Cognitive Function In Alzheimer's Disease Research Articles

Probing latent brain dynamics in Alzheimer's disease via recurrent neural network.

The impairment of cognitive function in Alzheimer's disease (AD) is clearly correlated to abnormal changes in cortical rhythm. However, the mechanisms underlying this correlation are still poorly understood. Here, we investigate how network structure and dynamical characteristics alter their abnormal changes in cortical rhythm. To that end, biological data of AD and normal participates are collected. By extracting the energy characteristics of different sub-bands in EEG signals, we find that the rhythm of AD patients is special particularly in theta and alpha bands. The cortical rhythm of normal state is mainly at alpha band, while that of AD state shift to the theta band. Furthermore, recurrent neural network (RNN) is trained to explore the rhythm formation and transformation between two neural states from the perspective view of neurocomputation. It is found that the neural coupling strength decreases significantly under AD state when compared with normal state, which weakens the ability of information transmission in AD state. Besides, the low-dimensional properties of RNN are obtained. By analyzing the relationship between the cortical rhythm transition and the low-dimensional trajectory, it is concluded that the low-dimensional trajectory update is slower and the communication cost is higher in AD state, which explains the abnormal synchronization of AD brain network. Our work reveals the causes for the formation of abnormal brain synchronous functional network status, which may expand our understanding of the mechanism of cognitive impairment in AD and provide an EEG biomarker for early AD.

Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer's Disease Mice Model.

Alzheimer's disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aβ amyloid clearance from the brain. However, some recent evidence suggests that astrocytes may play a significant role in the pathogenesis of AD. In this paper, we evaluated the effects of the optogenetic activation of Gq-coupled exogenous receptors expressed in astrocytes as a possible way of restoring brain function in the AD mouse model. We evaluated the effects of the optogenetic activation of astrocytes on long-term potentiation, spinal morphology and behavioral readouts in 5xFAD mouse model of AD. We determined that in vivo chronic activation of astrocytes resulted in the preservation of spine density, increased mushroom spine survival, and improved performance in cognitive behavioral tests. Furthermore, chronic optogenetic stimulation of astrocytes resulted in the elevation of EAAT-2 glutamate uptake transporter expression, which could be a possible explanation for the observed in vivo neuroprotective effects. The obtained results suggest that the persistent activation of astrocytes may be considered a potential therapeutic approach for the treatment of AD and possibly other neurodegenerative disorders.

Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease

BackgroundIcariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. MethodsThe PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. ResultsThe study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aβ via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca2+, and PI3K/Akt signaling. ICA exhibits neuroprotective properties by inhibiting neuronal apoptosis through the suppression of ER stress in AD mice, potentially linked to NF-κB, MAPK, ERK, and PERK/Eif2α signaling pathways. Moreover, ICA may safeguard neurons by attenuating mitochondrial oxidative stress injury. ICA can also enhance learning, memory, and cognition by improving synaptic structure via regulation of the PSD-95 protein. Furthermore, ICA can mitigate neuroinflammation by inactivating microglial activity through the upregulation of PPARγ, TAK1/IKK/NF-κB, and JNK/p38 MAPK signaling pathways. ConclusionThis study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD.

Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer’s dementia: A network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy

Alzheimer’s dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease. Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD. The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals. The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event. This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500–2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference = 3.00, 95% confidence intervals (95 %CIs) = 1.84–4.16]. Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR) = 0.46, 95 %CIs = 0.04 to 5.87] and safety profiles (OR = 1.24, 95 %CIs = 0.66 to 2.33)o. These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.

Guanidines: Synthesis of Novel Histamine H3R Antagonists with Additional Breast Anticancer Activity and Cholinesterases Inhibitory Effect.

This study examines the properties of novel guanidines, designed and synthesized as histamine H3R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. ADS10310 showed micromolar cytotoxicity against breast cancer cells, combined with nanomolar affinity at hH3R, and may represent a promising target for the development of an alternative method of cancer therapy. Some of the newly synthesized compounds showed moderate inhibition of BuChE in the single-digit micromolar concentration ranges. H3R antagonist with additional AChE/BuChE inhibitory effect might improve cognitive functions in Alzheimer's disease. For ADS10310, several in vitro ADME-Tox parameters were evaluated and indicated that it is a metabolically stable compound with weak hepatotoxic activity and can be accepted for further studies.

A Study of HDAC6 for Ameliorating the Cognitive Function in Alzheimer's Disease

One of the most prevalent causes of dementia, Alzheimer's disease (AD) is characterized by gradual mental decline and memory loss over time. Several drugs are currently available for the treatment of AD, but they only address the disease's symptoms rather than its underlying pathogenesis. Researchers looked into epigenetic therapy and found that histone deacetylase 6 (HDAC6) could be an effective treatment for Alzheimer's disease. This paper uses a literature review approach to investigate the roles of HDAC6 inhibition in AD models and HDAC6 inhibitors, as well as the hypotheses surrounding the pathogenesis of AD. The amyloid cascade hypothesis, the tau hypothesis, and the role of oxygen species are identified as the most prominent pathogenesis hypotheses in this paper. A decrease in Hdac6 levels improves associative and spatial memory in an Alzheimer's disease mouse model and reverses the mitochondrial trafficking impairment in hippocampal neurons in vitro and in vivo. Therefore, inhibiting HDAC6 may represent a novel approach to treating AD-related cognitive decline. As a result of these issues, the FDA has yet to approve any HDAC6 inhibitor for use in the treatment of Alzheimer's disease (FDA)

Evaluating the effects of glucagon-like peptide-1 receptor agonists on cognitive function in Alzheimer's disease: A systematic review and meta-analysis.

Alzheimer's disease (AD) is the most common type of dementia. At present, some drug and non-drug therapies can be used to slow disease progression or prevent cognitive deterioration. More treatment options still need to be explored. A meta-analysis was performed to compile the relevant evidence for the use of glucagon-like peptide-1 (GLP-1) receptor agonists in preventing AD. We systematically searched English and Chinese databases, including Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and Weipu website (VIP), based on the PICOS (Participants, Interventions, Comparisons, Outcomes, Study design) principles. The reviewers evaluated the search results and conducted the analysis; 5 articles with a total sample size of 184 patients were included. Changes in cognitive function, body mass index (BMI), blood glucose level, and insulin content were analyzed. A low risk of bias and no publication bias were found in these studies. The following results were obtained: 1) cognitive function: mean difference (MD) = 2.16, 95% confidence interval (95% CI): 1.45-2.88; 2) BMI change: MD = -1.16, 95% CI: -1.71--0.61; and 3) blood glucose change: standard MD (SMD) = -0.64, 95% CI: -1.21--0.88. No statistically significant difference was found in insulin content. In this review, we showed that GLP-1 receptor agonists can effectively change cognitive function, BMI and blood glucose levels in patients with AD. This provides relevant clues for the prevention of AD. However, more studies are needed to refine these conclusions.

Degradation of NLRP3 by p62-dependent-autophagy improves cognitive function in Alzheimer's disease by maintaining the phagocytic function of microglia.

Activation of the NLRP3 inflammasome promotes microglia to secrete inflammatory cytokines and induce pyroptosis, leading to impaired phagocytic and clearance functions of microglia in Alzheimer's disease (AD). This study found that the autophagy-associated protein p62 interacts with NLRP3, which is the rate-limiting protein of the NLRP3 inflammasome. Thus, we aimed to prove that the degradation of NLRP3 occurs through the autophagy-lysosome pathway (ALP) and also demonstrate its effects on the function of microglia and pathological changes in AD. The 5XFAD/NLRP3-KO mouse model was established to study the effect of NLRP3 reduction on AD. Behavioral experiments were conducted to assess the cognitive function of the mice. In addition, immunohistochemistry was used to evaluate the deposition of Aβ plaques and morphological changes in microglia. BV2 cells treated with lipopolysaccharide (LPS) followed by Aβ1-42 oligomers were used as in vitro AD inflammation models and transfected with lentivirus to regulate the expression of the target protein. The pro-inflammatory status and function of BV2 cells were detected by flow cytometry and immunofluorescence (IF). Co-immunoprecipitation, mass spectrometry, IF, Western blot (WB), quantitative real-time PCR, and RNA-seq analysis were used to elucidate the mechanisms of molecular regulation. Cognitive function was improved in the 5XFAD/NLRP3-KO mouse model by reducing the pro-inflammatory response of microglia and maintaining the phagocytic and clearance function of microglia to the deposited Aβ plaque. The pro-inflammatory function and pyroptosis of microglia were regulated by NLRP3 expression. Ubiquitinated NLRP3 can be recognized by p62 and degraded by ALP, slowing down the proinflammatory function and pyroptosis of microglia. The expression of autophagy pathway-related proteins such as LC3B/A, p62 was increased in the AD model in vitro. P62 recognizes and binds to ubiquitin-modified NLRP3. It plays a vital role in regulating the inflammatory response by participating in ALP-associated NLRP3 protein degradation, which improves cognitive function in AD by reducing the pro-inflammatory status and pyroptosis of microglia, thus maintaining its phagocytic function.

Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment

Probiotic supplements were shown to improve cognitive function in Alzheimer's disease (AD) patients. However, it is still unclear whether this applies to older individuals with mild cognitive impairment (MCI). We aimed to explore the effects of probiotic supplementation on multiple neural behaviors in older adults with MCI. Forty-two MCI patients (age > 60 years) were randomly divided into two groups and consumed either probiotics (n=21) or placebo (n=21) for 12 weeks. Various scale scores, gut microbiota measures and serological indicators were recorded pre- and posttreatment. After 12 weeks of intervention, cognitive function and sleep quality were improved in the probiotic group compared with those in the control group, and the underlying mechanisms were associated with changes in the intestinal microbiota. In conclusion, our study demonstrated that probiotic treatment enhanced cognitive function and sleep quality in older MCI patients, thus providing important insights into the clinical prevention and treatment of MCI.

The relationship between depressive symptoms and cognitive function in Alzheimer's disease: The mediating effect of amygdala functional connectivity and radiomic features

BackgroundDepressive symptoms are common in Alzheimer's disease (AD) and are associated with cognitive function. Amygdala functional connectivity (FC) and radiomic features related to depression and cognition. However, studies have yet to explore the neural mechanisms underlying these associations. MethodsWe enrolled eighty-two AD patients with depressive symptoms (ADD) and 85 healthy controls (HCs) in this study. We compared amygdala FC using the seed-based approach between ADD patients and HCs. The least absolute shrinkage and selection operator (LASSO) was used to select amygdala radiomic features. A support vector machine (SVM) model was constructed based on the identified radiomic features to distinguish ADD from HCs. We used mediation analyses to explore the mediating effects of amygdala radiomic features and amygdala FC on cognition. ResultsWe found that ADD patients showed decreased amygdala FC with posterior cingulate cortex, middle frontal gyrus (MFG), and parahippocampal gyrus involved in the default mode network compared to HCs. The area under the receiver operating characteristic curve (AUC) of the amygdala radiomic model was 0.95 for ADD patients and HCs. Notably, the mediation model demonstrated that amygdala FC with the MFG and amygdala-based radiomic features mediated the relationship between depressive symptoms and cognitive function in AD. LimitationsThis study is a cross-sectional study and lacks longitudinal data. ConclusionOur findings may not only expand existing biological knowledge of the relationship between cognition and depressive symptoms in AD from the perspective of brain function and structure but also may ultimately provide potential targets for personalized treatment strategies.

Neuroimaging studies of acupuncture on Alzheimer’s disease: a systematic review

BackgroundAcupuncture effectively improves cognitive function in Alzheimer’s disease (AD). Many neuroimaging studies have found significant brain alterations after acupuncture treatment of AD, but the underlying central modulation mechanism is unclear.ObjectiveThis review aims to provide neuroimaging evidence to understand the central mechanisms of acupuncture in patients with AD.MethodsRelevant neuroimaging studies about acupuncture for AD were retrieved from eight English and Chinese medicine databases (PubMed, Embase, Cochrane Library, Web of Science, SinoMed, CNKI, WF, VIP) and other resources from inception of databases until June 1, 2022, and their methodological quality was assessed using RoB 2.0 and ROBINS - I. Brain neuroimaging information was extracted to investigate the potential neural mechanism of acupuncture for AD. Descriptive statistics were used for data analysis.ResultsThirteen neuroimaging studies involving 275 participants were included in this review, and the overall methodological quality of included studies was moderate. The approaches applied included task-state functional magnetic resonance imaging (ts-fMRI; n = 9 studies) and rest-state functional magnetic resonance imaging (rs-fMRI; n = 4 studies). All studies focused on the instant effect of acupuncture on the brains of AD participants, including the cingulate gyrus, middle frontal gyrus, and cerebellum, indicating that acupuncture may regulate the default mode, central executive, and frontoparietal networks.ConclusionThis study provides evidence of the neural mechanisms underlying the effect of acupuncture on AD involving cognitive- and motor-associated networks. However, this evidence is still in the preliminary investigation stage. Large-scale, well-designed, multimodal neuroimaging trials are still required to provide comprehensive insight into the central mechanism underlying the effect of acupuncture on AD. (Systematic review registration at PROSPERO, No. CRD42022331527).

The impact of depression on language function in individuals with Alzheimer’s disease: a pre/post-treatment design

BackgroundIt is uncertain whether depression might affect cognitive function in Alzheimer’s disease (AD). Most of studies on the effect of depression treatment on cognitive function in AD were briefly evaluated by Mini-Mental State Examination (MMSE). MMSE is poor sensitive to detect cognitive change. This study examined the cognitive response to depression treatment in AD via multi-domain assessment. In addition, we explored whether effect of depression treatment in AD is different those of late-life depression (LLD).MethodsThis study include AD patients with depression (AD + D) and without depression (AD − D), LLD patients (LLD), and healthy controls (HC). The patients were treated according to their diagnosis for 16 weeks: acetylcholinesterase inhibitors (AChEIs) and selective serotonin reuptake inhibitors (SSRIs) for AD + D, AChEIs for AD − D, and SSRIs for LLD. The cognitive changes from pre- to post-treatment were compared between AD + D and AD − D or LLD and HC. An independent sample t test was performed to compare the degree of change between the groups. Paired t tests were used to determine cognitive function changes in each depression treatment responder group.ResultsAt baseline, AD + D had more impairment in language function compared to AD − D, and LLD had greater deficit in executive function than HC. After depression treatment, more impaired cognitive domains at baseline were improved in AD + D and LLD, respectively. Moreover, AD + D showed an improvement in the global cognitive function (MMSE).ConclusionsResults indicated that language function was influenced by depression in AD, which is first evidence for specific cognitive domain related to depression in AD. Our finding indicates that depression could negatively impact cognitive function, and depression treatment may have beneficial cognitive effect in both AD and LLD. This study suggests the importance of early detection and treatment of depression in AD and LLD.Trial registration Clinical Research Information Service, CRIS, ID#: KCT0004041, Registered 5 June 2019, retrospectively registered after first patient enrollment date (4 March 2014) https://cris.nih.go.kr/cris/search/detailSearch.do?seq=14140&status=5&seq_group=14140&search_page=M.

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

BackgroundAlzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress.MethodsHere, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.ResultsWe showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment.ConclusionOur results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

The effect of hippocampal radiomic features and functional connectivity on the relationship between hippocampal volume and cognitive function in Alzheimer's disease

Hippocampal volume is associated with cognitive function in Alzheimer's disease (AD). Hippocampal radiomic features and resting-state functional connectivity (rs-FC) are promising biomarkers and correlate with AD pathology. However, few studies have been conducted on how hippocampal biomarkers affect the cognition-structure relationship. Therefore, we aimed to investigate the effects of hippocampal radiomic features and resting-state functional connectivity (rs-FC) on this relationship in AD. We enrolled 70 AD patients and 65 healthy controls (HCs). The FreeSurfer software was used to measure hippocampal volume. We selected hippocampal radiomic features to build a model to distinguish AD patients from HCs and used a seed-based approach to calculate the hippocampal rs-FC. Furthermore, we conducted mediation and moderation analyses to investigate the effect of hippocampal radiomic features and rs-FC on the relationship between hippocampal volume and cognition in AD. The results suggested that hippocampal radiomic features mediated the association between bilateral hippocampal volume and cognition in AD. Additionally, patients with AD showed weaker rs-FC between the bilateral hippocampus and right ventral posterior cingulate cortex and stronger rs-FC between the left hippocampus and left insula than HCs. The rs-FC between the hippocampus and insula moderated the relationship between hippocampal volume and cognition in AD, suggesting that this rs-FC could exacerbate or ameliorate the effects of hippocampal volume on cognition and may be essential in improving cognitive function in AD. Our findings may not only expand existing biological knowledge of the interrelationships among hippocampal biomarkers and cognition but also provide potential targets for treatment strategies for AD.

Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer's disease.

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.

Study of the possible effect of sacubitril/valsartan combination versus valsartan on the cognitive function in Alzheimer's disease model in rats.

Objectives: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder. The proportion of elderly individuals at risk for AD and cardiovascular problems increases by raising life expectancy. The present study was designed to investigate the effect of the sacubitril/valsartan combination compared to that of valsartan alone in a rat model of AD. Methods: 72 male adult Wistar rats were divided into seven groups; control untreated rats received saline, control valsartan-treated rats received valsartan orally, control sacubitril/valsartan treated rats received sacubitril/valsartan orally, model rats received aluminum chloride i.p., model valsartan treated rats received aluminum chloride i.p. and valsartan orally and model sacubitril/valsartan treated rats received aluminum chloride i.p. and sacubitril/valsartan combination orally. All previous treatments continued on a daily basis for 6weeks. At the second, fourth, and sixth weeks of the experiment, behavioral changes were evaluated using the Morris water maze and novel object recognition tests, and systolic blood pressure was measured. In the end, rat brain malondialdehyde and amyloid-beta 1-42 levels were measured, and the isolated hippocampus was evaluated histopathologically. Results: Valsartan improved AD symptoms in the aluminum-induced rat model, while the sacubitril/valsartan combination significantly worsened all tested parameters in both control and model rats compared with untreated and valsartan-treated animals. Conclusion: Based on the current study's findings, valsartan did not increase the risk for AD development in control rats and improved AD symptoms in a rat model, while sacubitril/valsartan combination increased the risk of AD in control rats and worsened the condition in a rat model.

Supplemental Material for Further Evaluation of Narrative Description as a Measure of Cognitive Function in Alzheimer’s Disease

Supplemental Material for Further Evaluation of Narrative Description as a Measure of Cognitive Function in Alzheimer’s Disease

The Efficacy of Vitamin D Supplementation in Patients With Alzheimer's Disease in Preventing Cognitive Decline: A Systematic Review.

To evaluate the role of vitamin D supplementation in preventing cognitive decline in patients with Alzheimer's disease (AD), five databases such as PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), ScienceDirect, and Google Scholar were searched for articles relevant to the research question with filters such as English and human studies from 2011 to 2022. Two investigators extracted the data and assessed the quality of the study using the predefined criteria. We identified 24 relevant articles after the critical screening. There were five randomized controlled trials (RCTs), two observational studies, two systematic reviews and meta-analyses, one pilot study, and 14 review articles. Most RCTs showed no significant improvement in vitamin D supplementation except for one study, which reported significant improvement in cognition on taking vitamin D in Alzheimer's disease but was not taken much into consideration as it had a small sample size (n=210) and was for a shorter duration. Another study evidenced significant improvement in Mini-Mental State Examination (MMSE) score when memantine and vitamin D were taken together compared to when memantine and vitamin D were taken independently.Studies have shown that vitamin D deficiency is associated with an increased risk of developing cognitive impairment. But there is no sufficient evidence indicating vitamin D supplementation can improve cognitive function in Alzheimer's disease.

Lifelong experiences as a proxy of cognitive reserve moderate the association between connectivity and cognition in Alzheimer's disease

Alzheimer's disease (AD) is associated with alterations in functional connectivity (FC) of the brain. The FC underpinnings of CR, that is, lifelong experiences, are largely unknown. Resting-state FC and structural MRI were performed in 76 CSF amyloid-β (Aβ) negative healthy controls and 152 Aβ positive individuals as an AD spectrum cohort (ADS; 55 with subjective cognitive decline, SCD; 52 with mild cognitive impairment; 45 with AD dementia). Following a region-of-interest (ROI) FC analysis, intrinsic network connectivity within the default-mode network (INC-DMN) and anti-correlation in INC between the DMN and dorsal attention network (DMN:DAN) were obtained as composite scores. CR was estimated by education and Lifetime Experiences Questionnaire (LEQ). The association between INC-DMN and MEM was attenuated by higher LEQ scores in the entire ADS group, particularly in SCD. In ROI analyses, higher LEQ scores were associated with higher FC within the DMN in ADS group. INC-DMN remains relatively intact despite memory decline in individuals with higher lifetime activity estimates, supporting a role for functional networks in maintaining cognitive function in AD.

Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice.

Background:Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer’s disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment.Objective:The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP’s effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice.Methods:Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice.Results:The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice.Conclusion:Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.