Effects of transcranial direct current stimulation on cognition in MCI with Alzheimer's disease risk factors using Bayesian analysis.

Despite the growing interest in precision medicine-based therapies for Alzheimer's disease (AD), little research has been conducted on how individual AD risk factors influence changes in cognitive function following transcranial direct current stimulation (tDCS). This study evaluates the cognitive effects of sequential tDCS on 63 mild cognitive impairment (MCI) patients, considering AD risk factors such as amyloid-beta deposition, APOE ε4, BDNF polymorphism, and sex. Using both frequentist and Bayesian methods, we assessed the interaction of tDCS with these risk factors on cognitive performance. Notably, we found that amyloid-beta deposition significantly interacted with tDCS in improving executive function, specifically Stroop Word-Color scores, with strong Bayesian support for this finding. Memory enhancements were differentially influenced by BDNF Met carrier status. However, sex and APOE ε4 status did not show significant effects. Our results highlight the importance of individual AD risk factors in modulating cognitive outcomes from tDCS, suggesting that precision medicine may offer more effective tDCS treatments tailored to individual risk profiles in early AD stages.

Impact of transcranial direct current stimulation on white matter microstructure integrity in mild cognitive impairment patients according to effect modifiers as risk factors for Alzheimer's disease.

Background: Little research exists on how individual risk factors for Alzheimer's disease (AD) affect the intermediate phenotype after transcranial direct current stimulation (tDCS), despite the importance of precision medicine-based therapeutic approaches. Objective: To determine how an application of sequential tDCS (2 mA/day, left dorsolateral prefrontal cortex, 10 sessions) affects changes in white matter (WM) microstructure integrity in 63 mild cognitive impairment (MCI) patients with effect modifiers such as Aß deposition, APOE ε4 carrier status, BDNF Val66Met polymorphism status, and sex. Methods: We examined individual effect modifier-by-tDCS interactions and multiple effect modifiers-by-tDCS interactions for diffusion metrics. We also evaluated the association between baseline Aß deposition and changes in WM microstructure integrity following tDCS. Results: We found that APOE ε4 carrier status and sex had a significant interaction with tDCS, resulting in increased fractional anisotropy (FA) in the right uncinate fasciculus (UF) after stimulation. Additionally, we observed multiple effect modifiers-by-tDCS interactions on WM integrity of the right UF, leading to a more pronounced increase in FA values in APOE ε4 carriers and females with Val66 homozygotes. Finally, baseline Aß deposition was positively associated with a difference in FA of the left cingulum in the hippocampal area, which showed a positive association with the changes in the score for delayed memory. Conclusion: Our study shows the differential impact of individual AD risk factors on changes in the early intermediate phenotype after sequential tDCS in MCI patients. This research emphasizes the importance of precision medicine approaches in tDCS for the prodromal stages of AD.

Sensory processing deficits and related cortical pathological changes in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting cognitive functions. However, sensory deficits in AD start to draw attention due to their high prevalence and early onsets which suggest that they could potentially serve as diagnostic biomarkers and even contribute to the disease progression. This literature review examines the sensory deficits and cortical pathological changes observed in visual, auditory, olfactory, and somatosensory systems in AD patients, as well as in various AD animal models. Sensory deficits may emerge at the early stages of AD, or even precede the cognitive decline, which is accompanied by cortical pathological changes including amyloid-beta deposition, tauopathy, gliosis, and alterations in neuronal excitability, synaptic inputs, and functional plasticity. Notably, these changes are more pronounced in sensory association areas and superficial cortical layers, which may explain the relative preservation of basic sensory functions but early display of deficits of higher sensory functions. We propose that sensory impairment and the progression of AD may establish a cyclical relationship that mutually perpetuates each condition. This review highlights the significance of sensory deficits with or without cortical pathological changes in AD and emphasizes the need for further research to develop reliable early detection and intervention through sensory systems.

Decabromodiphenyl ethane induces locomotion neurotoxicity and potential Alzheimer's disease risks through intensifying amyloid-beta deposition by inhibiting transthyretin/transthyretin-like proteins.

As a major alternative to traditional brominated flame retardants (BFRs), decabromodiphenyl ethane (DBDPE) is widely used and has been commonly detected in various environmental media and organisms. Few previous studies have focused on DBDPE-induced locomotion neurotoxicity, and the exact molecular mechanisms and related health risks remain unclear. In this study, we first analyzed the locomotion indicators of nematodes following DBDPE exposure, demonstrated that DBDPE caused locomotion neurotoxicity, and identified that a series of the transthyretin (TTR)-like genes participated in the regulation of nematode motility by transcriptomic analysis, gene transcription validation and TTR-like mutant verification. Subsequently, this study demonstrated that DBDPE exacerbated amyloid-beta (Aß) deposition by repressing TTR/TTR-like gene transcription based on Alzheimer's disease (AD) model nematodes and human SH-SY5Y cells following DBDPE exposure and further revealed that DBDPE reduced the binding between TTR and Aß by competing with the strand G region sites on the TTR/TTR-like protein, ultimately exacerbating Aß deposition and the risk of AD. In short, our study demonstrated that DBDPE induced locomotion neurotoxicity and potential AD risks through intensifying Aß deposition by inhibiting TTR/TTR-like proteins, providing reference support for risk management and policy formulation related to DBDPE and similarly structured novel BFRs.

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer's Disease.

Rehmanniae Radix (RR, the dried tuberous roots of Rehmannia glutinosa (Gaertn.) DC.) is an important traditional Chinese medicine distributed in Henan, Hebei, Inner Mongolia, and Northeast in China. RR is frequently used to treat diabetes mellitus, cardiovascular disease, osteoporosis and aging-related diseases in a class of prescriptions. The oligosaccharides and catalpol in RR have been confirmed to have neuroprotective effects. However, there are few studies on the anti-Alzheimer's disease (AD) effect of oligosaccharides in Rehmanniae Radix (ORR). The chemical components and pharmacological effects of dried Rehmannia Radix (DRR) and prepared Rehmannia Radix (PRR) are different because of the different processing methods. ORR has neuroprotective potential, such as improving learning and memory in rats. Therefore, this study aimed to prove the importance of oligosaccharides in DRR (ODRR) and PRR (OPRR) for AD based on the Caenorhabditis elegans (C. elegans) model and the different roles of ODRR and OPRR in the treatment of AD. In this study, we used paralysis assays, lifespan and stress resistance assays, bacterial growth curve, developmental and behavioral parameters, and ability of learning and memory to explore the effects of ODRR and OPRR on anti-AD and anti-aging. Furthermore, the accumulation of reactive oxygen species (ROS); deposition of Aß; and expression of amy-1, sir-2.1, daf-16, sod-3, skn-1, and hsp-16.2 were analyzed to confirm the efficacy of ODRR and OPRR. OPRR was more effective than ODRR in delaying the paralysis, improving learning ability, and prolonging the lifespan of C. elegans. Further mechanism studies showed that the accumulation of ROS, aggregation, and toxicity of Aß were reduced, suggesting that ORR alleviated Aß-induced toxicity, in part, through antioxidant activity and Aß aggregation inhibiting. The expression of amy-1 was downregulated, and sir-2.1, daf-16, sod-3, and hsp-16.2 were upregulated. Thus, ORR could have a possible therapeutic effect on AD by modulating the expression of amy-1, sir-2.1, daf-16, sod-3, and hsp-16.2. Furthermore, ORR promoted the nuclear localization of daf-16 and further increased the expression of sod-3 and hsp-16.2, which significantly contributed to inhibiting the Aß toxicity and enhancing oxidative stress resistance. In summary, the study provided a new idea for the development of ORR.

Microglia in Alzheimer's Disease: An Unprecedented Opportunity as Prospective Drug Target.

Alzheimer's disease (AD) is an ever more common neurodegenerative disease among the elderly, characterized by recurrent neuroinflammation and amyloid beta (Aß) accumulation in the brain parenchyma. Recent genome-wide association studies (GWAS) have shown a distinct role for the innate immune system in AD, with microglia playing a key role. The function of microglial cells is stringently regulated by the neighboring microenvironment in the brain. Upon interruption in diseases, like AD, it demonstrates neurotoxic and neuroprotective action by M1 (neurotoxic) and M2 (neuroprotective) microglial phenotypes, respectively, in the brain. Microglial cells on activation by complement factors, toll-like receptors, and genetic variants result in Aß' phagocytosis, synaptic pruning, and reactivation of complement pathway. Recent studies have demonstrated the presence of potential therapeutic targets in microglial cells. Immune receptors revealed on microglia as potential drug targets can be paired immunoglobulin-like type 2 receptor (PILR), CD3358, and triggering receptor expressed on myeloid cells 2 (TREM2), as they can have impact on late-onset AD occurrence and progression. Thus, targeting these receptors can accentuate the beneficial effects of microglial cells required to decelerate the progression of AD. This review emphasizes the microglial phenotypes, its function in AD brain, and potential immunological and therapeutic targets to fight this highly progressive neurodegenerative disorder.

The Relationship of Plasma Transthyretin Level with Global or Regional Amyloid Beta Burden in Subjects with Amnestic Mild Cognitive Impairment: Cross-Sectional Amyloid PET Study.

Background: To investigate the relationships of plasma transthyretin levels with amyloid beta deposition and medial temporal atrophy in amnestic mild cognitive impairment. Methods: This is a cross-sectional study of association of subjects with amnestic mild cognitive impairment. Plasma transthyretin levels, brain magnetic resonance imaging, and 18F-florbetaben positron emission tomography were simultaneously measured in subjects with amnestic mild cognitive impairment. Results: Plasma transthyretin levels were positively associated with amyloid beta deposition in global (r = 0.394, P = .009), frontal cortex (r = 0.316, P = .039), parietal cortex (r = 0.346, P = .023), temporal cortex (r = 0.372, P = .014), occipital cortex (r = 0.310, P = .043), right posterior cingulate (r = 0.350, P = .021), left precuneus (r = 0.314, P = .040), and right precuneus (r = 0.398, P = .008). No association between plasma transthyretin level and medial temporal sub-regional atrophies was found. Conclusions: Our findings of positive association of plasma transthyretin levels with global and regional amyloid beta burden suggest upregulation of transthyretin level as a reactive response to amyloid beta deposition during the early stages of the Alzheimer's disease process.

Impact of Transcranial Direct Current Stimulation on Cognitive Function, Brain Functional Segregation, and Integration in Patients with Mild Cognitive Impairment According to Amyloid-Beta Deposition and APOE ε4-Allele: A Pilot Study.

Anodal transcranial direct current stimulation (anodal-tDCS) is known to improve cognition and normalize abnormal network configuration during resting-state functional magnetic resonance imaging (fMRI) in patients with mild cognitive impairment (MCI). We aimed to evaluate the impact of sequential anodal-tDCS on cognitive functions, functional segregation, and integration parameters in patients with MCI, according to high-risk factors for Alzheimer's disease (AD): amyloid-beta (Aß) deposition and APOE ε4-allele status. In 32 patients with MCI ([18 F] flutemetamol-: n = 10, [18 F] flutemetamol+: n = 22; APOE ε4-: n = 13, APOE ε4+: n = 19), we delivered anodal-tDCS (2 mA/day, five times/week, for 2 weeks) over the left dorsolateral prefrontal cortex and assessed the neuropsychological test battery and resting-state fMRI measurements before and after 2 weeks stimulation. We observed a non-significant impact of an anodal-tDCS on changes in neuropsychological battery scores between MCI patients with and without high-risk factors of AD, Aß retention and APOE ε4-allele. However, there was a significant difference in brain functional segregation and integration parameters between MCI patients with and without AD high-risk factors. We also found a significant effect of tDCS-by-APOE ε4-allele interaction on changes in the functional segregation parameter of the temporal pole. In addition, baseline Aß deposition significantly associated negatively with change in global functional integrity of hippocampal formation. Anodal-tDCS might help to enhance restorative and compensatory intrinsic functional changes in MCI patients, modulated by the presence of Aß retention and the APOE ε4-allele.

Associations of equol-producing status with white matter lesion and amyloid-ß deposition in cognitively normal elderly Japanese.

INTRODUCTION: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aß) deposition. METHODS: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using 11C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers. RESULTS: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aß positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend P < .01). Equol-producing status was not associated with Aß status. DISCUSSION: A randomized-controlled trial of equol targeting WML volume is warranted.

Cognitive Profiling Related to Cerebral Amyloid Beta Burden Using Machine Learning Approaches.

Background: Cerebral amyloid beta (Aß) is a hallmark of Alzheimer's disease (AD). Aß can be detected in vivo with amyloid imaging or cerebrospinal fluid assessments. However, these technologies can be both expensive and invasive, and their accessibility is limited in many clinical settings. Hence the current study aims to identify multivariate cost-efficient markers for Aß positivity among non-demented individuals using machine learning (ML) approaches. Methods: The relationship between cost-efficient candidate markers and Aß status was examined by analyzing 762 participants from the Alzheimer's Disease Neuroimaging Initiative-2 cohort at baseline visit (286 cognitively normal, 332 with mild cognitive impairment, and 144 with AD; mean age 73.2 years, range 55-90). Demographic variables (age, gender, education, and APOE status) and neuropsychological test scores were used as predictors in an ML algorithm. Cerebral Aß burden and Aß positivity were measured using 18F-florbetapir positron emission tomography images. The adaptive least absolute shrinkage and selection operator (LASSO) ML algorithm was implemented to identify cognitive performance and demographic variables and distinguish individuals from the population at high risk for cerebral Aß burden. For generalizability, results were further checked by randomly dividing the data into training sets and test sets and checking predictive performances by 10-fold cross-validation. Results: Out of neuropsychological predictors, visuospatial ability and episodic memory test results were consistently significant predictors for Aß positivity across subgroups with demographic variables and other cognitive measures considered. The adaptive LASSO model using out-of-sample classification could distinguish abnormal levels of Aß. The area under the curve of the receiver operating characteristic curve was 0.754 in the mild change group, 0.803 in the moderate change group, and 0.864 in the severe change group, respectively. Conclusion: Our results showed that the cost-efficient neuropsychological model with demographics could predict Aß positivity, suggesting a potential surrogate method for detecting Aß deposition non-invasively with clinical utility. More specifically, it could be a very brief screening tool in various settings to recruit participants with potential biomarker evidence of AD brain pathology. These identified individuals would be valuable participants in secondary prevention trials aimed at detecting an anti-amyloid drug effect in the non-demented population.

Synergistic interaction between APOE and family history of Alzheimer's disease on cerebral amyloid deposition and glucose metabolism.

BACKGROUND: Recently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults. METHODS: [11C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [18F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses. RESULTS: A significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aß) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions. CONCLUSIONS: Strong synergistic effects of APOE4 and FH on Aß deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aß. Other unspecified risk factors-genes and/or environmental-that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.

Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life.

Background: Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer's disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Aß) pathology and AD-related neurodegeneration in non-demented older adults. Methods: Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral Aß deposition and Aß positivity were measured using 11C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using 18F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire. Results: Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CAearly) was associated with significantly increased AD-CMglu (B = 0.035, SE = 0.013, P = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43-0.98, P = 0.04) but was not associated with Aß deposition or positivity. We observed no association between midlife CA (CAmid) and any AD-related brain changes. Late-life CA (CAlate) showed an association with both global Aß deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results. Conclusion: Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral Aß pathology.

Aß-related hyperactivation in frontoparietal control regions in cognitively normal elderly.

The accumulation of amyloid-beta (Aß) peptides, a pathologic hallmark of Alzheimer's disease, has been associated with functional alterations in cognitively normal elderly, most often in the context of episodic memory with a particular emphasis on the medial temporal lobes. The topography of Aß deposition, however, highly overlaps with frontoparietal control (FPC) regions implicated in cognitive control/working memory. To examine Aß-related functional alternations in the FPC regions during a working memory task, we imaged 42 young and 57 cognitively normal elderly using functional magnetic resonance imaging during a letter Sternberg task with varying load. Based on (18)F-florbetaben-positron emission tomography scan, we determined older subjects' amyloid positivity (Aß+) status. Within brain regions commonly recruited by all subject groups during the delay period, age and Aß deposition were independently associated with load-dependent frontoparietal hyperactivation, whereas additional compensatory Aß-related hyperactivity was found beyond the FPC regions. The present results suggest that Aß-related hyperactivation is not specific to the episodic memory system but occurs in the PFC regions as well.

Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment.

Despite potential implications for the early detection of impending Alzheimer's disease (AD), very little is known about the differences of large-scale brain networks between amnestic mild cognitive impairment (aMCI) with high cerebral amyloid-beta protein (Aß) deposition (i.e., aMCI+) and aMCI with no or very little Aß deposition (i.e., aMCI-). We first aimed to extend the current literature on altering intrinsic functional connectivity (FC) of the default mode network (DMN) and salience network (SN) from cognitively normal (CN) to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI-, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI-, and 11 AD dementia) subjects were included. All participants received comprehensive clinical and neuropsychological assessment, resting-state functional magnetic resonance imaging, structural MRI, and Pittsburgh compound-B-PET scans. FC data were preprocessed using multivariate exploratory linear optimized decomposition into independent components of FMRIB's Software Library. Group comparisons were carried out using the "dual-regression" approach. In addition, to verify presence of gray matter volume changes with intrinsic functional network alterations, voxel-based morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (particularly in the precuneus and cingulate gyrus). The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI- exhibited increased FC in the DMN compared to CN (primarily in the precuneus) as well as aMCI+. In terms of the SN, aMCI- exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI- showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite the similarity in cross-sectional cognitive features, aMCI- has quite different functional brain connectivity compared to aMCI+.