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Critical review of a biomedical intervention - Statins for Alzheimer
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Statins as potential treatment for patientswith history of or risk for Alzheimer’s
Disease: A Systematic Review
Study group 4.8 - BBS3003
Bachelor Biomedical Sciences
Faculty of Health, Medicine and Life Sciences (FHML)
Maastricht University
28 January 2022
,Abstract
Alzheimer´s Disease (AD) is the most common form of dementia among the elderly. More
recently, a link between AD pathogenesis and hypercholesteremia has been identified and the
treatment with statins suggested. Statins are a widely used family of cholesterol lowering
drugs, which have been found to exert promising effects in the treatment of AD. The purpose
of this review therefore was to discuss the key issues pertaining to the role of statins on
cognitive decline for people at risk/with a history of AD. The issues to be examined were the
following: (1) pharmacokinetics and pharmacodynamics of statins; (2) neuroprotective
effects of statins; (3) adverse effects of statins; (4) neurotoxic effects of statins.
A PubMed literature search was conducted using relevant key words for each described
subtopic.
It was found that 7 statins are approved in the US, which are classified according to chemical
structure, solubility, and origin. They were reported to exert their main functions as HMG-
CoA reductase inhibitors, lowering cholesterol and thus membrane cholesterol in the brain.
Neuroprotective effects were observed via this reduction of cholesterol, leading to a reduction
of Aβ plaque formation, as well as stabilization of anti- and pro-inflammatory cytokine
production and upregulation of Akt signalling, leading to protection of neuronal apoptosis.
Furthermore, a decrease in NFTs and oxidative stress has been observed.
No significant adverse effects were found, as well as no significantly impaired quality of life.
Neurotoxic effects of statins were found to be rare, but significant. These however seem to be
dose-dependent, as well as dependent on treatment group characteristics and statin type.
Conclusively, the role of statins in AD remains under debate due to varying outcomes
between different studies.
Keywords
Alzheimer’s Disease (AD), Statins, Amyloid-Beta (Aβ), neuroprotection, neurotoxicity
Introduction
AD is a progressive neurodegenerative disease which is characterised by progressive loss of
memory and cognition function (1). As of now, there are around 55 million people diagnosed
with dementia worldwide and an expected number of AD patients of 131 million in 2050.
1
,This is due to the demographic change to a rapidly ageing population (1). People affected by
AD are not only the patients themselves, but their caregivers as well, as AD is threatening
their health and wellbeing. The main pathological processes that are thought to be responsible
for AD are Amyloid-Beta (Aβ) and Tau protein deposition. While Aβ aggregation exhibits a
cytotoxic effect that leads to degradation of neurons, mutated Tau proteins lose their ability to
bind to microtubules and accumulate in the neurons, which leads to cell death (2).
Because of the absence of therapeutic modality to prevent, delay or treat AD, the emotional,
financial, and family costs for care of AD patients will increase enormously in the near future
(1). Given these facts, it is urgent to get more insight into the disease biochemistry and
pathology, but overall, the treatment options (3).
Previous population-based studies have shown an increased association between AD and
hypercholesterolemia. Higher cholesterol levels in adulthood are correlated with an increased
risk to suffer from AD later in life. There are different risk factors for AD, such as
polymorphisms in apolipoprotein E (apoE) and various proteins that are involved in
cholesterol metabolism (1, 4). Statins have the capacity to reduce cholesterol biosynthesis,
which has been suggested to be beneficial in neurodegenerative diseases, including AD.
Statins are known as a widely used family of cholesterol lowering drugs, which are mostly
prescribed for treatment of dyslipidaemias in cardiovascular diseases (5). The hypolipidemic
properties of statins were reported by various authors as a potential effective therapy to
reduce the risk or delay the onset of AD (1, 6). The efficacy of statin therapy on cognitive
decline in AD was tested by multiple studies over time. Recent studies showed that statins
exert neuroprotective effects in AD patients as immunomodulation, anti-inflammatory
responses, reduction of oxidative stress and increases cerebral blood perfusion (5).
Nevertheless, there is still a lot of inconsistency among the findings of those preclinical
studies. Whilst many studies conclude statins to have neuroprotective properties in the
treatment of AD, others find no statistically significant effects or dangerous side effects (7).
For instance, lipophilic statins have been reported to exert neurotoxic adverse effects,
including growth inhibition and cell death in cultured glial cells, whilst hydrophilic statins did
not exert these effects. In addition, studies have found age, cholesterol plasma levels prior to
treatment begin, dosage of the statins and the type of statin administered, to play major roles
(8, 9). These observed treatment outcomes seem to be dependent on characteristics of the
treatment group. Also, the exact mechanism of action remains to be fully understood, because
there are still scientific limitations in the pharmacokinetics of statins (10).
2
, The purpose of this review is to discuss the key issues pertaining to the role of statins on
cognitive decline for people at risk/with a history of AD. The issues to be examined are the
following: 1) pharmacokinetics and pharmacodynamics of statins; 2) neuroprotective effects
of statins; 3) adverse effects of statins; 4) neurotoxic effects of statins.
Results
Pharmacokinetics and Pharmacodynamics of statins
History of statins
In 1976, Rudolf Virchow discovered that cholesterol in arterial walls could be reduced by 3-
hydroxy-3-methylglutaryl coenzyme A inhibitors (statins). Since this discovery, there is a lot
of published literature about the pharmacokinetics and pharmacodynamics of statins (11).
Classification and characteristics of statins
Seven types of statins are currently approved by the U.S. Food and Drug Administrations
(FDA). The pharmacokinetic characteristics of statins are based on their solubility, chemical
structure, bioavailability, metabolism, half-time, hepatic excretion, and renal excretion. The
pharmacological activities of the different statins are displayed in table 1.
Table 1: Pharmacokinetic and Pharmacodynamic characteristics of Statin [3][4]
3
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