlled studies using the Cornell Scale for Depression in Dementia (CSDD) until February 2022. GRADE and Review Manager Version 5.4.1 were employed to assess the risk …of bias. A meta-analysis was conducted by R 4.0.2 software based on the changes in CSDD scores. Results: A total of 1,055 studies were retrieved from the databases, and six studies were included after screening. Some 406 people with dementia were included with an average age of over 80 years. Forest plot results showed that light intervention improved depression scores of dementia patients (MD = –2.59, 95% CI: –4.46 to –0.71), and light intensity less than 1,000 lux improved depression symptoms of dementia patients (MD = –2.76, 95% CI: –4.55 to –0.97). An intervention that lasted 8 to 12 weeks was the most effective (MD = –3.77, 95% CI: –6.93 to –0.60), and non-stable interventions such as ceiling LED lights exerted more positive effects (MD = –2.12, 95% CI: –3.38 to –0.85). Conclusion: The overall results of the meta-analysis suggested that light intervention can improve the depressive symptoms of older patients with dementia. Show more

Keywords: Alzheimer’s disease, cornell scale for depression in dementia, dementia, depression, light therapy, older patients

DOI: 10.3233/JAD-221204

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1223-1235, 2023

Authors: Abbate, Carlo

Article Type: Research Article

Abstract: Alzheimer’s disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this “reactive” pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario …involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission. Show more

Keywords: Amyloid, microglia, neurofibrillary tangles, neurogenesis, tauopathies

DOI: 10.3233/JAD-221279

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1237-1276, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Short Communication

Abstract: In clinical trials, lecanemab and donanemab showed statistically significant yet marginal slowdown of Alzheimer’s disease (AD)-associated cognitive decline. This could be due to their sub-optimal design and/or deployment; alternatively, their limited efficiency could be intrinsic. Distinguishing between the two is of great importance considering the acute need of efficient AD therapy and tremendous resources being invested in its pursuit. The present study analyzes the mode of operation of lecanemab and donanemab within the framework of recently proposed Amyloid Cascade Hypothesis 2.0 and concludes that the second possibility is correct. It suggests that substantial improvement of the efficiency of these drugs …in symptomatic AD is unlikely and proposes the alternative therapeutic strategy. Show more

Keywords: Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0, AβPP-independent iAβ generation in AD, intraneuronal Aβ, lecanemab, donanemab

DOI: 10.3233/JAD-230164

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1277-1284, 2023

Authors: Blusztajn, Jan Krzysztof | Slack, Barbara E.

Article Type: Article Commentary

Abstract: Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer’s disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo . However, until the advent of techniques capable of measuring thousands of metabolites in a single sample, it has not been possible to rank the relative magnitude of these abnormalities. A recent study provides evidence that the abnormal turnover of the brain’s most abundant phospholipids: phosphatidylcholine and phosphatidylethanolamine, constitutes a major metabolic pathology in AD. We place this observation in a historical context and discuss the implications of a central role for phospholipid metabolism in AD …pathogenesis. Show more

Keywords: Alzheimer’s disease, lipidomics, glycerophosphocholine, glycerophosphoethanolamine, metabolome, metabolomics, phosphatidylcholine, phosphatidylethanolamine

DOI: 10.3233/JAD-230061

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1285-1289, 2023

Authors: Zhou, Yujia | Dong, Jingyi | Song, Jingmei | Lvy, Chaojie | Zhang, Yuyan

Article Type: Research Article

Abstract: Background: Considering the strong correlation made between Alzheimer’s disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD. Objective: Reveal the pathological relationship between AD and insulin resistance. Methods: We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic …regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE). Results: 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p  < 0.001), FINS (p  < 0.001), and HOMA-IR (p  < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p  = 0.001) and positively related to the sex ratio (male versus female) (p  < 0.05). HOMA-IR obeyed lognormal distribution (p  > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p  = 0.479) was positively correlated to MMSE, while FINS (p  = 0.1657) was negatively correlated with MMSE. Conclusion: The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients. Show more

Keywords: Alzheimer’s disease, disease degree, glucose metabolism, incidence risk, systematic analysis

DOI: 10.3233/JAD-220751

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1291-1306, 2023

Authors: Yahagi-Estevam, Maristella | Farias-Itao, Daniela Souza | Leite, Renata Elaine Paraizo | Rodriguez, Roberta Diehl | Pasqualucci, Carlos Augusto | Nitrini, Ricardo | Jacob-Filho, Wilson | Power, Melinda C. | Suemoto, Claudia Kimie

Article Type: Research Article

Abstract: Background: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples. Objective: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study. Methods: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that …were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias. Results: In 253 participants (mean age = 78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95% CI = 0.69; 1.06, p  = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95% CI = 1.39; 11.6, p  = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95% CI = 0.60; 1.16, p  = 0.28). Conclusion: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples. Show more

Keywords: Aging, Alzheimer’s disease, atherosclerosis, bias, cognitive impairment, dementia

DOI: 10.3233/JAD-220820

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1307-1316, 2023

Authors: Yang, Mingfeng | Chen, Ben | Zhou, Huarong | Mai, Naikeng | Zhang, Min | Wu, Zhangying | Peng, Qi | Wang, Qiang | Liu, Meiling | Zhang, Si | Lin, Gaohong | Lao, Jingyi | Zeng, Yijie | Zhong, Xiaomei | Ning, Yuping

Article Type: Research Article

Abstract: Background: Both late-life depression (LLD) and short sleep duration increase the risk of cognitive impairment. Increased insular resting-state functional connectivity (FC) has been reported in individuals with short sleep duration and dementia. Objective: This study aimed to investigate whether short sleep duration is associated with impaired cognition and higher insular FC in patients with LLD. Methods: This case– control study recruited 186 patients with LLD and 83 normal controls (NC), and comprehensive psychometric assessments, sleep duration reports and resting-state functional MRI scans (81 LLD patients and 54 NC) were conducted. Results: Patients with LLD …and short sleep duration (LLD-SS patients) exhibited more severe depressive symptoms and worse cognitive function than those with normal sleep duration (LLD-NS patients) and NC. LLD-SS patients exhibited higher FC between the bilateral insula and inferior frontal gyrus (IFG) pars triangularis than LLD-NS patients and NC, while LLD-NS patients exhibited lower FC than NC. Increased insular FC was correlated with short sleep duration, severe depressive symptoms, and slower information processing speeds. Furthermore, an additive effect was found between sleep duration and LLD on global cognition and insular FC. Conclusion: LLD-SS patients exhibited impaired cognition and increased insular FC. Abnormal FC in LLD-SS patients may be a therapeutic target for neuromodulation to improve sleep and cognitive performance and thus decrease the risk of dementia. Show more

Keywords: Alzheimer’s disease, cognitive impairment, functional connectivity, late-life depression, MRI, sleep duration

DOI: 10.3233/JAD-220968

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1317-1327, 2023

Authors: Rakuša, Elena | Fink, Anne | Tamgüney, Gültekin | Heneka, Michael T. | Doblhammer, Gabriele

Article Type: Research Article

Abstract: Background: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. Objective: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer’s disease). Methods: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. …We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. Results: Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14–1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90–0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90–0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90–0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88–0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85–0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92–0.99). Conclusion: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance. Show more

Keywords: Alzheimer’s disease, antibiotics, conditional logistic regression, dementia, epidemiology, nested case-control studies

DOI: 10.3233/JAD-221153

Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1329-1339, 2023