Current Alzheimer Research - Volume 17, Issue 2, 2020

Objectives: Previous case-control studies have focused on the relationship between ALDH2 gene polymorphism and late-onset Alzheimer's Disease (LOAD), but no definite unified conclusion has been reached. Therefore, the correlation between ALDH2 Glu504Lys polymorphism and LOAD remains controversial. To analyze the correlation between ALDH2 polymorphism and the risk of LOAD, we implemented this up-to-date meta-analysis to assess the probable association. Methods: Studies were searched through China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, China Biology Medicine, PubMed, Cochrane Library, Clinical- Trials.gov, Embase, and MEDLINE from January 1, 1994 to December 31, 2018, without any restrictions on language and ethnicity. Results: Five studies of 1057 LOAD patients and 1136 healthy controls met our criteria for the analysis. Statistically, the ALDH2 GA/AA genotype was not linked with raising LOAD risk (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 0.96-2.28, p = 0.07). In subgroup analysis, the phenomenon that men with ALDH2*2 had higher risk for LOAD (OR = 1.72, 95%CI = 1.10-2.67, p = 0.02) was observed. Conclusion: This study comprehends only five existing case-control studies and the result is negative. The positive trend might appear when the sample size is enlarged. In the future, more large-scale casecontrol or cohort studies should be done to enhance the association between ALDH2 polymorphism and AD or other neurodegenerative diseases.

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

Background: To delay the decline in cognition and reduce the incidence of dementia, the precise detection of Mild Cognitive Impairment (MCI) is necessary. The application of Virtual Reality (VR) technology in this detection can overcome the shortage of traditional paper-and-pencil tests. Objective: This review aimed to summarize the research progress of the detection of MCI using VR. Methods: Eight databases from their inception to November 19, 2019, were systematically searched for studies applying VR in the detection of MCI. A thematic analysis was conducted according to the specific detection purpose and the main corresponding cognitive domains assessed were summarized; characteristics of the VR applications were also summarized. Results: Twenty-eight studies were finally included. The detection purposes included discrimination between healthy controls and those with MCI, discrimination between aMCI subtypes, detection of MCI patients at risk of Alzheimer’s Disease (AD), and discrimination between MCI and AD. VR tasks assessing spatial memory were applicable for all detection purposes, and the assessment of combinations of memory and executive function seemed more sensitive. Executive function and intentional episodic memory could be assessed to discriminate among healthy controls, individuals with MCI and those with AD. Incidental episodic memory was effective in detecting MCI with hippocampal atrophy. The most common characteristics of the VR applications were the use of semi-immersion, joysticks or gamepad interactions and simple, one-time behavioral assessments. Conclusion: VR applications are promising in the detection of MCI, but further research is needed for clinical use.

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Methods: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

Background: Individuals with amnestic Mild Cognitive Impairment (aMCI) are at heightened risk of developing Alzheimer's dementia. In recent years, much attention has been given to the search for new interventions to slow down the progression of cognitive decline of these patients. Wearable digital camera devices are one form of new technology that captures images of one’s life events, so they constitute a promising method to be used as a means to stimulate recent autobiographical memory. Objective: This preliminary study investigates the ability of a new cognitive intervention based on exposure to recent autobiographical memory captured by wearable cameras to improve episodic memory in patients with aMCI. Methods: Seventeen subjects wore a wearable camera while they went about their daily activities. The images captured were converted into eight different 3-minute films containing the most relevant information of each event. The intervention involved eight individualized weekly sessions during which patients were exposed to a different autobiographical event each week. Besides, several specific questions were formulated within each session. Clinical questionnaires assessing cognitive reserve, premorbid intelligence, depression, and anxiety were administered at baseline. Measures of objective episodic memory were applied at baseline and at post-treatment. Results: Significant improvements were observed at post-treatment in memory measures, and significant associations were found between memory change scores and age and cognitive reserve. Anyway, these associations did not reach statistical significance after adjusting for multiple comparisons. Conclusion: The present study provides preliminary evidence that aMCI patients may benefit from a cognitive intervention program based on re-experiencing recent autobiographical events. However, future studies incorporating a control group will be needed to confirm these preliminary findings.

Background: Subjective Cognitive Decline (SCD) is the early preclinical stage of Alzheimer's Disease (AD). Previous study provided an invaluable contribution by showing that a tactile angle discrimination system can be used to distinguish between healthy older individuals and patients with mild cognitive impairment and AD. However, that study paid little attention to the relationship between tactile angle discrimination and SCD. Therefore, a means of differentiating Normal Controls (NCs), elderly subjects with SCD, patients with amnestic Mild Cognitive Impairment (aMCI), and AD is urgently needed. Methods: In the present study, we developed a novel tactile discrimination device that uses angle stimulation applied to the index finger pad to identify very small differences in angle discrimination between the NC (n = 30), SCD (n = 30), aMCI (n = 30), and AD (n = 30) groups. Using a three-alternative forced-choice and staircase method, we analyzed the average accuracy and threshold of angle discrimination. Results: We found that accuracy significantly decreased while thresholds of angle discrimination increased in the groups in the following order: NC, SCD, aMCI, and AD. The area under the receiver operating characteristic curve also indicated that the tactile angle discrimination threshold was better than Mini-Mental State Examination scores in distinguishing NC individuals and SCD patients. Conclusion: These findings emphasize the importance of tactile working memory dysfunction in explaining the cognitive decline in angle discrimination that occurs in SCD to AD patients and offer further insight into the very early detection of subjects with AD.

Background: Intracranial Atherosclerotic Stenosis (ICAS) is an important risk factor for cognitive impairment. However, it is unclear whether patients with ICAS are more likely to develop cognitive impairment after an acute, non-disabling ischemic stroke (minor stroke). Objective: We aimed to investigate the association between ICAS and post-stroke cognitive impairment. Methods: In this cross-sectional study, patients with acute, non-disabling ischemic stroke underwent two cognitive tests and imaging evaluation for ICAS, within two weeks after the stroke. To determine the association between ICAS and post-stroke cognitive impairment, we performed a multivariate logistic regression analysis adjusted for several demographic and vascular risk factors. Results: Of the 164 patients with minor stroke in this study, 98 (59.76%) were diagnosed with poststroke cognitive impairment (Montreal Cognitive Assessment score<26). After adjusting for potential confounders, we found that patients with ICAS were more likely to develop cognitive impairment after an acute, non-disabling ischemic stroke, compared to patients without ICAS (Odds Ratio: 2.13; 95% Confidence Interval: 1.07-4.26), and underperformed in the tests of visuospatial and executive function. Conclusion: In this cross-sectional study of a population that has experienced a minor stroke, our findings demonstrated a positive association between ICAS and post-stroke cognitive impairment.

Background: Approximately 40 independent Single Nucleotide Polymorphisms (SNPs) have been associated with Alzheimer’s Disease (AD) or cognitive decline in genome-wide association studies. Objective: We aimed to evaluate the joint effect of genetic polymorphisms and environmental factors on the progression from Mild Cognitive Impairment (MCI) to AD (MCI-AD progression) in a Chinese community cohort. Methods: Demographic, DNA and incident AD diagnosis data were derived from the follow-up of 316 participants with MCI at baseline of the Shanghai Aging Study. The associations of 40 SNPs and environmental predictors with MCI-AD progression were assessed using the Kaplan-Meier method with the log-rank test and Cox regression model. Results: Rs4147929 at ATP-binding cassette family A member 7 (ABCA7) (AG/AA vs. GG, hazard ratio [HR] = 2.43, 95% confidence interval [CI] 1.24-4.76) and body mass index (BMI) (overweight vs. non-overweight, HR = 0.41, 95% CI 0.22-0.78) were independent predictors of MCI-AD progression. In the combined analyses, MCI participants with the copresence of non-overweight BMI and the ABCA7 rs4147929 (AG/AA) risk genotype had an approximately 6-fold higher risk of MCI-AD progression than those with an overweight BMI and a non-risk genotype (HR = 6.77, 95% CI 2.60-17.63). However, a nonsignificant result was found when participants carried only one of these two risk factors (nonoverweight BMI and AG/AA of ABCA7 rs4147929). Conclusion: ABCA7 rs4147929 and BMI jointly affect MCI-AD progression. MCI participants with the rs4147929 risk genotype may benefit from maintaining an overweight BMI level with regard to their risk for incident AD.

Background: In addition to the traditional risk predictors, whether anemia is an early biomarker of dementia, needs to be confirmed. Objective: This population-based cohort study aimed to investigate the dementia risk in patients with newly diagnosed anemia using data from the Taiwan National Health Insurance Research Database. Methods: All newly diagnosed anemia patients (n = 26,343) with no history of stroke hospitalization, central nervous disease other than dementia, psychiatric disorders, traumatic brain injury, major operations, or blood loss diseases, were enrolled. A group of non-anemic controls, 1:4 matched with anemic patients on the basis of demographics and comorbidities, was also included. A competing risk analysis was used to evaluate the dementia risk in anemic patients compared to that of their matched controls. Results: The adjusted subdistribution hazard ratio (SHR) of dementia risk in anemic patients was 1.14 (95% confidence interval [CI]: 1.08~1.21, p<0.001). Patients with iron supplements tended to exhibit a lower dementia risk (adjusted SHR: 0.84; 95% CI: 0.75~0.94, p=0.002) compared to patients without iron supplement. A subgroup analysis showed that a positive association between dementia and anemia existed in females, those aged 70 years and older, and patients without hypertension, diabetes, or hyperlipidemia. Conclusion: The present population-based cohort study identified that newly diagnosed anemia is a risk factor for dementia and also that iron supplementation was able to reduce the risk of dementia in people with iron deficiency anemia.