Current Alzheimer Research - Volume 19, Issue 3, 2022

Background: The hypothesis that a dyshomeostasis of Ca²⁺ increases the incidence of dementia has been established. Several discoveries have emphasized the concept that a decrease in the excess of Ca²⁺ could be an interesting pharmacological target to alleviate dementia symptoms. Aging along with a healthy brain can be supported by daily exercise, self-control in caloric ingestion, and participation in intellectually challenging events. These lifestyle factors may alleviate the excess of Ca²⁺ resulting from a Ca²⁺ dyshomeostasis. Curiously, epidemiological and clinical studies have also reported a clinical relationship between hypertension, diabetes, and other inflammatory processes, and a higher risk of cognition decline. Considering the cumulative data from the scientific literature, including data of high evidence such as meta-analysis and systematic reviews, we can now link a Ca²⁺ dyshomeostasis as an upstream factor for hypertension, diabetes and other inflammatory processes, and dementia. Several reports have also indicated that increasing cAMP levels may induce neuroprotective outcomes, thus alleviating dementia symptoms. Methods: With these concepts in mind, we found that the pharmacological manipulation of Ca²⁺/cAMP signalling could be a novel plausible target to treat dementia. This article puts together fundamental concepts and current therapies to treat dementia, including novel therapeutics coming from the pharmacological manipulation of Ca²⁺/cAMP signalling. Results: Then, combined with improvements in the lifestyle issues, these novel therapeutics may allow sustained improvements in the life quality of age-related neurological patients. Conclusions: In addition, considering coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviewed recent reports about Ca2+ channel blockers' role in restoring Ca²⁺ signalling disruption due to COVID-19. Finally, this article also presents a timeline of the major events in Ca²⁺/cAMP signaling.

Background: Conditions along the brain-gut-microbiota (BGM) axis can significantly contribute to the pathogenesis of Alzheimer's disease (AD). Evidence from animal studies indicates a role of probiotics in regulating mood, cognition, and stress response via the BGM axis. However, the effect of probiotics on AD needs to be better clarified in preclinical and clinical studies. Methods: We prepared this systematic review according to PRISMA. PubMed, Web of Science, Embase, and Virtual Health Library (VHL) were searched for original articles concerning the effects of probiotics in experimental AD. Results: Results were presented as a narrative synthesis according to the Synthesis Without Metaanalysis (SWiM) Guideline. Seventeen studies met the inclusion criteria. The results showed significant effects in the experimental models of AD treated with probiotics alone or in mixture due to expressive improvements in cognitive tests. Conclusion: Furthermore, in most of the included studies, it was possible to observe a reduction in inflammatory processes, an increase in the concentration of peptide hormones, insulin homeostasis in the brain, increased antioxidant enzymes, and a decrease in beta-amyloid deposition and tau hyperphosphorylation. Supplementation of probiotics seems to improve performance in cognitive tests and increase the concentration of substances capable of delaying the neurodegenerative process of AD in experimental models.

Background: Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are screened to distinguish whether the cognitive decline in older adults is attributed to pathological causes rather than normal aging. Objective: The purpose of this review was to analyze the diagnostic performance of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in screening for MCI and AD. Methods: Electronic searches were performed on MEDLINE, EMBASE, CINAHL, and PsycArticles databases using the following keywords: dementia and ADAS-Cog. The Quality Assessment of Diagnostic Accuracy Studies-2 was used to check the risk of bias in the diagnostic studies. Results: We reviewed 14 studies, including 3,875 patients who met the selection criteria. In 2,624 MCI patients from nine studies, the pooled sensitivity of ADAS-Cog was 0.80 (95% confidence interval [CI], 0.68–0.88), the pooled specificity was 0.84 (95% CI, 0.75–0.90), and the area under the curve of summary receiver-operating characteristic curves (SROC AUC) was 0.89 (SE = 0.03). In 2,517 AD patients from 10 studies, the pooled sensitivity and pooled specificity were 0.91 (95% CI, 0.86–0.95) and 0.93 (95% CI, 0.88–0.95), respectively, and the sROC AUC was 0.97 (SE = 0.01). Although sub-analyzed according to age and years of education, there was no significant difference in the predictive validity of the ADAS-Cog. Conclusion: The ADAS-Cog has high predictive validity as a screening tool in both MCI and AD and has better diagnostic performance in patients with AD. When early screening for AD is desired, ADAS-Cog is a first-stage screening tool that can be initially employed.

Introduction: Eye movement patterns during reading are well defined and documented. Each eye movement ends up in a fixation point, which allows the brain to process the incoming information and program the following saccade. In this work, we investigated whether eye movement alterations during a reading task might be already present in middle-aged, cognitively normal offspring of late-onset Alzheimer’s disease (O-LOAD). Methods: 18 O-LOAD and 18 age-matched healthy individuals with no family history of LOAD participated in the study. Participants were seated in front of a 20-inch LCD monitor, and single sentences were presented on it. Eye movements were recorded with an eye tracker with a sampling rate of 1000 Hz. Results: Analysis of eye movements during reading revealed that O-LOAD displayed more fixations, shorter saccades, and shorter fixation durations than controls. Conclusion: The present study shows that O-LOAD experienced alterations in their eye movements during reading. O-LOAD eye movement behavior could be considered an initial sign of oculomotor impairment. Hence, the evaluation of eye movement during reading might be a useful tool for monitoring well-defined cognitive resources.

Background: Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5–10% of all Alzheimer's disease (AD) cases. To date, although only 10-15% of familial EOAD cases have been explained, the genetic cause of the vast proportion of cases has not been explained. The variant Alzheimer's disease with spastic paraparesis (var- AD) is defined as a rare clinical entity characterized by early-onset dementia, spasticity of the lower extremities, and gait disturbance. Although the disease was first associated with variants in exon 9 of the PSEN1 gene, it was later shown that variations in other exons were also responsible for the disease. Objective: The current study aims to raise awareness of varAD, which occurs as a rare phenotype due to pathogenic variants in PSEN1. In addition, we aimed to evaluate the spectrum of mutations in varAD patients identified to date. Methods: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by Sanger sequencing. Also, a review of the molecularly confirmed patients with (varAD) from the literature was evaluated. Results: We identified a heterozygous splicing variant (c.869-1G>A) in the PSEN1 gene, in a family with two affected individuals who present with varAD. We reported the clinical and genetic findings from the affected individuals. Conclusion: We present the detailed clinical and genetic profiles of a Turkish patient with the diagnosis of varAD together with subjects from the literature. Together, we think that the clinical characteristics and the effect of the (c.869-1G>A) variant will facilitate our understanding of the PSEN1 gene in AD pathogenesis.

Background: Insulin-degrading enzyme (IDE) is a widely distributed Zn2+-binding metalloprotease that cleaves multiple short and medium-sized peptides prone to form β-structures. These include insulin and amyloid-β peptides. Accumulation and fibrillation of amyloid-β peptides leading to the formation of amyloid plaques is a characteristic sign of Alzheimer’s disease (AD) pathology. Objective: The study investigated the rs2421943 single nucleotide polymorphism (SNP) of the IDE gene as a risk factor for MCI (mild cognitive impairment) and AD. Methods: Two independent groups of 1670 patients and controls were included. The AD group consisted of 595 patients and 400 controls; the MCI group involved 135 patients and 540 matched controls. PCR and restriction fragment length analysis were used to analyze the rs2421943 polymorphism. Using the miRBase and RNA22 prediction tools in silico indicated that the rs2421943 polymorphism is a potential target for a specific miRNA (hsa-miR-7110-5p). Results: AG and GG genotypes of rs2421943 significantly increased the risk of AD, and the AG genotype increased the risk of MCI. It seems the G allele both increases the risk of AD and accelerates the transition through the MCI phase. In silico study revealed that rs2421943 is inside the sequence binding miRNA hsa-miR-7110-5p. The polymorphism could affect the rate of IDE pre-RNA (heterogeneous nuclear RNA, hnRNA) processing, resulting in slower translation, lower levels of IDE, deficient removal of amyloid-β fragments, and greater risk of and/or accelerated progression of AD. Conclusion: GG and AG genotypes of the single nucleotide polymorphism rs2421943 of insulindegrading enzyme gene increase the risk of AD and MCI.

Background: Alzheimer’s disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many acetylcholinesterase inhibitors, such as donepezil, are widely used for the treatment of AD. On the other hand, the efficacy of long-term donepezil use is limited. SIP3, a mixture of three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine. Objective: We assessed the synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice. Methods: In this study, a Drosophila AD model and SH-SY5Y clles were used to assess the toxicity of SIP3, and APPswe/PS1dE9 (APP/PS1) transgenic mice were used to evaluate the cognitive-behavioral and depression-like behavior effect of SIP3 and donepezil co-treatment on symptoms of AD. The cerebral cortex or hippocampus transcriptomes were analyzed by RNA sequencing and miRNA to investigate the molecular and cellular mechanisms underlying the positive effects of SIP3 on AD. Results: In the passive avoidance test (PAT) and Morris water maze (MWM) test, the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice in the mid-stage of AD compared to the group treated with donepezil only. In addition, co-administration of SIP3 and donepezil effectively reduced the depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of the cerebral cortex transcriptome and miRNA of the hippocampus showed that the gene expression profiles after a low dose SIP3 co-treatment were more similar to those of the normal phenotype mice than those obtained after the donepezil treatment alone. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, showed that differentially expressed genes were involved in the locomotor behavior and neuroactive ligand-receptor interactions. These results suggest that a co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice. Conclusion: Co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.