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Review
. 2023 Sep 29;7(11):102011.
doi: 10.1016/j.cdnut.2023.102011. eCollection 2023 Nov.

Creatine as a Therapeutic Target in Alzheimer's Disease

Aaron N Smith  1 , Jill K Morris  2   3 , Aaron F Carbuhn  1 , Trent J Herda  4 , Jessica E Keller  1 , Debra K Sullivan  1   2 , Matthew K Taylor  1   2
Affiliations
Review

Creatine as a Therapeutic Target in Alzheimer's Disease

Aaron N Smith et al. Curr Dev Nutr. .

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting approximately 6.5 million older adults in the United States. Development of AD treatment has primarily centered on developing pharmaceuticals that target amyloid-β (Aβ) plaques in the brain, a hallmark pathological biomarker that precedes symptomatic AD. Though recent clinical trials of novel drugs that target Aβ have demonstrated promising preliminary data, these pharmaceuticals have a poor history of developing into AD treatments, leading to hypotheses that other therapeutic targets may be more suitable for AD prevention and treatment. Impaired brain energy metabolism is another pathological hallmark that precedes the onset of AD that may provide a target for intervention. The brain creatine (Cr) system plays a crucial role in maintaining bioenergetic flux and is disrupted in AD. Recent studies using AD mouse models have shown that supplementing with Cr improves brain bioenergetics, as well as AD biomarkers and cognition. Despite these promising findings, no human trials have investigated the potential benefits of Cr supplementation in AD. This narrative review discusses the link between Cr and AD and the potential for Cr supplementation as a treatment for AD.

Keywords: Alzheimer’s disease; bioenergetics; brain; creatine; mitochondria.

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Figures

FIGURE 1
FIGURE 1
Creatine physiology in the brain and the proposed benefit of CrM in AD. Cr in peripheral circulation is transported through the BBB via a Cr transporter, which may increase due to CrM supplementation. This Cr transporter is also expressed by neurons to allow Cr transport into the cell. Neurons also endogenously produce creatine from the amino acids Arg and Gly via a two-step process. The first step is the formation of GAA by GATM, which then forms Cr by GAMT activity. Cr helps maintain energy flux as a chaperone for energy-producing phosphate groups. ATP generated by the ETC and the TCA cycle donate phosphate to Cr via mtCK to form PCr. PCr is an important storage form of high energy phosphate that can meet energy demand throughout the cell. In the AD brain, ATP levels are decreased. Increased Cr levels in the brain may signal mitochondria to upregulate aerobic respiration by replenishing free Cr chaperones for the Cr Phosphate shuttle. Increased Cr levels in the brain may have several benefits: free Cr may have antioxidant properties and may be able to sequester ROS, decrease neuroinflammation, increase mTORC1 signaling, and decrease AD neuropathologies. This figure was created with BioRender (www.biorender.com). Cr: creatine; CrM: creatine monohydrate; BBB: blood-brain barrier; CRT1: creatine transporter 1; Arg: arginine; Gly: glycine; GATM: glycine amidinotransferase, mitochondrial; GAA: guanidinoacetate; GAMT: guanidinoacetate N-methyltransferase; MtCK: mitochondrial Cr kinase; PCr: phosphorylated creatine; BB-CK: brain-specific Cr kinase; ATP: adenosine triphosphate; ADP: adenosine triphosphate; ETC: electron transport chain; TCA: tricarboxylic acid cycle; ROS: reactive oxygen species; mTORC1: mammalian target of rapamycin complex 1. BioRender.com
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