What are Statins?

Cardiovascular disease affects the heart and major blood vessels, mostly by causing the progressive atherosclerosis (hardening and narrowing) of arteries that supply various organs including the brain and the heart itself. Cardiovascular disease is amongst the biggest killers in the UK with death being caused by coronary heart disease, myocardial infarction (heart attack) and stroke. Patients with atherosclerosis may also develop cognitive impairment leading to vascular dementia.

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One of the biggest risk factors for developing cardiovascular disease is high levels of ‘bad’ cholesterol (LDL) in the blood. Statins are cholesterol-reducing drugs prescribed to people suffering from cardiovascular disease, or if they are likely to develop cardiovascular disease based on their lifestyle and family history.

The deposition of beta-amyloid, a major Alzheimer’s disease protein, is known to be affected by cholesterol levels in the blood. Therefore, one could hypothesize that reducing serum cholesterol levels may have a beneficial and protective effect against beta-amyloid deposition and aggregation into plaques.

Can Statins Protect Against Alzheimer’s?

The evidence for a protective role for statins in Alzheimer’s disease has been mixed, and no definitive conclusions can be drawn.

Some studies have even shown a negative correlation between statin usage and disease progression. There are many issues with generalizing data from these studies on the correlation between statin usage and a reduction in dementia risk and severity.

Most studies have focused on observational epidemiological data, rather than randomised controlled trials.

Information such as duration of usage, dosage, lifestyle and ethnicity  is often not considered. Some studies also fail to include the usage of other medication which may influence disease course.

Nonetheless, several recent studies have taken into consideration the above limitations and still show a positive correlation between statin usage and reduced Alzheimer’s risk, especially the earlier mild cognitive impairment stages, but not so much for vascular dementia.

The protective effect may be more pronounced in Alzheimer’s patients carrying the ApoE4 allele, compared to other genetic loci associated with the disease.

Gender and ethnicity may also influence the effects of different statins. For example, a study has shown that white American women prescribed statins at higher doses had an almost 15% lower risk of developing Alzheimer’s disease than those who had lower statin usage.

White American men on a high dosage of statins also showed up to 12% risk reduction, but this was not the case for black American men.

Statins that are able to cross the blood-brain-barrier (lipophilic) compared to those that do not readily cross it (hydrophilic) seem to have a more protective effect in black women, and in Hispanic men and women, whereas white women showed protective effects with all statins. Why this is the case is not understood fully, and needs to be investigated as to the specific mechanism of action of different statins when classified by the race and gender of the subject.

Potential Mechanisms

Aside from lowering serum cholesterol levels in the prevention of cardiovascular disease, statins may exert other protective effects on the body and the brain, potentially ameliorating Alzheimer’s disease pathology.

Many animal studies have shown that statin administration reduces the formation of beta-amyloid plaques due to a reduction of cholesterol in the brain.

Furthermore, the lowering of cholesterol levels also had an impact on the formation and number of neurofibrillary tangles composed of hyper-phosphorylated-tau (the second pathological hallmark of Alzheimer’s along with amyloid).

Together these effects may significantly reduce the risk of developing Alzheimer’s by reducing the number and ability of toxic proteins to form.

Another key factor in Alzheimer’s disease pathogenesis and progression is neuroinflammation. Some studies have shown that statins may exert anti-inflammatory effects within the brain.

For example, levels of key pro-inflammatory interleukins e.g., IL-1 and IL-6 were shown to be reduced in the hippocampi of Alzheimer’s models administered statins. Therefore, by reducing amyloid-mediated inflammation, statins may delay the onset of Alzheimer’s or reduce the overall risk due to a lowered brain inflammatory state.

In conclusion, a growing body of evidence suggests that statin usage may be protective against Alzheimer’s risk if used in the early stages. Observational data has suggested that this effect may be more pronounced for white women with higher statin dosages compared to other genders and ethnicities.

However much more research is needed to make definitive conclusions through randomised controlled clinical trials, as well as assessing the effect of different statins on different ethnicities and gender groups to ensure a more personalized recommendation for the future.

Further Reading

• All Statin Content
• What are Statins?
• Statin History
• Safety of Statins
• Statin Drugs

Written by

Osman Shabir

Osman is a Neuroscience PhD Research Student at the University of Sheffield studying the impact of cardiovascular disease and Alzheimer's disease on neurovascular coupling using pre-clinical models and neuroimaging techniques.