The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration.

Understanding the molecular underpinnings of neurodegeneration processes is a pressing challenge for medicine and neurobiology. Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent forms of neurodegeneration. To date, a substantial body of experimental evidence has strongly implicated hypoxia in the pathogenesis of numerous neurological disorders, including AD, PD, and other age-related neurodegenerative conditions. Hypoxia-inducible factor (HIF) is a transcription factor that triggers a cell survival program in conditions of oxygen deprivation. The involvement of HIF-1α in neurodegenerative processes presents a complex and sometimes contradictory picture. This review aims to elucidate the current understanding of the interplay between hypoxia and the development of AD and PD, assess the involvement of HIF-1 in their pathogenesis, and summarize promising therapeutic approaches centered on modulating the activity of the HIF-1 complex.

Chronic Traumatic Encephalopathy as the Course of Alzheimer's Disease.

This editorial investigates chronic traumatic encephalopathy (CTE) as a course of Alzheimer's disease (AD). CTE is a debilitating neurodegenerative disease that is the result of repeated mild traumatic brain injury (TBI). Many epidemiological studies show that experiencing a TBI in early or middle life is associated with an increased risk of dementia later in life. Chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD) present a series of similar neuropathological features that were investigated in this work like recombinant tau into filaments or the accumulation and aggregation of Aß protein. However, these two conditions differ from each other in brain-blood barrier damage. The purpose of this review was to evaluate information about CTE and AD from various articles, focusing especially on new therapeutic possibilities for the improvement in cognitive skills.

Dietary factors and Alzheimer's disease risk: a Mendelian randomization study.

BACKGROUND: Prior observational research has investigated the association between dietary patterns and Alzheimer's disease (AD) risk. Nevertheless, due to constraints in past observational studies, establishing a causal link between dietary habits and AD remains challenging. METHODS: Methodology involved the utilization of extensive cohorts sourced from publicly accessible genome-wide association study (GWAS) datasets of European descent for conducting Mendelian randomization (MR) analyses. The principal analytical technique utilized was the inverse-variance weighted (IVW) method. RESULTS: The MR analysis conducted in this study found no statistically significant causal association between 20 dietary habits and the risk of AD (All p > 0.05). These results were consistent across various MR methods employed, including MR-Egger, weighted median, simple mode, and weighted mode approaches. Moreover, there was no evidence of horizontal pleiotropy detected (All p > 0.05). CONCLUSION: In this MR analysis, our finding did not provide evidence to support the causal genetic relationships between dietary habits and AD risk.

Serotonergic dysfunction may mediate the relationship between alcohol consumption and Alzheimer's disease.

The impact of Alzheimer's disease (AD) and its related dementias is rapidly expanding, and its mitigation remains an urgent social and technical challenge. To date there are no effective treatments or interventions for AD, but recent studies suggest that alcohol consumption is correlated with the risk of developing dementia. In this review, we synthesize data from preclinical, clinical, and epidemiological models to evaluate the combined role of alcohol consumption and serotonergic dysfunction in AD, underscoring the need for further research on this topic. We first discuss the limitations inherent to current data-collection methods, and how neuropsychiatric symptoms common among AD, alcohol use disorder, and serotonergic dysfunction may mask their co-occurrence. We additionally describe how excess alcohol consumption may accelerate the development of AD via direct effects on serotonergic function, and we explore the roles of neuroinflammation and proteostasis in mediating the relationship between serotonin, alcohol consumption, and AD. Lastly, we argue for a shift in current research to disentangle the pathogenic effects of alcohol on early-affected brainstem structures in AD.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.

The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.

Preventive effect of propolis on cognitive decline in Alzheimer's disease model mice.

Brazilian green propolis (propolis) is a chemically complex resinous substance that is a potentially viable therapeutic agent for Alzheimer's disease. Herein, propolis induced a transient increase in intracellular Ca2+ concentration ([Ca2+]i) in Neuro-2A cells; moreover, propolis-induced [Ca2+]i elevations were suppressed prior to 24-h pretreatment with amyloid-ß. To reveal the effect of [Ca2+]i elevation on impaired cognition, we performed memory-related behavioral tasks in APP-KI mice relative to WT mice at 4 and 12 months of age. Propolis, at 300-1000 mg/kg/d for 8 wk, significantly ameliorated cognitive deficits in APP-KI mice at 4 months, but not at 12 months of age. Consistent with behavioral observations, injured hippocampal long-term potentiation was markedly ameliorated in APP-KI mice at 4 months of age following repeated propolis administration. In addition, repeated administration of propolis significantly activated intracellular calcium signaling pathway in the CA1 region of APP-KI mice. These results suggest a preventive effect of propolis on cognitive decline through the activation of intracellular calcium signaling pathways in CA1 region of AD mice model.

Periodontitis: A Plausible Modifiable Risk Factor for Neurodegenerative Diseases? A Comprehensive Review.

The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer's disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson's disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged.

APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Unlocking the Potential of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease: A Meta-Analysis of Randomized Clinical Trials to Optimize Intervention Strategies.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an advanced and noninvasive technology that uses pulse stimulation to treat cognitive impairment. However, its specific effects have always been mixed with those of cognitive training, and the optimal parameter for Alzheimer's disease (AD) intervention is still ambiguous. Objective: This study aimed to summarize the therapeutic effects of pure rTMS on AD, excluding the influence of cognitive training, and to develop a preliminary rTMS treatment plan. Methods: Between 1 January 2010 and 28 February 2023, we screened randomized controlled clinical trials from five databases (PubMed, Web of Science, Embase, Cochrane, and ClinicalTrials. gov). We conducted a meta-analysis and systematic review of treatment outcomes and rTMS treatment parameters. Result: A total of 4,606 articles were retrieved. After applying the inclusion and exclusion criteria, 16 articles, comprising 655 participants (308 males and 337 females), were included in the final analysis. The findings revealed that rTMS significantly enhances both global cognitive ability (p = 0.0002, SMD = 0.43, 95% CI = 0.20-0.66) and memory (p = 0.009, SMD = 0.37, 95% CI = 0.09-0.65). Based on follow-up periods of at least 6 weeks, the following stimulation protocols have demonstrated efficacy for AD: stimulation sites (single or multiple targets), frequency (20 Hz), stimulation time (1-2 s), interval (20-30 s), single pulses (≤2500), total pulses (>20000), duration (≥3 weeks), and sessions (≥20). Conclusions: This study suggests that rTMS may be an effective treatment option for patients with AD, and its potential therapeutic capabilities should be further developed in the future.

Mitochondrial disorders leading to Alzheimer's disease-perspectives of diagnosis and treatment.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia globally. The pathogenesis of AD remains still unclear. The three main features of AD are extracellular deposits of amyloid beta (Aß) plaque, accumulation of abnormal formation hyper-phosphorylated tau protein, and neuronal loss. Mitochondrial impairment plays an important role in the pathogenesis of AD. There are problems with decreased activity of multiple complexes, disturbed mitochondrial fusion, and fission or formation of reactive oxygen species (ROS). Moreover, mitochondrial transport is impaired in AD. Mouse models in many research show disruptions in anterograde and retrograde transport. Both mitochondrial transportation and network impairment have a huge impact on synapse loss and, as a result, cognitive impairment. One of the very serious problems in AD is also disruption of insulin signaling which impairs mitochondrial Aß removal.Discovering precise mechanisms leading to AD enables us to find new treatment possibilities. Recent studies indicate the positive influence of metformin or antioxidants such as MitoQ, SS-31, SkQ, MitoApo, MitoTEMPO, and MitoVitE on mitochondrial functioning and hence prevent cognitive decline. Impairments in mitochondrial fission may be treated with mitochondrial division inhibitor-1 or ceramide.

[Oral diseases and dementia]. / Möjliga samband mellan orala sjukdomar och demens.

The aging population makes the increase in cognitive disorders a challenge. One of the risk factors is old age, but also oral diseases, especially periodontitis, have been linked to an increased risk of dementia, especially Alzheimer's disease (AD), although research studies show varying correlations. Dental care utilization also decreases after a dementia diagnosis. The periodontal diseases are inflammatory disorders and common in the adult population. Periodontitis leads to loss of the supporting tissue of the tooth and, if untreated, to loss of teeth. Inflammation also plays a role in AD, the most common form of dementia. The reason for an association could be that periodontitis may lead to a spread of pro-inflammatory mediators and oral microorganisms to the brain. Another explanation suggests that chewing may stimulate nerve impulses and increase the blood flow to the brain. Fewer teeth could lead to less stimulation and reduced blood flow. In conclusion, oral diseases and dementia appear to be associated. Whether this connection constitutes a causal connection is more uncertain.

Machine learning and XAI approaches highlight the strong connection between O 3 and N O 2 pollutants and Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia with millions of affected patients worldwide. Currently, there is still no cure and AD is often diagnosed long time after onset because there is no clear diagnosis. Thus, it is essential to study the physiology and pathogenesis of AD, investigating the risk factors that could be strongly connected to the disease onset. Despite AD, like other complex diseases, is the result of the combination of several factors, there is emerging agreement that environmental pollution should play a pivotal role in the causes of disease. In this work, we implemented an Artificial Intelligence model to predict AD mortality, expressed as Standardized Mortality Ratio, at Italian provincial level over 5 years. We employed a set of publicly available variables concerning pollution, health, society and economy to feed a Random Forest algorithm. Using methods based on eXplainable Artificial Intelligence (XAI) we found that air pollution (mainly O 3 and N O 2 ) contribute the most to AD mortality prediction. These results could help to shed light on the etiology of Alzheimer's disease and to confirm the urgent need to further investigate the relationship between the environment and the disease.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults.

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aß) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aß 1-42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer's Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aß or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Motoric Cognitive Risk Syndrome and the Risk of Incident Dementia: A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: Epidemiologic studies have indicated an association of motoric cognitive risk syndrome (MCR), a pre-dementia stage characterized by the presence of cognitive complaints and a slow gait, with increased risk of incident dementia. OBJECTIVES: We aimed to clarify this association using meta-analysis. METHODS: We systematically searched the PubMed, Embase, and Web of Science databases up to December 2022 for relevant studies that investigated the association between MCR and incident all-cause dementia and Alzheimer's disease (AD). The random-effects model was used to determine a pooled-effect estimate of the association. RESULTS: We identified seven articles that corresponded with nine cohort studies investigating the association between MCR and the risk of dementia. Pooled analysis showed that MCR was associated with a significantly increased risk of incident all-cause dementia (HR = 2.28; 95% CI: 1.90-2.73) and AD (HR = 2.05; 95% CI: 1.61-2.61). Sensitivity analysis showed that there was no evidence that individual studies influenced the pooled-effect estimate, verifying the robustness of the results. CONCLUSIONS: Our results confirm that MCR is an independent risk factor of incident all-cause dementia and AD. Future studies are needed to better understand the mechanisms underlying this association.

Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank.

BACKGROUND: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention. METHODS: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models. FINDINGS: Among 502,408 participants, 9352 had dementia. As expected, AD PRS was associated with greater risk for dementia (odds ratio (OR) 1.62, 95% confidence interval (CI), 1.59-1.65). A total of 94,237 participants had PDPD, of whom 2.6% (n = 2519) developed subsequent dementia, compared to 1.7% (n = 6833) of 407,871 participants without PDPD. Accordingly, PDPD were associated with 73% greater risk of incident dementia (OR 1.73, 1.65-1.83). Among dementia subtypes, the risk increase was 1.5-fold for AD (n = 3365) (OR 1.46, 1.34-1.59) and 2-fold for vascular dementia (VaD, n = 1823) (OR 2.08, 1.87-2.32). Our data indicated that PDPD were neither a dementia prodrome nor a mediator for AD PRS. Shared factors for both PDPD and dementia likely substantially account for the observed association, while a causal role of PDPD in dementia could not be excluded. AUD could be one of the shared causes for PDPD and dementia. INTERPRETATION: Psychiatric diagnoses were associated with subsequent dementia in UKB participants, and the association is orthogonal to established dementia genetic risks. Investigating shared causes for psychiatric disorders and dementia would shed light on this dementia pathway. FUNDING: US NIH (K08AG054727).

Respiratory Dysfunction in Alzheimer's Disease-Consequence or Underlying Cause? Applying Animal Models to the Study of Respiratory Malfunctions.

Alzheimer's disease (AD) is a neurodegenerative brain disease that is the most common cause of dementia among the elderly. In addition to dementia, which is the loss of cognitive function, including thinking, remembering, and reasoning, and behavioral abilities, AD patients also experience respiratory disturbances. The most common respiratory problems observed in AD patients are pneumonia, shortness of breath, respiratory muscle weakness, and obstructive sleep apnea (OSA). The latter is considered an outcome of Alzheimer's disease and is suggested to be a causative factor. While this narrative review addresses the bidirectional relationship between obstructive sleep apnea and Alzheimer's disease and reports on existing studies describing the most common respiratory disorders found in patients with Alzheimer's disease, its main purpose is to review all currently available studies using animal models of Alzheimer's disease to study respiratory impairments. These studies on animal models of AD are few in number but are crucial for establishing mechanisms, causation, implementing potential therapies for respiratory disorders, and ultimately applying these findings to clinical practice. This review summarizes what is already known in the context of research on respiratory disorders in animal models, while pointing out directions for future research.

Agricultural activities and risk of Alzheimer's disease: the TRACTOR project, a nationwide retrospective cohort study.

Data regarding Alzheimer's disease (AD) occurrence in farming populations is lacking. This study aimed to investigate whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with AD than others, using nationwide data from the TRACTOR (Tracking and monitoring occupational risks in agriculture) project. Administrative health insurance data (digital electronic health/medical records and insurance claims) for the entire French agricultural workforce, over the period 2002-2016, on the entire mainland France were used to estimate the risk of AD for 26 agricultural activities with Cox proportional hazards model. For each analysis (one for each activity), the exposed group included all FMs that performed the activity of interest (e.g. crop farming), while the reference group included all FMs who did not carry out the activity of interest (e.g. FMs that never farmed crops between 2002 and 2016). There were 5067 cases among 1,036,069 FMs who worked at least one year between 2002 and 2016. Analyses showed higher risks of AD for crop farming (hazard ratio (HR) = 3.72 [3.47-3.98]), viticulture (HR = 1.29 [1.18-1.42]), and fruit arboriculture (HR = 1.36 [1.15-1.62]). By contrast, lower risks of AD were found for several animal farming types, in particular for poultry and rabbit farming (HR = 0.29 [0.20-0.44]), ovine and caprine farming (HR = 0.50 [0.41-0.61]), mixed dairy and cow farming (HR = 0.46 [0.37-0.57]), dairy farming (HR = 0.67 [0.61-0.73]), and pig farming (HR = 0.30 [0.18-0.52]). This study shed some light on the association between a wide range of agricultural activities and AD in the entire French FMs population.

Association between Helicobacter pylori infection and incident risk of dementia: The AMI cohort.

BACKGROUND: Chronic infectious diseases are increasingly being considered as potential contributors to dementia risk. Among those infections, Helicobacter pylori, the main cause of chronic gastritis worldwide, has been suggested. As the prevalence of H. pylori infection has decreased, the main objective of this work was to reconsider the association between H. pylori infection and the risk of incident dementia, including Alzheimer's disease. METHODS: Prospective cohort of 689 older (≥65 years) agricultural workers from Southwest France. Descriptive and comparative analyses were performed according to H. pylori status determined by serology at baseline. The risk of incident dementia according to H. pylori status over a 7-year follow-up was explored by survival analyses: Kaplan-Meier curve and Cox proportional hazards models. RESULTS: Two-hundred (29.0%) participants were H. pylori-positive at baseline. Compared to H. pylori-negative participants, they showed worse cognitive performances at baseline. Eighty-five incident dementia cases were diagnosed during the follow-up period. After adjustment for age, sex, education, apolipoprotein ε4, and several cardiovascular risk factors, H. pylori remained associated with an increased risk of dementia (HR 1.70, 95% CI, 1.05-2.74). The risk was stronger for Alzheimer's disease (HR 2.85, 95% CI, 1.58-5.12). CONCLUSIONS: Despite an observed decrease in H. pylori infection prevalence, this study provides evidence for the association between H. pylori infection and dementia. These results should encourage further research on the mechanisms underlying the contribution of infectious diseases to pathological brain aging, especially the influence of gut inflammation on the brain.