From particulates to pathways: environmental exposures and their impact on Alzheimer's disease.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

Circadian fragmentation: a harbinger of Alzheimer's disease?

Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder influenced by genetic and environmental factors. Conditions such as type 2 diabetes (T2D), cardiovascular disease, obesity, depression, and obstructive sleep apnea (OSA) increase AD risk and progression. This study aimed to examine the genetic predisposition to these conditions and their effect on AD pathophysiology, risk, and progression. A retrospective analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a North American prospective cohort. Polygenic risk scores (PRSs) for OSA, T2D, coronary artery disease (CAD), major depression, and body mass index (BMI) were generated for 752 non-Hispanic White participants with whole-genome sequencing data. Logistic regression was used to evaluate associations between PRSs and progression from mild cognitive impairment (MCI) to AD. Time to progression across PRS quartiles was analyzed using Cox proportional hazards models. PET amyloid and tau deposition rates, regional neocortical atrophy, and cognitive composite score declines were compared across OSA PRS quartiles using analysis of variance (ANOVA). Among 463 ADNI participants with baseline MCI (mean age 72.6 ± 7.3 years, 43.4% female), the OSA PRS, adjusted for BMI, was significantly associated with MCI-to-AD progression. The highest OSA PRS quartile had an odds ratio of 1.86 (95% CI 1.03-3.37) at 3 years and 2.02 (95% CI 1.16-3.51) at 5 years, compared with the lowest quartile. PRSs for T2D, CAD, major depression, and BMI were not associated with MCI-to-AD progression. Participants in the highest OSA PRS quartile had higher PET amyloid deposition and greater cognitive decline. In 752 participants (mean age 74.1 ± 7.3 years, 43.6% female), OSA PRS was significantly associated with baseline levels of PET amyloid, CSF amyloid-β 42, phosphorylated tau (p-tau), visinin-like protein 1, tumor necrosis factor receptor 1, and plasma neurofilament light after multiple testing adjustments. Individuals with high polygenic susceptibility to OSA exhibited an increased risk of MCI-to-AD progression and a higher amyloid deposition rate, suggesting potential modifier effects of OSA or OSA-associated genes on AD progression and pathophysiology. However, the small sample size and lack of objective OSA diagnosis limit interpretation of these genetic effects.

Smoking cessation and Alzheimer’s disease: facts, fallacies and promise

Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease

Plasma ceramide mediates the association of peripheral T cells with Alzheimer's disease.

Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer's disease spectrum.

The hippocampus is a vulnerable and plastic brain structure that is damaged by a variety of stimuli, e.g. hypoxia, hypoperfusion, hypoglycaemia, stress and seizures. Alzheimer's disease is a common and important disorder in which hippocampal atrophy is reported. Indeed, the available evidence suggests that hippocampal atrophy is the starting point of the pathogenesis of Alzheimer's disease and a significant number of patients with hippocampal atrophy will develop Alzheimer's disease. Studies indicate that hippocampal atrophy has functional consequences, e.g. cognitive impairment. Deposition of tau protein, formation of neurofibrillary tangles and accumulation of β-amyloid (Aβ) contributes to hippocampal atrophy together with damage caused by several other factors. Some of the factors associated with the development of hippocampal atrophy in Alzheimer's disease have been identified, e.g. hypertension, diabetes mellitus, hyperlipidaemia, seizures, affective disturbances and stress, and more is being learnt about other factors. Hypertension can potentially damage the hippocampus through ischaemia caused by atherosclerosis and cerebral amyloid angiopathy. Diabetes can produce hippocampal lesions via both vascular and non-vascular pathologies and can reduce the threshold for hippocampal damage. Carriers of the apolipoprotein E (ApoE)-ε4 genotype have been shown to have greater mesial temporal atrophy and poorer memory functions than non-carriers. In addition to giving rise to abnormal lipid metabolism, the ApoE-ε4 allele can affect the course of Alzheimer's disease via both Aβ-dependent and -independent pathways. Repetitive seizures can increase Aβ-peptide production and cause neurotransmission dysfunction and cytoskeletal abnormalities or a combination of these. Affective disturbances and stress are proposed to increase corticosteroid-induced hippocampal damage in many different ways. In the absence of any specific markers for predicting Alzheimer's disease progression, it seems appropriate to learn more about the various predictors of hippocampal atrophy that determine the progression of Alzheimer's disease from mild cognitive impairment (MCI), and then attempt to address these. It would be interesting to know to what extent these predictors play a role in the development of MCI or hasten the conversion of MCI to full-blown Alzheimer's disease. Finally, it would be useful to know the extent to which these predictors can worsen or aggravate existing Alzheimer's disease. Of the clinically used drugs in Alzheimer's disease, anticholinesterases have been shown to slow down the rate of progression of hippocampal atrophy. One study observed that the neuroprotective effect of these agents is possibly due to an anti-Aβ effect produced by cholinergic stimulation. Similarly, antihypertensive and antihyperglycaemic drugs (pioglitazone and insulin) have been shown to reduce the risk of Alzheimer's disease or disease progression. Currently, there are no disease-modifying therapies available for Alzheimer's disease. It has been suggested that for treatment to be most effective, the regimen must be started before significant downstream damage has occurred (i.e. before the clinical diagnosis of Alzheimer's disease, at the stage of MCI or earlier). Since the hippocampus is a plastic structure and atrophy of this structure is closely related to the pathophysiology of Alzheimer's disease, if we could control blood pressure, regulate blood sugar, treat behavioural and psychological symptoms, achieve satisfactory lipid lowering and maintain a seizure-free state in patients with Alzheimer's disease, this may not only improve disease control but could also potentially affect the rate of disease progression.

Using human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which Apolipoprotein E (APOE) contributes to Alzheimer’s disease (AD) risk

Alzheimer's disease (AD) is a complex, progressive, neurodegenerative disorder. As with other common chronic diseases, multiple risk factors contribute to the onset and progression of AD. Many researchers have evaluated the epidemiologic and pathophysiological association between AD, cardiovascular diseases (CVDs), and cerebrovascular diseases (CBVDs), including commonly reported risk factors such as diabetes, hypertension, and dyslipidemia. Relevant therapies of CVDs/CBVDs for the attenuation of AD have also been empirically investigated. Considering the challenges of new drug development, in terms of cost and time, multifactorial approaches such as therapeutic repositioning of CVD/CBVD medication should be explored to delay the onset and progression of AD. Thus, in this review, we discuss our current understanding of the association between cardiovascular risk factors and AD, as revealed by clinical and non-clinical studies, as well as the therapeutic implications of CVD/CBVD medication that may attenuate AD. Furthermore, we discuss future directions by evaluating ongoing trials in the field.

Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease.

This review investigates the relationship between lifestyle factors, including diet, physical activity, and cognitive engagement, and their implications for the risk of developing Alzheimer's disease. The purpose of this research is to establish a robust foundation for potential interventions and strategies for this neurodegenerative disease. To achieve a comprehensive understanding, this research will adopt a holistic approach, beginning with an extensive systematic review of existing literature to discern trends and potential therapeutic avenues in the field. Evidence highlights the protective effects of nutrient-rich dietary patterns against cognitive decline and Alzheimer's disease. These diets, rich in antioxidants, vitamins, and omega-3 fatty acids, mitigate oxidative stress and inflammation, enhance synaptic plasticity, and reduce amyloid-beta accumulation. Physical activity is a crucial preventive measure. Long-term studies show that regular exercise improves cerebral blood flow, promotes neuroplasticity, and enhances neurogenesis, particularly in the hippocampus. These benefits contribute to maintaining cognitive functions and delaying Alzheimer's disease onset. Adequate sleep is essential for memory consolidation, learning, and emotional regulation. Poor sleep quality, associated with amyloid-beta plaque and Tau protein accumulation, increases Alzheimer's disease risk. Sleep interventions that improve sleep quality can support cognitive health and potentially mitigate Alzheimer's disease progression. Chronic stress significantly impairs cognitive function through elevated cortisol levels, leading to hippocampal damage and increased amyloid-beta and Tau tangle accumulation. Stress management techniques like mindfulness and meditation can counteract these effects by lowering cortisol levels and promoting neuroplasticity. Limiting exposure to harmful substances, including illicit drugs, excessive alcohol, and smoking, is vital for cognitive health. Substance abuse introduces toxins that cause oxidative stress, inflammation, and vascular damage, accelerating cognitive decline. Avoiding these substances supports overall brain health and reduces Alzheimer's disease risk. This review advocates for a holistic approach to identifying lifestyle factors contributing to AD. Evidence-based interventions suggest that maintaining a balanced nutrition, regular physical activity, quality sleep, stress management, and avoidance of harmful substances can significantly reduce the risk of Alzheimer's disease. Public health initiatives should promote these lifestyle factors to enhance cognitive resilience and mitigate the burden of Alzheimer's disease.

Alzheimer's Disease (AD) is a complex neurological condition caused by various factors. Diet, oxidative stress, and the gut microbiota all play critical roles in the development of AD. Recent studies suggested a bidirectional relationship between the gut and the brain, emphasizing the pivotal role of the gut microbiome in influencing cognitive functions. For instance, dysbiosis, a disruption in the balance of gut microbial communities, has been linked to neuroinflammation and the accumulation of amyloid-beta plaques, hallmark features of AD. Oxidative stress, arising from an imbalance between free radicals and antioxidants, contributes significantly to AD pathology. The molecular mechanisms through which oxidative stress impacts neuronal health and exacerbates the cognitive decline in AD patients are also relevant. Moreover, nutritional interventions emerge as promising strategies to modulate these inflecting factors. Dietary components, such as antioxidants, omega-3 fatty acids, and polyphenols, exhibit neuroprotective effects, potentially mitigating AD progression. In contrast, the Western diet has a high potential to abet AD onset. Mediterranean diet and/or intermittent fasting are more valuable diets that may help delay the AD onset or progression. Limitations like individual differences affect the efficacy of nutritional interventions. As a supporting therapy, personalized diets should be applied according to the patients' special needs/microbiomes in the future. To gather current knowledge on the interconnected roles of the gut microbiome, oxidative stress, and nutritional interventions in AD is crucial. Understanding these interactions may pave the way for novel therapeutic approaches, as well as disputing the potential diets that can help improve AD patients' quality of life.

The close relationship between trace elements (Cu, Fe, Zn, Se, Rb, Si, Cr, and V) and Alzheimer's disease: Research progress and insights.