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.

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.

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.

[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.

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.

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.

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.

Update on modifiable risk factors for Alzheimer's disease and related dementias.

PURPOSE OF REVIEW: All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual's genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer's disease and related dementia (ADRD) cases. RECENT FINDINGS: Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss. SUMMARY: While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.

[Traumatic brain injury as risk factor of Alzheimer's disease and possibilities of pathogenetic therapy]. / Cherepno-mozgovaya travma kak faktor riska bolezni Al'tsgeimera i vozmozhnosti patogeneticheskoi terapii.

The article examines the potential role of brain mechanical damage as a trigger for the development of neurodegenerative changes. Attention is paid to dysfunction of the neurovascular unit, and disruption of the functional and compensatory capabilities of blood flow. The importance of microhemorrhages that occur in the acute period of injury and the formation of first focal and then diffuse neuroinflammation is emphasized. The importance of mitochondrial dysfunction was separately determined as a significant factor in increasing the risk of developing Alzheimer's disease (AD) in patients after traumatic brain injury (TBI). In TBI, there is a decrease in the expression of tight junction (TC) proteins of endothelial cells, such as occludin, claudin, JP, which leads to increased permeability of the blood-brain barrier. TBI, provoking endothelial dysfunction, contributes to the development of metabolic disorders of ß-amyloid and tau protein, which in turn leads to worsening vascular damage, resulting in a vicious circle that can ultimately lead to the development of AD and dementia. Age-related changes in cerebral arteries, which impair perivascular transport of interstitial fluid, are currently considered as an important part of the «amyloid cascade¼, especially against the background of genetically mediated disorders of glial membranes associated with defective aquaporin-4 (encoded by the APOE4). Studies in animal models of TBI have revealed an increase in tau protein immunoreactivity and its phosphorylation, which correlates with the severity of injury. A comprehensive analysis of research results shows that the cascade of reactions triggered by TBI includes all the main elements of the pathogenesis of AD: disorders of energy metabolism, microcirculation and clearance of cerebral metabolic products. This leads to a disruption in the metabolism of amyloid protein and its accumulation in brain tissue with the subsequent development of tauopathy. Cerebrolysin, by modulating the permeability of the blood-brain barrier, blocks the development of neuroinflammation, reduces the accumulation of pathological forms of proteins and may be slow down the progression of neurodegeneration.

The Importance of Complement-Mediated Immune Signaling in Alzheimer's Disease Pathogenesis.

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Current understanding of the Alzheimer's disease-associated microbiome and therapeutic strategies.

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aß antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.

The multifaceted functions of ß-arrestins and their therapeutic potential in neurodegenerative diseases.

Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, ß-arrestin1, ß-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of ß-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that ß-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). ß-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, ß-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, ß-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the ß2AR regulates SNCA gene expression. In this review, we aim to provide an overview of ß-arrestin1 and ß-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of ß-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.

Tau Protein Alterations Induced by Hypobaric Hypoxia Exposure.

Tauopathies are a group of neurodegenerative diseases whose central feature is dysfunction of the microtubule-associated protein tau (MAPT). Although the exact etiology of tauopathies is still unknown, it has been hypothesized that their onset may occur up to twenty years before the clear emergence of symptoms, which has led to questions about whether the prognosis of these diseases can be improved by, for instance, targeting the factors that influence tauopathy development. One such factor is hypoxia, which is strongly linked to Alzheimer's disease because of its association with obstructive sleep apnea and has been reported to affect molecular pathways related to the dysfunction and aggregation of tau proteins and other biomarkers of neurological damage. In particular, hypobaric hypoxia exposure increases the activation of several kinases related to the hyperphosphorylation of tau in neuronal cells, such as ERK, GSK3ß, and CDK5. In addition, hypoxia also increases the levels of inflammatory molecules (IL-ß1, IL-6, and TNF-α), which are also associated with neurodegeneration. This review discusses the many remaining questions regarding the influence of hypoxia on tauopathies and the contribution of high-altitude exposure to the development of these diseases.

Recent advances in understanding of sleep disorders and disturbances for dementia risk and prevention.

PURPOSE OF REVIEW: To synthesise the recent work examining the relationship between sleep disturbances and dementia, emphasising studies involving individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) and/or those investigating AD biomarkers. Additionally, we provide an update on recent interventions targeting sleep-related issues in older adults with MCI or AD. RECENT FINDINGS: Various studies have examined obstructive sleep apnoea, sleep duration, and circadian alterations in relation to Alzheimer's pathology and dementia risk, with an emerging body of evidence suggesting that cardiovascular disease, hypertension, glymphatic function, and inflammation might serve as plausible pathophysiological mechanisms contributing to dementia during critical brain periods. Conversely, recent studies investigating insomnia have produced disparate results. Regarding intervention studies, the scarcity of prospective randomised control trials poses a challenge in establishing the benefits of addressing sleep disorders and disturbances. SUMMARY: Recent work examining the pathophysiological links between sleep and dementia is strongest for obstructive sleep apnoea and sleep duration, while findings in insomnia studies exhibit inconsistency, possibly due to varied associations with dementia among different insomnia subtypes. It is apparent that more longitudinal studies examining the underlying pathophysiological mechanisms are necessary, alongside more rigorous clinical trials. Although some trials are underway in this field, there is still scarcity in trials examining interventions for circadian disturbances.

Feelings of tense and risk of incident dementia: A prospective study of 482,360 individuals.

BACKGROUND: The relationship between feelings of tense, as a significant emotional distress, and dementia remains unclear. This study aimed to evaluate the association between feelings of tense and dementia. METHODS: In UK Biobank, feelings of tense were measured with a standard item. The primary outcome was all cause of dementia (ACD) and its subtypes (Alzheimer's disease (AD), vascular dementia (VD), and other dementia). Cox regression models analyzed the association between feelings of tense and dementia risk, while linear regression examined the correlation with neuroimaging outcomes. The potential association and joint effects of AD and tenseness were evaluated based on the established genetic risk score (GRS). RESULTS: During a median follow-up of 12.7 years among 482,360 participants, 7331 dementia cases were identified. Individuals with feelings of tense had a significantly increased risk of ACD (HR, 1.194; 95 % CI: 1.115-1.278), VD (HR, 1.164; 95 % CI: 1.007-1.346), and other dementia (HR, 1.181; 95 % CI: 1.081-1.289), but not AD in multi-adjusted models. This association persisted across various sensitivity analyses and exhibited some heterogeneity in subgroup analyses. Furthermore, feelings of tense are associated with total brain volume shrinkage, higher white matter hyperintensities, and decreased partial subcortical volume, particularly in the hippocampus. No interaction between tenseness and AD genetic susceptibility was observed (P for interaction =0.346). LIMITATIONS: Our study only considered feelings of tense measured at a one-time point. CONCLUSIONS: Our findings demonstrate a significant association between feeling of tense and elevated dementia risk, indicating that tenseness could serve as a modifiable psychological determinant for dementia.

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.