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Background: Blood metabolites have emerged as promising candidates in the search for biomarkers for Alzheimer's disease (AD), as evidence shows that various metabolic derangements contribute to neurodegeneration in AD. Objective: We aim to identify metabolic biomarkers for AD diagnosis. Methods: We conducted an in-depth analysis of the serum metabolome of AD patients and age, sex-matched cognitively unimpaired older adults using ultra-high-performance liquid chromatography-high resolution mass spectrometry. The biomarkers associated with AD were identified using machine learning algorithms. Results: Using the discovery dataset and support vector machine (SVM) algorithm, we identified a panel of 14 metabolites predicting AD with a 1.00 area under the curve (AUC) of receiver operating characteristic (ROC). The SVM model was tested against the verification dataset using an independent cohort and retained high predictive accuracy with a 0.97 AUC. Using the random forest (RF) algorithm, we identified a panel of 13 metabolites that predicted AD with a 0.96 AUC when tested against the verification dataset. Conclusions: These findings pave the way for an efficient, blood-based diagnostic test for AD, holding promise for clinical screenings and diagnostic procedures. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease's neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability—epitomized by the dictum "no on-site protection, no protection"—and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success. [ABSTRACT FROM AUTHOR]

This article examines the relationship between cholesterol levels and Alzheimer's disease (AD), beginning with the early observation that individuals who died from heart attacks often had brain amyloid deposition. Subsequent animal model research proved that high cholesterol could hasten amyloid accumulation. In contrast, cholesterol-lowering treatments appeared to counteract this effect. Human autopsy studies reinforced the cholesterol-AD connection, revealing that higher cholesterol levels during midlife significantly correlated with higher brain amyloid pathology. This effect was especially pronounced in individuals aged 40 to 55. Epidemiological data supported animal research and human tissue observations and suggested that managing cholesterol levels in midlife could reduce the risk of developing AD. We analyze the main observational studies and clinical trials on the efficacy of statins. While observational data often suggest a potential protective effect against AD, clinical trials have not consistently shown benefit. The failure of these trials to demonstrate a clear advantage is partially attributed to multiple factors, including the timing of statin therapy, the type of statin and the appropriate selection of patients for treatment. Many studies failed to target individuals who might benefit most from early intervention, such as high-risk patients like APOE4 carriers. The review addresses how cholesterol is implicated in AD through various biological pathways, the potential preventive role of cholesterol management as suggested by observational studies, and the difficulties encountered in clinical trials, particularly related to statin use. The paper highlights the need to explore alternate therapeutic targets and mechanisms that escape statin intervention. [ABSTRACT FROM AUTHOR]

Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) has traditionally been recognized as progressive dementia with brain deposits of amyloid (Aβ) and Tau (MAPT) proteins starting 20 and 10 years before the onset of clinical symptoms. Aggregation and deposition of Aβ and Tau proteins have been successfully studied in vitro, cell cultures, and animal models, but clinical deficits have been more difficult to assess. Behavior in mice is a complex phenomenon and subject to variation based on mouse interest, moods, stress‐induced distraction, and other undefined parameters. We have attempted to optimize the novel and displaced object assays to improve behavior studies to evaluate animal models of neurodegeneration. Method: 5xFAD, hTau, and related mice were habituated in the field for 15 minutes twice on day‐1, followed by familiarization with two identical objects twice for 15 minutes on day‐2. The final testing on day‐3 started with novel followed by displaced object analysis. We compared three opaque arenas –rectangular (34 × 24 cm), large square (40 cm), and small square (25 cm) and objects of several heights and types. We also assessed handling mice by cupping to make them more interactive and relaxed for the study. Result: Mice tend to jump over the arena walls and escape when handled by their tail but are contained when handled by cupping through a cylinder. All the systems were equally able to discriminate between novel and familiar objects. However, we could only distinguish between the familiar and displaced objects in the smaller 25 cm square arena. Also, object interaction time was longer in the smaller field. Conclusion: It is critical to handle mice by cupping to ensure reduced stress and optimum object interaction. A smaller arena may promote object interaction; taller objects reduce detection artifacts. NIH grants supported the study. [ABSTRACT FROM AUTHOR]

Research has been conducted on the apoE4, a risk factor for the late-onset sporadic Alzheimer's disease development. The addition of the melatonin to the A(beta) protein in the apoE presence resulting in a potent isoform-specific fibril formation exhibition is reported and the results indicate that this effect is structure-dependent and is not related to the melatonin's antioxidant properties.