Alzheimer's Disease Symptoms Research Articles

Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?

AbstractBackgroundRecent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.MethodAssess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.ResultBased on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.ConclusionQuantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated.

Donanemab in Early Symptomatic Alzheimer’s Disease: Efficacy and Safety in TRAILBLAZER‐ALZ 2, a Phase 3 Randomized Clinical Trial

AbstractBackgroundIn TRAILBLAZER‐ALZ, donanemab cleared brain amyloid plaques and significantly slowed disease progression in early symptomatic Alzheimer’s disease (AD).MethodsTRAILBLAZER‐ALZ 2 (NCT04437511), a multicenter, randomized, double‐blind, placebo‐controlled trial, enrolled participants with early symptomatic AD and amyloid and tau pathology by positron‐emission tomography. The study randomized participants with low/medium‐tau (n = 1182) and high‐tau (n = 552) pathology (missing tau category, n = 2). Participants (randomized 1:1) received donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks (w) for 72w. Donanemab participants meeting amyloid clearance treatment completion criteria at 24w or 52w were switched to placebo in a blinded procedure.The primary outcomes were change in Integrated AD Rating Scale (iADRS) score from baseline at 76w in either the low/medium‐tau or combined (low/medium‐tau and high‐tau) populations. Statistical testing allocated most power (80% alpha spend) to low/medium‐tau population outcomes, with the remainder for combined population outcomes, which included clinical and biomarker assessments.ResultsIn the low/medium‐tau population, change in iADRS score at 76w was ‐6.02 with donanemab and ‐9.27 with placebo (difference, 3.25; 95% CI, 1.88 to 4.62; P<0.001), representing a 35.1% slowing of disease progression. Change in Clinical Dementia Rating Scale (CDR) – Sum of Boxes, the key secondary outcome, was 1.20 with donanemab and 1.88 with placebo (difference, ‐0.67; 95% CI ‐0.95 to ‐0.40; P<0.001), representing a 36.0% slowing. Participants receiving donanemab experienced a 38.6% lower risk of progressing to the next disease stage versus placebo over 76w (CDR‐Global score, Hazard Ratio = 0.61; P<0.001). Amyloid clearance at 24w, 52w and 76w was achieved in 34.2%, 71.3% and 80.1% of donanemab‐treated participants, respectively. Plasma P‐tau217 was significantly reduced by 39.3% from baseline with donanemab and increased by 8.4% with placebo at 76w (P<0.001). Significant, positive results across all clinical endpoints were also observed in the combined population. The incidence of serious adverse events was 17.4% (donanemab) and 15.8% (placebo), with three deaths among patients treated with donanemab who experienced serious ARIA. Adverse events with donanemab included amyloid‐related imaging abnormalities (ARIA)‐E (24.0%, 6.1% symptomatic); ARIA‐H (31.4%); and infusion‐related reactions (8.7%).ConclusionDonanemab treatment significantly slowed clinical progression at 76w and had a safety profile consistent with earlier studies.

Remote assessment of functional impairment in Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer’s disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer’s disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia.MethodFour study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida’s research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams.ResultCompliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity).ConclusionThe RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

MiRNA-137-5p improves spatial memory and cognition in Alzheimer's mice by targeting ubiquitin-specific peptidase 30.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder causing progressive dementia. Research suggests that microRNAs (miRNAs) could serve as biomarkers and therapeutic targets for AD. Reduced levels of miR-137 have been observed in the brains of AD patients, but its specific role and downstream mechanisms remain unclear. This study sought to examine the therapeutic potential of miR-137-5p agomir in alleviating cognitive dysfunction induced in AD models and explore its potential mechanisms. This study utilized bioinformatic analysis and a dual-luciferase reporter assay to investigate the relationship between miR-137-5p and ubiquitin-specific peptidase 30 (USP30). Invitro experiments were conducted using SH-SY5Y cells to assess the impact of miR-137-5p on Aβ1-42 neurotoxicity. Invivo experiments on AD mice evaluated the effects of miR-137-5p on cognition, Aβ1-42 deposition, Tau hyperphosphorylation, and neuronal apoptosis, as well as its influence on USP30 levels. It was discovered that miR-137-5p mimics efficiently counteract Aβ1-42 neurotoxicity in SH-SY5Y cells, a protective effect that is negated by USP30 overexpression. Invivo experiments demonstrated that miR-137-5p enhances the cognition and mobility of AD mice, significantly reducing Aβ1-42 deposition, Tau hyperphosphorylation, and neuronal apoptosis within the hippocampus and cortex regions. Mechanistically, miR-137-5p significantly suppresses USP30 levels in mice, though USP30 overexpression partially buffers against miR-137-5p-induced AD symptom improvement. Our study proposes that miR-137-5p, by instigating the downregulation of USP30, has the potential to act as a novel and promising therapeutic target for AD.

Detection of Brain‐derived Neurotrophic Factor Expression in Insulin‐Resistant SH‐SY5Y Neuroblastoma Cells

AbstractBackgroundMore researchers are coining Alzheimer’s disease (AD) “type 3 diabetes” due to its significant comorbidity and shared pathology with type 2 diabetes mellitus (T2DM). A bi‐directional relationship between T2DM and AD exists, by which 50‐75% of individuals with T2DM have a greater risk of developing AD compared to non‐diabetes and that AD symptoms progress with impaired glucose utilization. Interestingly, brain‐derived neurotrophic factor (BDNF), a small protein that maintains neuron health and glucose homeostasis, has been implicated in both AD and IR. As such, this experiment investigates if insulin resistance (IR) alters BDNF expression in SH‐SY5Y neuroblastoma cells.MethodObjective 1: create a model of insulin resistance at 24, 48, 72 and 96 hours (hr) and determine expression of pAkt (S473), tAkt, insulin receptor b (INSRB) and pINSR (T1362) on Western blots. (n = 5)Objective 2: Detect mRNA and protein BDNF via Rt‐PCR and Western blotting. (n = 5)Objectives 3: Determine alterations to BDNF expression via Western blotting and qPCR. (n = 5)ResultLevels of pAkt expression were significantly decreased in insulin‐pretreated and activated samples at each timepoint of 24, 48, 72 and 96 hr; although, with each timepoint, pAkt does appear to steadily increase. pro‐BDNF and mature BDNF were detected at their respective sizes, 27kDa and 19kDa, on a Western blot and BDNF mRNA was detected on an agarose gel after PCR.ConclusionIt appears that insulin resistance is occurring at 24, 48, 72 and 96 hr solely based off Akt expression. This result will be further confirmed with the the completion of INSR‐B and p‐INSR blots. Ongoing experiments include western blots and qPCRs of BDNF to determine if there is any alteration to expression.

Evaluation of the cognitive enhancing properties of diosmin in lipopolysaccharide‐induced memory impairment in mice

AbstractBackgroundCognitive impairment is a major feature of many neurodegenerative disorders such as Alzheimer’s disease, dementia etc. The progressive cognitive decline in Alzheimer’s disease (AD) can be attributed to the fact that current anti‐Alzheimer’s drug only treat AD symptoms without completely reversing cognitive impairment in AD patients. Therefore, it is imperative to develop new therapeutic remedies that can improve memory and ameliorate cognitive impairment in AD patients. Disomin is a flavone with antioxidant, anti‐inflammatory and anti‐apoptotic properties. This study evaluated the neuroprotective effects of diosmin on LPS‐induced cognitive impairment in mice.MethodThirty‐six Swiss mice were randomly divided into six groups (n = 6). Group 1 received vehicle, group 2 received vehicle, groups 3 to 5 received diosmin (50, 100 and 200 mg/kg, p.o.) respectively group 6 received donepezil (50 mg/kg, p.o.). Sixty minutes after the treatment with the vehicle/Diosmin/Donepezil, lipopolysaccharide (LPS) (250ug/kg, i.p.) was administered daily to groups 2 to 6 for seven days. Twenty‐four hours after treatment on day 7, mice were subjected to Y‐maze test and the Novelty object recognition test (NORT) to assess their spatial and non‐spatial working memory. Subsequently, the mice were sacrificed and their brain samples were harvested for biochemical analysis (TNF‐alpha, Interferon gamma and interleukin‐12), immunohistochemical examinations (Amyloid beta, BDNF, IBA‐1, NLRP3 expression) and Golgi staining procedure for morphological alterations.ResultOur data shows that diosmin increased percentage alternation in Y‐maze test and discrimination ratio in NORT compared with the control group. Diosmin significantly (p<0.05) decreased TNF‐alpha, Interferon gamma and interleukin‐12 and reduced neurodegeneration in the CA1 region of the hippocampus & dendate gyrus when compared with the control group.ConclusionDiosmin reversed LPS‐induced cognitive impairment, which can be attributed to its neuroprotective and anti‐inflammatory properties.

Toxoplasma gondii‐induced amyloid reduction and neuroimmune responses in Alzheimer’s disease

AbstractBackgroundToxoplasma gondii is a foodborne parasite that induces monocyte recruitment and microglial activation during infection of the brain. Similarly, in Alzheimer’s disease (AD), activated immune cells are often found in the brain and these localize near amyloid beta plaques. However, after infection with T. gondii in AD mouse models, there are fewer amyloid beta plaques in the brain, increased microglial activation, and decreased severity of AD symptoms. We hypothesize that T. gondii infection activates and enhances the phagocytic ability of microglia to clear amyloid beta.MethodFemale 5xFAD mice were infected with T. gondii or PBS treated, and their brains harvested after 6 weeks of infection. Brain tissue from these animals was analyzed for amyloid (Amyloglo) and immune cell markers for microglia, monocytes, and T cells (IBA1, CD68, CD11c, CD11b, CD45, CD3) by light sheet imaging, confocal microscopy, or flow cytometry. Mice were also fitted with headplates and cranial windows and injected with methoxy‐X04 (10 mg/kg) to enable longitudinal imaging of amyloid over the span of infection.ResultConfocal microscopy of brain sections and light sheet imaging of intact brains from infected and uninfected 5xFAD mice have shown increased microglial activation markers (IBA1 and CD68) and decreased amyloid surface area and volume throughout infected brains in infected animals. Infected mouse brains also have increased co‐localization of amyloid and CD68 compared to uninfected mouse brains. Two‐photon imaging reveals that amyloid plaque area in vivo no longer increases in infected mouse brains as early as three weeks post‐infection and lasts as long as thirteen weeks post‐infection. Additionally, after six weeks of infection, we see an increase in Disease Associate Microglia (DAM) by flow cytometry, as well as an influx of other immune cells in the brain of infected mice as compared to PBS treated control mice.ConclusionOur data show that infection with T. gondii increases microglial markers associated with the DAM profile and these cells likely increase phagocytosis of amyloid beta. Infection with T. gondii appears to modulate the neuroimmune environment, including responding microglial cells, resulting in a neuroprotective phenotype.

Falls and Cognition in Adults Aging with Down Syndrome

AbstractBackgroundAdults with Down syndrome (DS), who are at risk, will show the neuropathological changes of Alzheimer’s Disease (AD) within their 40s, partially due to an overexpression of beta‐amyloid, which accumulates in the brain across their lifespan. The risk of developing AD in adults aging with DS increases with age and is marked by increased confusion, short‐term memory problems, and/or a loss of the ability to complete daily activities. There is limited evidence on the functional changes that happen to adults aging with DS prior to any marked AD symptoms. Growing evidence suggests that functional mobility abnormalities and an increase in falls may precede cognitive impairment and marked AD symptoms. The relationship between falls and cognition in adults with DS has not been thoroughly investigated; and could potentially serve as a less invasive method of assessment.MethodThe purpose of this study is to assess patterns of falls and functional mobility impairments that occur within an adult population aging with DS and their relationship with cognition. The participant receives an initial home visit, conducted by the PI, who completes and collects data on functional performance, fall risk(s), and the environment. The participant agrees to document any fall incidents using a calendar journal, and completes the monthly check‐in calls and/or emails initiated by the study team.ResultWe conducted a correlation analysis with the preliminary data from this cohort of 17 participants, 9 male and 8 female, with a mean age of 38.5 years (SD = 8.81). Increased falls were significantly related (p < .05) to impaired gait speed (r = .528) and balance (r = ‐.624), while cognition (r = .474, p >.05) was not associated with falls. Increased fear of falling assessment scores were correlated with impaired gait speed (r = .687), lower extremity (r = ‐.502) and mean grip strength (r = ‐.492), and balance (r = ‐.596).ConclusionWe demonstrated that (1) participants were willing to enroll; (2) the assessment and monitoring plan were well tolerated; and (3) fear of falling scores and decreased functional mobility were similar in aging adult with DS populations to older adult (≥ 65 years of age) populations.

DECREASE: Decrease Cognitive Decline in Alzheimer’s Disease Through Occupational Therapy: A Randomized Controlled Phase III Trial Protocol

Introduction: Alzheimer’s disease (AD) accounts for more than 80% of dementia cases worldwide and imposes a significant economic burden on the healthcare system. Currently, there is no cure for AD, and pharmacological treatments alleviate AD symptoms but fail to decrease cognitive decline. Occupational Therapy (OT) for AD patients targets symptoms without the side effects of drugs and may even play a disease-modifying role by preserving cognitive functions. The DECREASE trial aims to assess the effectiveness of a cognitive-based OT intervention amongst AD patients. Methods: The DECREASE Trial is a randomized, controlled, multicentric, phase III, superiority trial comparing the effect of OT and standard of care versus standard of care alone on cognition in AD patients. OT will entail a five-week group cognitive rehabilitation program with remote maintenance sessions until six months of follow-up. We will include 278 mild AD patients aged between 65 and 80. Changes in cognitive function between groups will be measured and compared by the ADAS-cog after six months. Discussion: The strengths of this OT program are that it is non-invasive, safe, highly standardized, and accessible to occupational therapists and caretakers worldwide. There is broad evidence of the benefits of functionality. Nevertheless, there needs to be more literature on its effect on cognitive function. AD is a public health emergency that needs to be promptly addressed. This trial will finally determine if an OT-based intervention can decrease cognitive decline and whether it should be included in the standard of care for AD.

Traditional Chinese Medicine studies for Alzheimer's disease via network pharmacology based on entropy and random walk.

Alzheimer's disease (AD) is a common neurodegenerative disease having complex pathogenesis, approved drugs can only alleviate symptoms of AD for a period of time. Traditional Chinese medicine (TCM) contains multiple active ingredients that can act on multiple targets simultaneously. In this paper, a novel algorithm based on entropy and random walk with the restart of heterogeneous network (RWRHE) is proposed for predicting active ingredients for AD and screening out the effective TCMs for AD. First, Six TCM compounds containing 20 herbs from the AD drug reviews in the CNKI (China National Knowledge Internet) are collected, their active ingredients and targets are retrieved from different databases. Then, comprehensive similarity networks of active ingredients and targets are constructed based on different aspects and entropy weight, respectively. A comprehensive heterogeneous network is constructed by integrating the known active ingredient-target association information and two comprehensive similarity networks. Subsequently, bi-random walks are applied on the heterogeneous network to predict active ingredient-target associations. AD related targets are selected as the seed nodes, a random walk is carried out on the target similarity network to predict the AD-target associations, and the associations of AD-active ingredients are inferred and scored. The effective herbs and compounds for AD are screened out based on their active ingredients' scores. The results measured by machine learning and bioinformatics show that the RWRHE algorithm achieves better prediction accuracy, the top 15 active ingredients may act as multi-target agents in the prevention and treatment of AD, Danshen, Gouteng and Chaihu are recommended as effective TCMs for AD, Yiqitongyutang is recommended as effective compound for AD.

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

BackgroundSynaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.MethodsHippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.ResultscircRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.ConclusionsIn conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03). In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Impact of Nutritional Interventions on Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The most prevalent type of dementia, especially in older persons, is Alzheimer's disease (AD), which has clinical signs of progressive cognitive decline and functional impairment. However, new research indicates that AD patients' dietary patterns and nutritional intake could hold the key to staving off some of the complications. Therefore, the primary aim of this investigation was to analyze various dietary patterns and the subsequent impact of the resulting nutritional intake on AD patients. Various online databases (PubMed, Scopus, Web of Science, and Google Scholar) were searched using appropriate keywords, reference searches, and citation searches. The databases were accessed using the search phrases "Alzheimer's disease," "dietary habits," "minerals," "nutritional profile," and "vitamins." Fifteen of the 21 investigations that we selected for our systematic review and subsequent meta-analysis revealed that micronutrient supplementation and some dietary patterns were helpful in alleviating a few of the symptoms of AD, especially with regard to the progression of dementia in the assessed patients. It was shown that dietary interventions and nutritional adjustments can considerably delay the onset of AD and the varying degrees of dementia that often accompany it. However, there were some areas of ambiguity in our findings because a few of the chosen studies did not document any noticeable improvements in the patient's conditions.

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer’s disease mouse model

BackgroundThe gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer’s disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown.MethodsFive familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age.ResultsIn this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib−/− mice.ConclusionTherefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

Targeting CaN/NFAT in Alzheimer's brain degeneration.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of cognitive functions. While the exact causes of this debilitating disorder remain elusive, numerous investigations have characterized its two core pathologies: the presence of β-amyloid plaques and tau tangles. Additionally, multiple studies of postmortem brain tissue, as well as results from AD preclinical models, have consistently demonstrated the presence of a sustained inflammatory response. As the persistent immune response is associated with neurodegeneration, it became clear that it may also exacerbate other AD pathologies, providing a link between the initial deposition of β-amyloid plaques and the later development of neurofibrillary tangles. Initially discovered in T cells, the nuclear factor of activated T-cells (NFAT) is one of the main transcription factors driving the expression of inflammatory genes and thus regulating immune responses. NFAT-dependent production of inflammatory mediators is controlled by Ca2+-dependent protein phosphatase calcineurin (CaN), which dephosphorylates NFAT and promotes its transcriptional activity. A substantial body of evidence has demonstrated that aberrant CaN/NFAT signaling is linked to several pathologies observed in AD, including neuronal apoptosis, synaptic deficits, and glia activation. In view of this, the role of NFAT isoforms in AD has been linked to disease progression at different stages, some of which are paralleled to diminished cognitive status. The use of classical inhibitors of CaN/NFAT signaling, such as tacrolimus or cyclosporine, or adeno-associated viruses to specifically inhibit astrocytic NFAT activation, has alleviated some symptoms of AD by diminishing β-amyloid neurotoxicity and neuroinflammation. In this article, we discuss the recent findings related to the contribution of CaN/NFAT signaling to the progression of AD and highlight the possible benefits of targeting this pathway in AD treatment.

Alzheimer's disease-related brain insulin resistance and the prospective therapeutic impact of metformin.

Besides COVID-19, two of the most critical outbreaks of our day are insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). Each disease's pathophysiology is well established. Furthermore, a substantial overlap between them has coexisted. Uncertainty remains on whether T2DM and AD are parallel illnesses with the same origin or separate illnesses linked through violent pathways. The current study was aimed at testing whether the insulin resistance in the brain results in AD symptoms or not. Insulin resistance was induced in the brains of rats using a single intracerebroventricular streptozotocin (STZ) dose. We then measured glucose, insulin receptor substrate 2 (IRS-2), amyloid β (Aβ) deposition, and tau phosphorylation in the brain to look for signs of insulin resistance and AD. The results of this study indicated that a single dose of STZ was able to induce insulin resistance in the brain and significantly decline IRS-2. This resistance was accompanied by obvious memory loss, Aβ deposition, and tau phosphorylation, further visible diminishing in neurotransmitters such as dopamine and acetylcholine. Furthermore, oxidative stress was increased due to the antioxidant system being compromised. Interestingly, the pancreas injury and peripheral insulin resistance coexisted with brain insulin resistance. Indeed, the antidiabetic metformin was able to enhance all these drastic effects. In conclusion, brain insulin resistance could lead to AD and vice versa. These are highly linked syndromes that could influence peripheral organs. Further studies are required to stabilize this putative pathobiology relationship between them.

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Patterns of use of symptomatic treatments for Alzheimer's disease dementia (AD)

BackgroundSymptomatic treatment for Alzheimer's disease (AD) dementia could temporarily slow symptom worsening and improve the quality of life for both AD dementia patients and their caregivers. A comprehensive evaluation of symptomatic treatment patterns using recent data for newly diagnosed AD dementia has not been performed and compared across different countries.MethodsThe drug name, time to the first therapy, duration, discontinuation or switches were described in newly diagnosed AD dementia patients in two databases (a major U.S. health plan [US] and UK-Clinical Practice Research Datalink [CPRD GOLD]). This analysis included patients with newly diagnosed AD dementia in 2018–2019, who initiated symptomatic AD drug therapy, with ≥ 1 year baseline period and ≥ 1 year of follow-up.ResultsOver median follow-ups of 698 and 645 days, 63% and 65% of AD dementia patients used symptomatic treatments, with 34% and 77% newly initiating therapy, constituting analytic samples of 7637 patients in the US database and 4470 patients in the CPRD, respectively. The median time to the first therapy was 14 days for US and 49 days for CPRD; donepezil ranked the as most frequently used (69% vs 61%), followed by memantine (19% vs 28%) in the US database and CPRD, respectively. Median time on first therapy was 213 and 334 days, and 30% and 12% of patients proceeded to a second treatment in the US and CPRD databases, respectively.ConclusionApproximately two thirds of newly diagnosed AD dementia patients utilized approved symptomatic treatment. Time on first therapy was relatively short (< 1 year) and the majority did not move to a second therapy, highlighting the need for better adherence and persistence to existing AD symptomatic therapies and the need for additional therapies to alleviate the significant burden of AD dementia.

Lithium, a Treatment Option for Alzheimer's Disease? A Review of Existing Evidence and Discussion on Future Perspectives.

After over 50 years of use, lithium-salts remain the first-line therapy for the management of bipolar disorder. Throughout this period, the potential for lithium salts has been extensively studied and numerous data favor its use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We reviewed existing evidence gathered from clinical case reports and studies on the effect of lithium on neuropsychological symptoms of AD and as a disease-modifying treatment acting on cognitive symptoms. The review summarizes the molecular pathways, involving GSK-3β inhibition and neuroprotection, through which lithium is proposed to exert its effect. Limitations to its current use in AD are discussed and future perspectives as a potential treatment option for AD are considered in regard to ongoing clinical trials using different forms of lithium.

Abstract 13370: Single-Cell RNA-seq Reveals Transcriptomic Modulation of Alzheimer’s Disease by Activated Protein C

Introduction: Alzheimer’s Disease (AD) causes neuroinflammation characterized by degradation of neurological functions resulting in memory loss and confusion. Activated Protein C (APC), a plasma zymogen, has shown promising cytoprotection, anti-inflammation, and anti-apoptotic properties. ScRNA-seq allows for examining the underlying mechanisms by which APC therapy on AD at the cellular level. Hypothesis: APC treatment can ameliorate AD symptoms of 5xFAD transgenic mice. The scRNA Seq analysis could provide detailed responses of various cell populations to Alzheimer's disease pathogenesis and molecular aspects of APC therapy. Methods: Whole brain tissue were collected at 7 months, APC-treated 5xFAD mice received daily recombinant APC or saline injections. The 10x Genomics Next Gem kit was used to dissociate the tissue for sequencing. Bioinformatic analysis was performed using Seurat in R and an integrated dataset was used to compare multiple single-cell samples. Results: Bioinformatic analysis of 5xFAD versus wild type (WT) C57BL/6J mouse brain revealed much of the sample consists of microglial cells. Interestingly, 5xFAD versus WT brains have notable decreases in astrocyte and neuron populations. Administration of recombinant APC rebounds these populations to comparable levels as WT while dramatically reduces the microglial population in 5xFAD versus WT brain. The largest proportion of oligodendrocytes are also recorded after APC treatment. Differential expression testing conveys transcriptomic regulation of known AD critical genes such as Apoe , Ctsb , Trem2 , and Tyrobp by APC. Consequently, GO term enrichment uncovers inflammatory biological processes such as microglial activation to be downregulated by APC-treated 5xFAD. Additionally, recuperation of nervous system developmental processes was found in APC-treated 5xFAD mice. Conclusions: APC treatment drastically impacts the cellular pathophysiology of AD. Differential expression testing of APC treated 5xFAD versus WT mice revealed transcriptomic downregulation of AD implicated genes throughout multiple cell-types. Administration of APC significantly impacts AD implicated genes associated with AD pathogenesis through enrichment analysis.