The therapeutic potential of the ketogenic diet in selected neurodegenerative diseases and psychiatric disorders

How do energy metabolism disorders and neuroinflammation collectively contribute to the pathogenesis of Alzheimer's disease?

Alzheimer's disease (AD), as the leading cause of dementia, poses an increasingly severe socioeconomic burden in the context of global ageing. Traditionally defined by amyloid-β and tau pathology, it's increasingly recognized as a systems disorder in which impaired glucose metabolism, mitochondrial dysfunction, and neuroinflammation interact across neural cell types and disease stages. However, the interaction among these three mechanisms, their role in promoting the classical pathology of AD, and their verification in major neural cell types remains unclear. This review summarizes the alterations in glucose metabolism and mitochondrial metabolism in neurons, astrocytes and microglia in AD and their relationship with neuroinflammation, while also discussing some unaddressed questions, outlining therapeutic strategies, and future promising directions. Biomarkers that reflect disease stage and pathological status, multitarget therapeutic strategies, individualized precision medicine, and the integration of pharmacological with non-pharmacological interventions represent particularly promising directions for the future.

Emerging Advances in Neuropharmacology: Novel Therapeutic Targets for Neurodegenerative Disorders

Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders, which are characterized by selective neuronal destruction, synaptic malfunction and progressive cognitive and locomotor dysfunction. The major ones are Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis which are a formidable and growing global health and socio-economic burden mainly due to demographic aging. Even despite the advances in the symptomatic treatment, predominantly through the cholinergic, dopaminergic, glutamatergic, and GABAergic system, the current treatment regimens are not able to stop the underlying neurodegenerative events or reverse them. There is mounting evidence that convergent pathogenic mechanisms, such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, synaptic dysfunction, and chronic neuroinflammation, are convergent mechanisms. These convergent molecular and cellular cascades provide a strong rationale behind the identification of new neuropharmacological targets, which include: kinases, phosphatases, epigenetic regulators, neurotrophic signalling pathways and neuroimmune mediators. Advances in the biomarker discovery, genomics and systems biology have further enabled the use of precision based therapeutic stratification and early-intervention approaches. Genetic, nanotechnology, and RNA-based therapeutics as well as biologics are reconfiguring translational models in neurodegeneration. A mechanism-based, multi-target, precision neuropharmacological approach, as a group, has significant potential in achieving long-term neuroprotection, improved clinical and disease modification in neurodegenerative diseases.

Connecting mechanistic roles of vitamins in dementia: An overview on translational insights from preclinical models to clinical promise.

Dementia, a progressive neurodegenerative disorder, is a primary cause of disability and dependence in the elderly. It has become prevalent worldwide, affecting more than 55 million people. This increasing epidemiological and mechanistic evidence indicates that neuroinflammation, mitochondrial dysfunction, oxidative stress, and neurotransmitter levels are solely related to the disease pathophysiology. Essential micronutrients, such as lipid and water-soluble vitamins, have been identified as potential neuroprotective substances due to their multiple important biochemical roles in maintaining the integrity and functioning of neurons. These oil and water-soluble vitamins (Vitamin A-K) support several important activities of the central nervous system, including the synthesis of neurotransmitters, antioxidant activity, neuroprotective role, and regulation of inflammation, lipid metabolism, and gene expression, all of which are essential in maintaining brain function and neural plasticity. Therefore, the purpose of this review is to critically evaluate the molecular mechanisms by which these vitamins provide neuroprotection as evident in the literature, in both preclinical models and clinical studies. Additionally, this review examines whether these potential vitamins have an adjunctive role in delaying or preventing neurodegenerative disease. Conclusively, optimizing vitamin levels in the body may present a promising, multifaceted role for the management of dementia and related CNS disorders.

The potential of vitamins in Huntington’s disease: bridging mechanistic evidence with translational limitations and future strategies

Ketogenic Diet and Alzheimer's Disease: A Narrative Review of the Connection Between Nutrition and Neuroprotection

The search for therapies capable of reversing or attenuating the pathological damage associated with Alzheimer's Disease (AD) has intensified alongside global population aging. In this context, nutritional management through the Ketogenic Diet (KD) has gained increasing attention due to its potential effects on key pathological pathways and signaling mechanisms involved in AD. This review aimed to gather and synthesize recent evidence regarding the management of AD through the KD. A literature search was conducted in the PubMed and SciELO databases using the keywords "ketogenic diet," "medium-chain triglycerides," "Alzheimer's disease," and "beta-amyloid" in both English and Portuguese. Original studies and systematic reviews published within the last 10 years were included. Eighteen articles were selected, comprising seven systematic reviews or meta-analyses, six preclinical studies, and five clinical trials. The main findings indicate that the KD influences pathways involved in AD pathogenesis and improves cognition, functional performance, and quality of life in APOE-negative patients with mild to moderate AD. The KD appears to be a promising adjunct to conventional pharmacological treatment. Based on the available evidence, the KD represents a potential therapeutic strategy, highlighting the need for more robust clinical trials to further elucidate its long-term applicability and safety.

Neuroinflammatory and molecular pathways in Alzheimer's disease: mechanistic crosstalk and emerging therapeutic opportunities.

Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.