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Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches
Julia R Clarke1, Felipe C Ribeiro2,3, Rudimar L Frozza4
1School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract:
Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.
Insights
Alzheimer's disease (AD) treatments are limited, but new research highlights metabolic dysfunction as a key factor. Targeting these metabolic defects offers a promising therapeutic strategy for AD and dementia.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Pharmacology
Background:
- Despite extensive research, effective Alzheimer's disease (AD) treatments remain elusive, with limited options for dementia care.
- Growing evidence links AD to central and peripheral metabolic dysfunction, including impaired insulin sensitivity and inflammation.
- Recent basic and preclinical studies are uncovering the underlying pathophysiological mechanisms of these metabolic defects.
Purpose of the Study:
- To review current basic and clinical findings on the role of metabolic defects in AD pathophysiology.
- To propose a therapeutic framework for AD that targets metabolic dysfunction.
- To explore potential for drug repurposing and novel target identification for AD treatment.
Main Methods:
- Review of recent basic science research.
- Analysis of preclinical study findings.
- Synthesis of clinical and neuropathological data.
Main Results:
- Metabolic defects are increasingly recognized as central to Alzheimer's disease (AD) pathogenesis.
- Aberrant brain stress signaling, inflammation, and impaired insulin sensitivity are key mechanisms.
- Clinical and neuropathological data support the concept of central and peripheral metabolic deregulation in AD patients.
Conclusions:
- Metabolic dysfunction is a core feature of Alzheimer's disease (AD) pathogenesis.
- Future therapeutic strategies should incorporate the targeting of metabolic defects.
- This approach may enhance disease understanding and accelerate the development of novel treatments for AD and dementia.