Statins and Alzheimer's: The Controversy on its Protective Role

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting millions of people worldwide. It is an irreversible, untreatable disease characterized by cognitive and behavioral dysfunctions such as memory, language and judgement. The accumulation of amyloid beta plaques (AB) and tau tangles define AD and promote pathological events, such as inflammation, hypoxia, oxidative stress and receptor alteration that leads to neuron damage and brain dysfunction.

Statins, one of the most prescribed drugs in the world, are HMG-CoA reductase inhibitors used as lipid lowering medications for hypercholesteremia and cardiovascular diseases. They block the rate limiting step of the mevalonate pathway inhibiting cholesterol, ubiquinone, geranylgeranyl and farnesyl which may influence essential cellular mechanisms such as mitochondrial respiration and protein prenylation. In addition to statins’ pleiotropic effects involving inflammation and oxidative mechanisms influencing thus the different body organs including the brain.

While many have reported on the beneficial role of statins in the prevention of AD, others accounted the opposite. In this review, we screened the literature on the potential contributing mechanisms of statins in AD and those alluding to its role. Studies included clinical reports as well as both in-vivo and in-vitro investigations.

Our search alluded to mechanisms that may underlie the controversial effects of statins on cholesterol level in brain cells hence potential contribution to AD. It is worth noting that statins in addition to cholesterol they decrease the level of many cellular metabolites of important signaling and bioenergetics roles. Literature provides evidence that statin while lowering cholesterol level, it influences the AB production in dose dependent manner, but disturbs the cholesterol homeostasis in the myelin sheath, altering myelination –remyelination. Moreover, the decrease in protein farnesylation and geranylgeranylation inhibit key proteins: Ras and Rho that reduce tau aggregation, inflammation and oxidative stress while affecting the function of brain receptors, glial cells, energy production and AD drug effect.

Still, no confirmatory studies emphasize the definite effect of statins on Alzheimer’s disease as many variables will stand upon having one general outcome. The genetic and environmental variations are impossible to monitor for, while most studies are done in-vitro and on animals that differ in their genetic composition from that of human. Hence, more studies should investigate the possible factors that determine the impact of statin on the brain, and whether this can actually be applied at the clinical level.