Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Abstract

Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β-amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear-cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Figure 1

Clinical trials with the search term “Mitochondria” for neurological conditions classified as “brain diseases,” “dementia,” or “Alzheimer's disease” (AD). (a) Includes all results; (b) includes only the interventional trials

Figure 2

Clinical trials involving metabolism pathways or lifestyle modification interventions for Alzheimer's disease (AD). (a) AD “Metabolism” is the major focus in clinical trials targeting cell energy pathways and does not meaningfully overlap with AD “Mitochondria” trials. (b) Lifestyle interventions that may affect biological energy pathways in AD include diet and exercise; only two AD “mitochondria” trials overlap with AD “diet” trials. (c) Most clinical trials testing antioxidants for AD are registered in a category distinct from interventions involving the mitochondria or other metabolism pathways

Figure 3

Amyloid is the major focus in clinical trials for Alzheimer's disease (AD). (a) Relationship between clinical trials for AD with search terms “amyloid,” “tau,” or “APOE.” (b) Trials investigating mitochondria in AD relative to trials investigating amyloid or tau