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Nutrients Jan 2021The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and... (Review)
Review
The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.
Topics: Aged; Alzheimer Disease; Gastrointestinal Microbiome; Humans
PubMed: 33504065
DOI: 10.3390/nu13020361 -
Atencion Primaria May 2020The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a...
OBJECTIVE
The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment.
DESIGN
Systematic review.
DATA SOURCES
We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles.
DATA EXTRACTION
The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus.
RESULTS
We identified 75 articles, of which 23 were finally included in the review.
CONCLUSIONS
Most of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Brain; Exercise; Humans; Magnetic Resonance Imaging; Neuroimaging; Positron-Emission Tomography
PubMed: 31153668
DOI: 10.1016/j.aprim.2018.09.010 -
Advances in Clinical and Experimental... Oct 2023Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the...
Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the treatment of Alzheimer's disease (AD) patients, and will most likely also approve a 3rd one, donanemab, soon. While these antibodies have been shown to significantly reduce amyloid in the brain, there is little, if any, evidence that they provide clinically meaningful benefit for AD patients by slowing cognitive decline. I have said it before, and I say it again: the reported benefits of anti-amyloid antibodies observed in clinical trials are erroneous and based on misinterpretation of data and a trivial miscalculation. For example, Sims et al. (2023) reported in a phase III clinical trial that donanemab treatment of early symptomatic AD patients with amyloid and tau pathology provided 35% and 36% slowing of clinical progression and cognitive decline, respectively, as measured using the Integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) psychometric tests. Here, in this editorial, I show that 2.5% and 9.6% would be better estimates for less cognitive impairment with donanemab treatment.
Topics: United States; Humans; Alzheimer Disease; Antibodies, Monoclonal
PubMed: 37831471
DOI: 10.17219/acem/172673 -
Journal of Internal Medicine Aug 2021The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and... (Review)
Review
The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.
Topics: Alzheimer Disease; Humans; Primary Health Care; Time Factors
PubMed: 33458891
DOI: 10.1111/joim.13244 -
Stem Cell Reviews and Reports Feb 2022During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study mechanisms of human neural development, disease modeling, and drug... (Review)
Review
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study mechanisms of human neural development, disease modeling, and drug discovery in vitro. Especially in the field of Alzheimer's disease (AD), where this treatment is lacking, tremendous effort has been put into the investigation of molecular mechanisms behind this disease using induced pluripotent stem cell-based models. Numerous of these studies have found either novel regulatory mechanisms that could be exploited to develop relevant drugs for AD treatment or have already tested small molecules on in vitro cultures, directly demonstrating their effect on amelioration of AD-associated pathology. This review thus summarizes currently used differentiation strategies of induced pluripotent stem cells towards neuronal and glial cell types and cerebral organoids and their utilization in modeling AD and potential drug discovery.
Topics: Alzheimer Disease; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Neurons; Organoids
PubMed: 35107767
DOI: 10.1007/s12015-021-10254-3 -
Nature Communications Oct 2023Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether...
Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether these biomarkers can predict AD in Chinese populations is yet to be fully explored. We therefore tested the performance of these plasma biomarkers in 126 participants with preclinical AD and 123 controls with 8-10 years of follow-up from the China Cognition and Aging Study. Plasma Aβ42, p-tau181, and NfL were significantly correlated with cerebrospinal fluid counterparts and significantly altered in participants with preclinical AD. Combining plasma Aβ42, p-tau181, and NfL successfully discriminated preclinical AD from controls. These findings were validated in a replication cohort including 51 familial AD mutation carriers and 52 non-carriers from the Chinese Familial Alzheimer's Disease Network. Here we show that plasma Aβ42, p-tau181, and NfL may be useful for predicting AD 8 years before clinical onset in Chinese populations.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; East Asian People; tau Proteins
PubMed: 37875471
DOI: 10.1038/s41467-023-42596-6 -
Antioxidants & Redox Signaling Mar 2021Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is currently ranked as the sixth leading cause of death, but some sources put it as... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is currently ranked as the sixth leading cause of death, but some sources put it as third, after heart disease and cancer. Currently, there are no effective therapeutic approaches to treat or slow the progression of chronic neurodegeneration. In addition to the accumulation of amyloid-β (Aβ) and tau, AD patients show progressive neuronal loss and neuronal death, also high oxidative stress that correlates with abnormal levels or overload of brain metals. Several promising compounds targeting oxidative stress, redox metals, and neuronal death are under preclinical or clinical evaluation as an alternative or complementary therapeutic strategy in mild cognitive impairment and AD. Here, we present a general analysis and overview, discuss limitations, and suggest potential directions for these treatments for AD and related dementia. Most of the disease-modifying therapeutic strategies for AD under evaluation in clinical trials have focused on components of the amyloid cascade, including antibodies to reduce levels of Aβ and tau, as well as inhibitors of secretases. Unfortunately, several of the amyloid-focused therapeutics have failed the clinical outcomes or presented side effects, and numerous clinical trials of compounds have been halted, reducing realistic options for the development of effective AD treatments. The focus of research on AD and related dementias is shifting to alternative or innovative areas, such as ApoE, lipids, synapses, oxidative stress, cell death mechanisms, neuroimmunology, and neuroinflammation, as well as brain metabolism and bioenergetics.
Topics: Alzheimer Disease; Ferroptosis; Humans; Metals; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress
PubMed: 32486897
DOI: 10.1089/ars.2020.8134 -
Journal of Alzheimer's Disease : JAD 2023Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include... (Review)
Review
Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.
Topics: Humans; Alzheimer Disease; Cross-Sectional Studies; Prospective Studies; Diet; Risk Factors
PubMed: 37955087
DOI: 10.3233/JAD-230418 -
Neurology Mar 2020To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data.
METHODS
EMBASE, PubMed, and Web of Science databases were consulted until July 2019.
RESULTS
Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.
CONCLUSION
We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals' belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.
Topics: Alzheimer Disease; Humans
PubMed: 32047067
DOI: 10.1212/WNL.0000000000009058 -
BMC Geriatrics Aug 2022Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably,...
BACKGROUND
Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably, genetic and environmental factors are now considered contributors to AD progression.
OBJECTIVE
To assess the association between sleep duration, genetic susceptibility, and AD.
METHODS AND RESULTS
Based on 483,507 participants from the UK Biobank (UKB) with an average follow-up of 11.3 years, there was a non-linear relationship between AD incidence and sleep duration (P for non-linear < 0.001) by restricted cubic splines (RCS). Sleep duration was categorized into short sleep duration (< 6 h/night), normal sleep duration (6-9 h/night), and long sleep duration (> 9 h/night). No statistically significant interaction was identified between sleep duration and the AD-GRS (Alzheimer's disease genetic risk score, P for interaction = 0.45) using Cox proportional risk model. Compared with the participants who had a low AD-GRS and normal sleep duration, there was associated with a higher risk of AD in participants with a low AD-GRS and long sleep duration (HR = 3.4806; 95% CI 2.0011-6.054, p < 0.001), participants with an intermediate AD-GRS and long sleep duration (HR = 2.0485; 95% CI 1.3491-3.1105, p < 0.001), participants with a high AD-GRS and normal sleep duration (HR = 1.9272; 95% CI 1.5361-2.4176, p < 0.001), and participants with a high AD-GRS and long sleep duration (HR = 5.4548; 95% CI 3.1367-9.4863, p < 0.001).In addition, there was no causal association between AD and sleep duration using Two Sample Mendelian randomization (MR).
CONCLUSION
In the UKB population, though there was no causal association between AD and sleep duration analyzed using Two Sample MR, long sleep duration (> 9 h/night) was significantly associated with a higher risk of AD, regardless of high, intermediate or low AD-GRS. Prolonged sleep duration may be one of the clinical predictors of a higher risk of AD.
Topics: Alzheimer Disease; Biological Specimen Banks; Genetic Predisposition to Disease; Humans; Sleep; United Kingdom
PubMed: 35918656
DOI: 10.1186/s12877-022-03298-8