Showing papers in "Journal of Alzheimer's Disease in 2019"
TL;DR: In this paper, the authors present a review of combination therapy regimens for Alzheimer's disease, including symptomatic and disease-modifying regimens, and discuss the regulatory and drug development landscape for combination therapy.
Abstract: Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.
290 citations
TL;DR: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia.
Abstract: BACKGROUND: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia. OBJECTIVE: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia. METHODS: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299Results:From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5), nitrogen dioxide (NO2), nitrous oxides (NOx), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5, NO2/NOx, and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal. CONCLUSION: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia.
274 citations
TL;DR: Low levels of social isolation characterized by high engagement in social activity and large social networks were associated with better late-life cognitive function and there was no difference according to gender or number of years follow-up.
Abstract: Background There is some evidence to suggest that social isolation may be associated with poor cognitive function in later life. However, findings are inconsistent and there is wide variation in the measures used to assess social isolation. Objective We conducted a systematic review and meta-analysis to investigate the association between social isolation and cognitive function in later life. Methods A search for longitudinal studies assessing the relationship between aspects of social isolation (including social activity and social networks) and cognitive function (including global measures of cognition, memory, and executive function) was conducted in PsycInfo, CINAHL, PubMed, and AgeLine. A random effects meta-analysis was conducted to assess the overall association between measures of social isolation and cognitive function. Sub-analyses investigated the association between different aspects of social isolation and each of the measures of cognitive function. Results Sixty-five articles were identified by the systematic review and 51 articles were included in the meta-analysis. Low levels of social isolation characterized by high engagement in social activity and large social networks were associated with better late-life cognitive function (r = 0.054, 95% CI: 0.043, 0.065). Sub-analyses suggested that the association between social isolation and measures of global cognitive function, memory, and executive function were similar and there was no difference according to gender or number of years follow-up. Conclusions Aspects of social isolation are associated with cognitive function in later life. There is wide variation in approaches to measuring social activity and social networks across studies which may contribute to inconsistencies in reported findings.
220 citations
TL;DR: Serum GFAP correlated with the Mini-Mental State Examination score and might be a follow-up marker in clinical trials and the first blood biomarker in the differential diagnosis of AD and bvFTD.
Abstract: Reliable blood biomarkers for Alzheimer's disease (AD) are missing. We measured astroglial GFAP in patients with AD (n = 28), frontotemporal dementia (bvFTD, n = 35), Parkinson's disease (n = 11), Lewy body dementias (n = 19), and controls (n = 34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r= -0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be the first blood biomarker in the differential diagnosis of AD and bvFTD.
158 citations
TL;DR: An overview of how systemic stress-dependent biological responses common to particulate matter and ozone may provide insight into early CNS effects of pollutants, including links with oxidative, inflammatory, and metabolic processes is provided.
Abstract: Air pollution is a risk factor for cardiovascular and respiratory morbidity and mortality. A growing literature also links exposure to diverse air pollutants (e.g., nanoparticles, particulate matter, ozone, traffic-related air pollution) with brain health, including increased incidence of neurological and psychiatric disorders such as cognitive decline, dementia (including Alzheimer's disease), anxiety, depression, and suicide. A critical gap in our understanding of adverse impacts of pollutants on the central nervous system (CNS) is the early initiating events triggered by pollutant inhalation that contribute to disease progression. Recent experimental evidence has shown that particulate matter and ozone, two common pollutants with differing characteristics and reactivity, can activate the hypothalamic-pituitary-adrenal (HPA) axis and release glucocorticoid stress hormones (cortisol in humans, corticosterone in rodents) as part of a neuroendocrine stress response. The brain is highly sensitive to stress: stress hormones affect cognition and mental health, and chronic stress can produce profound biochemical and structural changes in the brain. Chronic activation and/or dysfunction of the HPA axis also increases the burden on physiological stress response systems, conceptualized as allostatic load, and is a common pathway implicated in many diseases. The present paper provides an overview of how systemic stress-dependent biological responses common to particulate matter and ozone may provide insight into early CNS effects of pollutants, including links with oxidative, inflammatory, and metabolic processes. Evidence of pollutant effect modification by non-chemical stressors (e.g., socioeconomic position, psychosocial, noise), age (prenatal to elderly), and sex will also be reviewed in the context of susceptibility across the lifespan.
140 citations
TL;DR: It is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies in accurately calculating the full costs to society.
Abstract: While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.
131 citations
TL;DR: Positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults are found.
Abstract: While the role of diet and nutrition in cognitive health and prevention of dementia in older adults has attracted much attention, the efficacy of different dietary patterns remains uncertain. Previous reviews have mainly focused on the Mediterranean diet, but either omitted other dietary patterns, lacked more recent studies, were based on cross-sectional studies, or combined older and younger populations. We followed PRISMA guidelines, and examined the efficacy of current research from randomized controlled trials and cohort studies on the effects of different dietary patterns. We reviewed the Mediterranean diet, Dietary Approach to Stop Hypertension (DASH) diet, the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diet, Anti-inflammatory diet, Healthy diet recommended by guidelines via dietary index, or Prudent healthy diets generated via statistical approaches, and their impact on cognitive health among older adults. Of 38 studies, the Mediterranean diet was the most investigated with evidence supporting protection against cognitive decline among older adults. Evidence from other dietary patterns such as the MIND, DASH, Anti-inflammatory, and Prudent healthy diets was more limited but showed promising results, especially for those at risk of cardiovascular disease. Overall, this review found positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults. These dietary patterns are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods. Better understanding of the underlying mechanisms and effectiveness is needed to develop comprehensive and practical dietary recommendations against age-related cognitive decline among older adult.
121 citations
TL;DR: Biochemical analysis indicates that metformin improved memory in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze by decreasing APPc99 and pTau.
Abstract: Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer's disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCɛ), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.
104 citations
TL;DR: Current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer's disease are discussed and genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer’s disease-related oxidative stress are identified.
Abstract: Alzheimer's disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-β deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer's disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer's disease-related oxidative stress.
96 citations
TL;DR: There is a lack of midlife specific data, limited data on VaD, and a lack on geographical representation for many risk factors for dementia, which needs to be considered before recommendations are made about the relevance of risk factors in mid- or late-life or for dementia subtypes.
Abstract: Background The translation of evidence on dementia risk factors into clinical advice requires careful evaluation of the methodology and scope of data from which risk estimates are obtained. Objective To evaluate the quantity, quality, and representativeness of evidence, we conducted a review of reviews of risk factors for Alzheimer's disease (AD), Vascular dementia (VaD), and Any Dementia. Methods PubMed, Cochrane library, and the Global Index Medicus were searched to identify meta-analyses of observational studies of risk factors for AD, VaD, and Any Dementia. PROSPERO CRD42017053920. Results Meta-analysis data were available for 34 risk factors for AD, 26 risk factors for Any Dementia and eight for VaD. Quality of evidence varied greatly in terms of the number of contributing studies, whether data on midlife exposure was available, and consistency of measures. The most evidence was available for cardiovascular risk factors. The most geographically representative evidence (five of six global regions) was available for alcohol, physical activity, diabetes, high midlife BMI, antihypertensives, and motor function. Evidence from Australia/Oceana or Africa was limited. With the exception of diabetes, meta-analysis data were unavailable from Latin America/Caribbean. Midlife specific data were only available for cholesterol and arthritis. Conclusion There is a lack of midlife specific data, limited data on VaD, and a lack of geographical representation for many risk factors for dementia. The quality, quantity, and representativeness of evidence needs to be considered before recommendations are made about the relevance of risk factors in mid- or late-life or for dementia subtypes.
93 citations
TL;DR: Alzheimer’s disease clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events.
Abstract: Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease.
TL;DR: This study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension.
Abstract: Background Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer's disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. Objective To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. Methods Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., systolic hypertension > 140 mmHg or > 160 mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. Results Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 - 1.47, p = 0.0065). Similarly, for systolic hypertension > 140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 - 1.35, p = 0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. Conclusions Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD.
TL;DR: This narrative literature review is to discuss present treatment algorithms and potential future therapies in Alzheimer's disease, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness.
Abstract: An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.
TL;DR: The current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies are discussed, and the opportunities for therapeutic and preventative interventions are analyzed.
Abstract: Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed, especially Alzheimer's disease (AD) and cerebrovascular ischemic disease (CVID), rather than pure AD. While these could be just two frequent unrelated comorbidities in the elderly, epidemiological research has reinforced the idea that mid-life (age <65 years) vascular risk factors increase the risk of late-onset (age ≥ 65 years) dementia, and specifically AD. By contrast, healthy lifestyle choices such as leisure activities, physical exercise, and Mediterranean diet are considered protective against AD. Remarkably, several large population-based longitudinal epidemiological studies have recently indicated that the incidence and prevalence of dementia might be decreasing in Western countries. Although it remains unclear whether these positive trends are attributable to neuropathologically definite AD versus CVID, based on these epidemiological data it has been estimated that a sizable proportion of AD cases could be preventable. In this review, we discuss the current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies, and analyze the opportunities for therapeutic and preventative interventions.
TL;DR: The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.
Abstract: There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau’s binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the “tau prion”. Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.
TL;DR: The scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the Alzheimer Precision Medicine Initiative are presented.
Abstract: Precision medicine (PM) is an evolving scientific renaissance movement implementing key breakthrough technological and scientific advances to overcome the limitations of traditional symptom- and sign-based phenotypic diagnoses and clinical "one-size-fits-all, magic bullet drug development" in these largely heterogeneous target populations. It is a conceptual shift from ineffective treatments for biologically heterogeneous "population averages" to individually-tailored biomarker-guided targeted therapies. PM is defining which therapeutic approach will be the most effective for a specific individual, at a determined disease stage, across multiple medical research fields, including neuroscience, neurology and psychiatry. The launch of the Alzheimer Precision Medicine Initiative (APMI) and its associated cohort program in 2016-facilitated by the academic core coordinating center run by the Sorbonne University Clinical Research Group in Alzheimer Precision Medicine (Sorbonne University GRC n°21 APM)"-is geared at transforming healthcare, conventional clinical diagnostics, and drug development research in Alzheimer's disease. Ever since the commencement of the APMI, the international interdisciplinary research network has introduced groundbreaking translational neuroscience programs on the basis of agnostic exploratory genomics, systems biology, and systems neurophysiology applying innovative "big data science", including breakthrough artificial intelligence-based algorithms. Here, we present the scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the APMI.
TL;DR: MBI, especially the affective dysregulation domain, increases the risk of dementia in this psychiatric outpatient population, and psychiatric clinicians should keep prodromal dementia on their differential diagnosis when assessing those with new onset psychiatric symptomatology in older adults.
Abstract: BACKGROUND Mild behavioral impairment (MBI) has been proposed as risk factor for dementia, and for some, an early manifestation of dementia. OBJECTIVE We examined the prevalence of MBI in the psychiatric outpatient clinic, and compared the incidence of dementia in MBI with that in other psychiatric diseases. METHODS Retrospective chart review was conducted in 2,853 consecutive outpatients over the age of 50. MBI was diagnosed according to the International Society to Advance Alzheimer's Research and Treatment research diagnostic criteria. The incidence rate of dementia was examined in the patients who were followed up for at least 1 month. Kaplan-Meier survival analyses and Cox proportional hazards regression models were performed to compare the time to onset of dementia between MBI and other psychiatric diseases. RESULTS The prevalence of MBI was 3.5% and the incidence of dementia was 30.7 cases per 1000 person-years. The hazard ratio (HR) for dementia was higher for MBI than other psychiatric diseases (HR: 8.07, 95% confidence interval: 4.34-15.03, p < 0.001). In MCI patients, the cumulative survival in MCI with affective dysregulation tended to be lower than that in MCI without (p = 0.090). CONCLUSIONS Psychiatric outpatients often meet MBI criteria. MBI, especially the affective dysregulation domain, increases the risk of dementia in this psychiatric outpatient population. Since late-onset psychiatric and behavioral symptoms may be prodromal symptoms of dementia in some, careful observation is needed, and psychiatric clinicians should keep prodromal dementia on their differential diagnosis when assessing those with new onset psychiatric symptomatology in older adults.
TL;DR: The nanoparticles observed in roadside environment are a complex mixture of particles from several sources affected by atmospheric processing, local co-pollutants and meteorology.
Abstract: Atmospheric nanoparticles can be formed either via nucleation in atmosphere or be directly emitted to the atmosphere. In urban areas, several combustion sources (engines, biomass burning, power generation plants) are directly emitting nanoparticles to the atmosphere and, in addition, the gaseous emissions from the same sources can participate to atmospheric nanoparticle formation. This article focuses on the sources and formation of nanoparticles in traffic-influenced environments and reviews current knowledge on composition and characteristics of these nanoparticles. In general, elevated number concentrations of nanoparticles are very typically observed in traffic-influenced environments. Traffic related nanoparticles can originate from combustion process or from non-exhaust related sources such as brake wear. Particles originating from combustion process can be divided to three different sources; 1) primary nanoparticles formed in high temperature, 2) delayed primary particles formed as gaseous compounds nucleate during the cooling and dilution process and 3) secondary nanoparticles formed from gaseous precursors via the atmospheric photochemistry. The nanoparticles observed in roadside environment are a complex mixture of particles from several sources affected by atmospheric processing, local co-pollutants and meteorology.
TL;DR: Socioeconomic differences in dementia risk can be partly explained by differences in modifiable health conditions and lifestyle factors.
Abstract: Background Differences in dementia risk across the gradient of socioeconomic status (SES) exist, but their determinants are not well understood. Objective This study investigates whether health conditions and lifestyle-related risk factors explain the SES inequalities in dementia risk. Methods 6,346 participants from the English Longitudinal Study of Ageing were followed up from 2008/2009 until 2014/2015. We used Cox regression adjusted for age, gender, wealth/education, and clustering at the household level to examine the association between SES markers (wealth, education) and time to dementia in a structural equation model including potential mediation or effect modification by a weighted compound score of twelve modifiable risk and protective factors for dementia ('LIfestyle for BRAin health' (LIBRA) score). Results During a median follow-up of 6 years, 192 individuals (3.0%) developed dementia. LIBRA scores decreased with increasing wealth and higher educational level. A one-point increase in the LIBRA score was associated with a 13% increase in dementia risk (hazard ratio (HR) = 1.13, 95% confidence interval 1.07-1.19). Higher wealth was associated with a decreased dementia risk (HR = 0.58, 0.39-0.85). Mediation analysis showed that 52% of the risk difference between the highest and lowest wealth tertile was mediated by differences in LIBRA (indirect effect: HR = 0.75, 0.66-0.85). Education was not directly associated with dementia (HR = 1.05, 0.69-1.59), but was a distal risk factor for dementia by explaining differences in wealth and LIBRA scores (indirect effect high education: HR = 0.92, 0.88-0.95). Conclusion Socioeconomic differences in dementia risk can be partly explained by differences in modifiable health conditions and lifestyle factors.
TL;DR: Exercise training alters CBF and improves cognitive performance in older adults with and without cognitive impairment and differentially altered CBF depending on cognitive status.
Abstract: Background Exercise training has been associated with greater cerebral blood flow (CBF) in cognitively normal older adults (CN). Alterations in CBF, including compensatory perfusion in the prefrontal cortex, may facilitate changes to the brain's neural infrastructure. Objective To examine the effects of a 12-week aerobic exercise intervention on resting CBF and cognition in CN and those with mild cognitive impairment (MCI). We hypothesized individuals with MCI (versus CN) would exhibit greater whole brain CBF at baseline and that exercise would mitigate these differences. We also expected CBF changes to parallel cognitive improvements. Methods Before and after a 12-week exercise intervention, 18 CN and 17 MCI participants (aged 61-88) underwent aerobic fitness testing, neuropsychological assessment, and an MRI scan. Perfusion-weighted images were collected using a GE 3T MR system. Repeated measures analyses of covariance were used to test within- and between-group differences over time, followed by post-hoc analyses to examine links between CBF changes and cognitive improvement. Results At baseline, individuals with MCI (versus CN) exhibited significantly elevated perfusion in the left insula. Twelve weeks of aerobic exercise reversed this discrepancy. Additionally, exercise improved working memory (measured by the Rey Auditory Verbal Learning Test) and verbal fluency (measured by the Controlled Oral Word Association Test) and differentially altered CBF depending on cognitive status. Among those with MCI, decreased CBF in the left insula and anterior cingulate cortex was associated with improved verbal fluency. Conclusions Exercise training alters CBF and improves cognitive performance in older adults with and without cognitive impairment. Future studies must evaluate the mediating effects of CBF on the association between exercise training and cognition.
TL;DR: Molecular triggers to the disease process are highlighted and factors, including age, gender, lifestyle, epigenetic factors, and type 2 diabetes, that are involved in late-onset AD are reviewed.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. With the increased aging population, AD is a major health concern in society. Morphological and pathological studies revealed that AD is associated with the loss of synapses, defective mitochondria, and the proliferation of reactive astrocytes and microglia, in addition to the presence amyloid-β and phosphorylated tau in learning and memory regions of the brain in AD patients. AD occurs in two forms: early-onset familial and late-onset sporadic. Genetic mutations in APP, PS1, and PS2 loci cause familial AD. Multiple factors are reported to be involved in late-onset AD, including APOE4 genotype, polymorphisms in several gene loci and type 2 diabetes, traumatic brain injury, stroke, and age-related factors, including increased reactive oxygen species production and dysfunction in mitochondria. It is widely accepted that synaptic damage and mitochondrial dysfunction are early events in disease process. The purpose of this article is to highlight molecular triggers to the disease process. This article also reviews factors, including age, gender, lifestyle, epigenetic factors, and type 2 diabetes, that are involved in late-onset AD. This article also discusses recent developments in research of mitochondrial structure, function, physiology, dynamics, biogenesis, mitophagy, and mitochondrial DNA changes in healthy and diseased states.
TL;DR: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies, and the review of 57 fMRI studies suggests substantial inconsistency.
Abstract: BACKGROUND Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. OBJECTIVE We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. METHODS PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. RESULTS Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. CONCLUSIONS The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.
TL;DR: The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of theTXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.
Abstract: Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.
TL;DR: Preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.
Abstract: Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.
TL;DR: Dietary and total zinc, iron, copper, and selenium intakes might be inversely associated with the prevalence of low cognitive performance.
Abstract: Background The association of zinc, iron, copper, and selenium intakes with cognitive function is poorly understood so far. Objective To examine the associations of dietary and total zinc, iron, copper, and selenium intakes with low cognitive performance. Methods Cross-sectional study data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 was used. Zinc, iron, copper, and selenium intakes from foods and supplements were estimated from two non-consecutive 24-hour diet recalls. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Word Learning sub-test, Animal Fluency test, and Digit Symbol Substitution test (DSST). For each cognitive measurement, people whose score were lower than the age group stratified lowest quartile were defined as low cognitive performance. Logistic regression and restricted cubic spline models were applied to examine the associations of dietary and total zinc, iron, copper, and selenium intakes with different measures of low cognitive performance. Results A total of 2,332 adults aged 60 years or older were included. The association between zinc, iron, copper, and selenium intake and low cognitive performance was significant in different test. Compared with the lowest quartile of total copper intake, the weighted multivariate adjusted ORs (95% CI) of the highest quartile were 0.34 (0.16-0.75) for low cognitive performance in DSST. L-shaped associations between total copper or selenium and low cognitive performance in DSST and animal fluency were found. Conclusion Dietary and total zinc, copper, and selenium intakes might be inversely associated with the prevalence of low cognitive performance.
TL;DR: The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD.
Abstract: The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
TL;DR: Loading curcumin in NLCs is an effective strategy for increasingCurcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment.
Abstract: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is caused by accumulation of amyloid-β (Aβ) peptide and is associated with neurological abnormalities in learning and memory. The protective role of curcumin on nerve cells, along with a potent antioxidant and free radical scavenging activity, has been widely studied. However, its low bioavailability and limited transport ability across the blood-brain barrier are two major drawbacks of its application in the treatment of different neurodegenerative diseases. The present study was designed to improve the effectiveness of curcumin in the treatment of Aβ-induced cognitive deficiencies in a rat model of AD by loading it into nanostructured lipid carriers (NLCs). The accumulation rate of curcumin (505.76±38.4 ng/g-1 h) in rat brain, as well as its serum levels, were significantly increased by using curcumin-loaded NLCs. The effective role of NLCs for brain delivery of curcumin was confirmed by reduced oxidative stress parameters (ROS formation, lipid peroxidation, and ADP/ATP ratio) in the hippocampal tissue and improvement of spatial memory. Also, histopathological studies revealed the potential of Cur-NLCs in decreasing the hallmarks of Aβ in AD in the animal model. The result of studying the neuroprotective potential of Cur-NLC in both pre-treatment and treatment modes showed that loading curcumin in NLCs is an effective strategy for increasing curcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment.
TL;DR: This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.
Abstract: Background Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations. Objective Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains. Methods Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington's disease, two major depressive disorder, and one Parkinson's disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. Results Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains. Conclusion This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.
TL;DR: Given their toxicity, abundance in roadside air, and nanoscale dimensions, traffic-derived magnetite pollution nanoparticles may constitute a chronic and pernicious neurotoxicant, and hence an environmental risk factor for AD, for large population numbers globally.
Abstract: Fewer than 5% of Alzheimer's disease (AD) cases are demonstrably directly inherited, indicating that environmental factors may be important in initiating and/or promoting the disease. Excess iron is toxic to cells; iron overload in the AD brain may aggressively accelerate AD. Magnetite nanoparticles, capable of catalyzing formation of reactive oxygen species, occur in AD plaques and tangles; they are thought to form in situ, from pathological iron dysfunction. A recent study has identified in frontal cortex samples the abundant presence of magnetite nanoparticles consistent with high-temperature formation; identifying therefore their external, not internal source. These magnetite particles range from ∼10 to 150 nm in size, and are often associated with other, non-endogenous metals (including platinum, cadmium, cerium). Some display rounded crystal morphologies and fused surface textures, reflecting cooling and crystallization from an initially heated, iron-bearing source material. Precisely-matching magnetite 'nanospheres' occur abundantly in roadside air pollution, arising from vehicle combustion and, especially, frictional brake-wear. Airborne magnetite pollution particles < ∼200 nm in size can access the brain directly via the olfactory and/or trigeminal nerves, bypassing the blood-brain barrier. Given their toxicity, abundance in roadside air, and nanoscale dimensions, traffic-derived magnetite pollution nanoparticles may constitute a chronic and pernicious neurotoxicant, and hence an environmental risk factor for AD, for large population numbers globally. Olfactory nerve damage displays strong association with AD development. Reported links between AD and occupational magnetic fields (e.g., affecting welders, machinists) may instead reflect inhalation exposure to airborne magnetic nanoparticles.
TL;DR: Findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κB signaling, thus suggesting monocytes-macrophage serve as a circulating pool of Aβ in patients with periodontitis.
Abstract: Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer's disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770, CatB, Aβ1-42, and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB significantly inhibited the P. gingivalis-induced expression of IL-1β, AβPP770, Aβ1-42, and Aβ3-42 in RAW264.7 cells. Aβ3-42, but not Aβ1-42, induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42. Additionally, the expression of AβPP770, CatB, Aβ1-42, and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κB signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression.