Current Alzheimer Research - Volume 20, Issue 8, 2023

The issue of the genetics in brain imaging phenotypes serves as a crucial link between two distinct scientific fields: neuroimaging genetics (NG). The articles included here provide solid proof that this NG link has considerable synergy. There is a suitable collection of articles that offer a wide range of viewpoints on how genetic variations affect brain structure and function. They serve as illustrations of several study approaches used in contemporary genetics and neuroscience. Genome-wide association studies and candidate-gene association are two examples of genetic techniques. Cortical gray matter structural/volumetric measures from magnetic resonance imaging (MRI) are sources of information on brain phenotypes. Together, they show how various scientific disciplines have benefited from significant technological advances, such as the single-nucleotide polymorphism array in genetics and the development of increasingly higher-resolution MRI imaging. Moreover, we discuss NG’s contribution to expanding our knowledge about the heterogeneity within Alzheimer’s disease as well as the benefits of different network analyses.

Background: Alzheimer's disease is the most common neurodegenerative disorder. Recent development in sciences has also identified the pivotal role of microRNAs (miRNAs) in AD pathogenesis.Objectives: We proposed a novel method to identify AD pathway-specific statistically significant miRNAs from the targets of known AD drugs. Moreover, microRNA scaffolds and corresponding drug scaffolds of different pathways were also discovered.Material and Methods: A Wilcoxon signed-rank test was performed to identify pathway-specific significant miRNAs. We generated feed-forward loop regulations of microRNA-TF-gene-based networks, studied the minimum free energy structures of pre-microRNA sequences, and clustered those microRNAs with their corresponding structural motifs of robust transcription factors. Conservation analyses of significant microRNAs were done, and the phylogenetic trees were constructed. We identified 3’UTR binding sites and chromosome locations of these significant microRNAs.Results: In this study, hsa-miR-4261, hsa-miR-153-5p, hsa-miR-6766, and hsa-miR-4319 were identified as key miRNAs for the ACHE pathway and hsa-miR-326, hsa-miR-6133, hsa-miR-4251, hsa-miR-3148, hsa-miR-10527-5p, hsa-miR-527, and hsa-miR-518a were identified as regulatory miRNAs for the NMDA pathway. These miRNAs were regulated by several AD-specific TFs, namely RAD21, FOXA1, and ESR1. It has been observed that anisole and adamantane are important chemical scaffolds to regulate these significant miRNAs.Conclusion: This is the first study that developed a detailed correlation between known AD drug scaffolds and their AD target-specific miRNA scaffolds. This study identified chromosomal locations of microRNAs and corresponding structural scaffolds of transcription factors that may be responsible for miRNA co-regulation for Alzheimer's disease. Our study provides hope for therapeutic improvements in the existing microRNAs by regulating pathways and targets.

Background: The development of biomarkers that are easy to collect, process, and store is a major goal of research on current Alzheimer’s Disease (AD) and underlies the growing interest in plasma biomarkers. Biomarkers with these qualities will improve diagnosis and allow for better monitoring of therapeutic interventions. However, blood collection strategies have historically differed between studies. We examined the ability of various ultrasensitive plasma biomarkers to predict cerebral amyloid status in cognitively unimpaired individuals when collected using acid citrate dextrose (ACD). We then examined the ability of these biomarkers to predict cognitive impairment independent of amyloid status.Methods: Using a cross-sectional study design, we measured amyloid beta 42/40 ratio, pTau-181, neurofilament-light, and glial fibrillary acidic protein using the Quanterix Simoa® HD-X platform. To evaluate the discriminative accuracy of these biomarkers in determining cerebral amyloid status, we used both banked plasma and 18F-AV45 PET cerebral amyloid neuroimaging data from 140 cognitively unimpaired participants. We further examined their ability to discriminate cognitive status by leveraging data from 42 cognitively impaired older adults. This study is the first, as per our knowledge, to examine these specific tests using plasma collected using acid citrate dextrose (ACD), as well as the relationship with amyloid PET status.Results: Plasma AB42/40 had the highest AUC (0.833, 95% C.I. 0.767-0.899) at a cut-point of 0.0706 for discriminating between the two cerebral amyloid groups (sensitivity 76%, specificity 78.5%). Plasma NFL at a cut-point of 20.58pg/mL had the highest AUC (0.908, 95% CI 0.851- 0.966) for discriminating cognitive impairment (sensitivity 84.8%, specificity 89.9%). The addition of age and apolipoprotein e4 status did not improve the discriminative accuracy of these biomarkers.Conclusion: Our results suggest that the Aβ42/40 ratio is useful in discriminating clinician-rated elevated cerebral amyloid status and that NFL is useful for discriminating cognitive impairment status. These findings reinforce the growing body of evidence regarding the general utility of these biomarkers and extend their utility to plasma collected in a non-traditional anticoagulant.

Objectives: Cerebral blood flow (CBF) is an important index for measuring brain function. Studies have shown that regional CBF changes inconsistently in mild cognitive impairment (MCI). Arterial spin labeling (ASL) is widely used in the study of CBF in patients with MCI. However, alterations in CBF connectivity in these patients remain poorly understood.Methods: In this study, 3D pseudo-continuous arterial spin labeling (3D-pCASL) technology was used to investigate the changes in regional CBF and CBF connectivity between 32 MCI patients and 32 healthy controls. The normalized CBF was used to reduce inter-subject variations. Both group comparisons in the CBF and correlations between CBF alterations and cognitive scores were assessed. CBF connectivity of brain regions with regional CBF differences was also compared between groups.Results: We found that compared with that in controls, the CBF was significantly reduced in the left superior parietal gyrus in MCI patients, whereas it was increased in the left precentral gyrus, right superior temporal gyrus, right putamen, and left supplementary motor area. In patients with MCI, significant correlations were identified between CBF and neuropsychological scales. Importantly, MCI patients exhibited CBF disconnections between the left supplementary motor area and the left superior parietal gyrus.Conclusion: This study found that there are not only changes in regional CBF but also in CBF connectivity patterns in MCI patients compared with controls. These observations may provide a novel explanation for the neural mechanism underlying the pathophysiology in patients with Alzheimer’s disease and MCI.

Objectives: Evaluate the acceptability and efficacy of an online dementia prevention intervention based on a cognitive behavioral shared decision-making model.Materials and Methods: This was an unblinded pilot study in which participants were randomly assigned to one of two treatment groups. This study was carried out remotely via telephone, video conferencing, and online data collection. Eighteen English-speaking persons 40 years of age and older interested in developing more brain-healthy lifestyles. Both groups received 12 weekly sessions on lifestyle factors related to cognitive decline. The treatment-as-usual (TAU) group received the information and was encouraged to make lifestyle changes. The cognitive behavioral shared decision- making model (CBSDM) group received structured weekly sessions with support for evidence- informed personal goal choices and behavior change strategies. Primary outcome measures were the Alzheimer's Disease Risk Inventory and the Memory Self-Efficacy and Dementia Knowledge Assessment Scales. Participants reported brain health activities during the first, sixth, and 12th weeks of the study.Results: No significant between-group changes were seen in the three primary outcome measures. The intervention was viewed positively by participants, who all said they would participate in it again. Participants in the CBSDM group showed increases in knowledge of dementia risk factors and exercise. Other outcomes were consistent with moderate to large effect sizes for both groups.Conclusion: An online intervention providing psychoeducation and behavior change support was viewed positively by older adults. Results provide preliminary support for the CBSDM intervention’s efficacy in promoting brain health in older adults.Clinical Trial Registration Number: NCT04822129.

Background: To evaluate the efficacy and pharmacological mechanisms of resveratrol in Alzheimer’s disease (AD) patients.Methods: We conducted a thorough exploration of existing randomized controlled trials concerning the treatment of Alzheimer's disease patients using resveratrol, utilizing accessible open databases. Quantitative variables were represented as a standardized mean difference (SMD), accompanied by a 95% confidence interval (CI). Additionally, we examined the potential targets and plausible pathways associated with the impact of resveratrol on Alzheimer's disease using network pharmacology techniques.Results: Our meta-analysis comprised five trials involving 271 AD patients, of whom 139 received resveratrol treatment and 132 received placebo treatment. Compared with placebo therapy, resveratrol treatment resulted in a significant improvement in Alzheimer’s Disease Cooperative Study— Activities of Daily Living (ADAS-ADL) scores (SMD=0.51; 95% CI, 0.24 to 0.78) and cerebrospinal fluid (CSF) Aβ40 (SMD=0.84; 95% CI, 0.21 to 1.47) and plasma Aβ40 levels (SMD=0.43; 95% CI, 0.07 to 0.79). However, the improvement in the resveratrol-treated group compared with the placebo treatment group on the Mini-Mental State Examination (MMSE) score, CSF Aβ42 and plasma Aβ42 levels, and brain volume was not significant. There were no noteworthy statistical variances in the occurrence of adverse effects noted between the two groups. The outcomes of network pharmacology divulged that the principal enriched interaction pathway between resveratrol and Alzheimer's disease is primarily concentrated within the PI3K signaling pathways. Resveratrol's potential key targets for the treatment of AD include MAKP1, HRAS, EGFR, and MAPK2K1.Conclusion: While having a high safety profile, resveratrol has efficacy in AD patients to a certain extent, and more data are required to validate the efficacy of resveratrol for the treatment of AD in the future. Suppression of the PI3K signaling pathways could hold significant importance in the treatment of AD patients using resveratrol.