Speakers

Biography

Jurcau Anamaria: MD, PhD, Senior neurologist at the Clinical Emergency County Hospital Bihor, Associate Professor at the Faculty of Medicine and Pharmacy, University of Oradea, Department of Psycho-Neurosciences and Rehabilitation, Romania. Main areas of interest: ischemic stroke; oxidative stress; neurodegenerative diseases . She published several manuscripts highlighting the involvement of oxidative stress and mitochondrial dysfunction in the development of ischemia/reperfusion injuries as well as in the molecular pathophysiological pathways of neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease. In close connection with these topics, I was also interested in the relationship between cholesterol and cognitive functions in elderly patients.

Abstract

The results of the Scandinavian Simvastatin Survival Study (4S) released in 1994 led to a series of studies which showed beneficial effects of statins (HMGCoA reductase inhibitors) in preventing vascular events. Based on these results, successively issued guidelines pushed for lower and lower levels of LDL-cholesterol as targets for statin treatment. However, post-marketing reports that drew attention to transient cognitive impairment and short-term memory losses caused by statin treatment prompted the Food and Drug Administration (FDA) to issue a warning regarding the potential for reversible cognitive impairment in statin users in 2012.

The cholesterol content of the nervous system is very high, cholesterol being the basic constituent of membranes and myelin sheaths, and influencing the properties of membranes as well as the activity of receptors and ion channels. Its synthesis via the mevalonate pathway is crucial in the early stages of development, but the transcripts of the enzymes necessary for cholesterol synthesis remain in neurons throughout life and serve to obtain dolichols, ubiquinones and isoprenoids that modify proteins and small GTPases which are critical for axon growth and guidance, growth cone motility, dendritic arborization, as well as synapse formation. Although the brain is largely separated from the periphery through the blood brain barrier, most of the currently marketed statins are lipophilic and can gain access to the CNS, where they can inhibit HMGCoA reductase in the mevalonate pathway, thereby interfering with the myelination process and with synaptogenesis, with the formation of neuronal circuits, as well as with neuronal excitability via disturbing the function of ion channels. In addition, coenzyme Q10 is depleted, leading to mitochondrial dysfunction, which has been convincingly implicated in the pathogenesis of dementia.

As neurologists, we use statins mainly in primary or secondary prevention of ischemic strokes. Nonetheless, there are many subtypes of ischemic stroke. While in thrombotic stroke LDL-cholesterol and atherosclerotic plaques have a significant contribution, in other subtypes, such as embolic stroke, the role of cholesterol is less well established. Moreover, cardioembolisms tend to occur in older patients, often frail and in a poor nutritional status, with lower LDL-cholesterol levels compared to patients with thrombotic events. We would obviously wish to prevent strokes in our patients, but we would also avoid trading the brain for the heart.

In 2013, the American College of Cardiology/American Heart Association reviewed the safety issues raised by statin therapy and concluded that the evidence on statin-induced cognitive impairment is inconsistent. However, their conclusions were based mainly on the JUPITER, PROSPER and HPS trials, which did not perform detailed neuropsychological assessments because cognitive dysfunction was neither primary nor secondary outcome measure. Several studies addressed the issue of the effects of long-term use of statins on cognition and yielded conflicting results. A meta-analysis of observational studies (Poly et al, 2020) concluded that hydrophilic statins were associated with a lower risk of all-cause dementia, while lipophilic ones lowered the risk of AD but not of vascular dementia.

Until future studies will provide a definite answer to the question of the effect of long-term statin use on cognition, we suggest to thoroughly balance the benefits versus possible risks in elderly patients before prescribing statin therapy, to favour hydrophilic over lipophilic ones, and to use ezetimibe or PCSK9 inhibitors to meet the target LDL-cholesterol levels.