Dr. Neville Wilson.
In the USA, Alzheimer’s disease is the leading cause of dementia, with a prevalence of 1%-3% among persons 60 to 64 years of age, and in Taiwan, the prevalence was 2%-4% in the same age group in 2000 (1).
Dementia is a state of chronic impairment of mental functions, caused either by damage to the brain, or deterioration, over the passage of time, characterized by increasing loss of memory and alterations of the personality, resulting in confusion, anxiety and steady deterioration in general health.
Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by memory decline, mood swings, confusion, anxiety, behavioural changes, and difficulties with reasoning and speech.
According to findings by Gerontology researchers at the National Taiwan University Hospital in Taipei, Taiwan, risk factors for dementia are multiple, and may include age, ethnicity, sex, genetic factors, physical activity, smoking, drug use, educational level, alcohol consumption, body-mass index, comorbidity and environmental factors. (1)
DO STATINS PREVENT DEMENTIA ?
A recent report by the Taiwanese researchers reflects their finding that the use of statin drugs by elderly Taiwanese (>65 years ) correlated with a reduced risk for dementia. (2)
In the study of almost 58000 aged Taiwanese people, followed up for four and a half years, those who had taken the highest dosage of statin drugs (atorvastatin & rosuvastatin) exhibited a lower risk of developing symptoms of pre-senile and senile dementia.
This announcement was widely proclaimed as headline news throughout the world, prompting speculation that a possible remedy for senile dementia could be found in the use of statin drugs, commonly used as cholesterol lowering agents.
According to lead investigator, Dr Lin, “it was the potency of the statins….which was a major determinant in reducing dementia “
The statin drugs which were reported to have achieved the benefits of risk reduction for dementia, were atorvastatin 10 mg and rosuvastatin 5 mg, locally marketed as Lipitor and Crestor.
Interestingly, another statin drug, lovastatin, used in this study, had the opposite effect and slightly increased the risk of dementia.
Candidates for the study were over the age 65 years and reportedly free of dementia at the start of the four and a half year study.
Candidates who had a history of vascular dementia were excluded at the commencement of the study, so there was no data to evaluate whether those with vascular dementia would have been helped, or hindered, by statin therapy over the study period.
CAUSES OF DEMENTIA (AD) :
AD is thought to be caused by the development of protein plaques in the brain, altering brain structure and function, and premature death of brain cells.
We do not have information which enables us to identify the likely causes of dementia in these subjects, recorded at the end of the study, given only that subjects with a history of vascular dementia were excluded at it’s commencement.
Neither do we know whether subjects who were free of vascular dementia at the commencement of the study, remained free at the conclusion of the study.
While there may be several other causes for dementia, vascular disease resulting in atherosclerosis, and restricted blood flow to the brain, may be one such common cause in the elderly.
The presence or impact of other causes, which are non vascular, are not reported in this study.
The increased incidence of dementia, as noted in the group not using statins, may be due to other factors endemic in China, given that the overall risk for stroke is higher in China than in other population groups.
The results from an observational study in a single population group are not necessarily applicable in other population groups. Variations in the prevalence of dementia between Taiwanese populations and American populations may indicate differences in causal factors. (1)
More recently, a link has been detected between environmental microbial diversity and the aetiology of Alzheimer’s Disease, suggesting that personal immune status may influence the risk of developing Alzheimer’s Disease, and that countries with better hygiene were linked to high AD risk. (3)
The 14th Congress of the European Society for Biomedical Research has this month reported that fish oil (EPA / DHA-omega-3) may help to protect alcohol abusers from dementia, stating that there is “ 90% less neuro-inflammation and neuronal death in brain cells exposed to DHA” (4), thereby offering an additional reason for reduced levels of dementia.
Nutritional causes , as above, environmental factors, head injuries, smoking and Diabetes may all contribute to Alzheimers’s Disease, a common cause of dementia.
Patients with AD have been shown to have low levels of carnosine, a di-peptide which protects against the cellular damaging effects of oxidation, glycosylation, and DNA damage. (5)
Glycosylation is an organ damaging process in which sugars cross link with organ proteins to form toxic agents called Advanced Glycosylation End Products (AGES), resulting in brain cell damage, and clinical dementia.
Carnosine is also protective against damage to chromosomal telomeres, slowing down their rate of shortening, and ultimately their premature aging, and has been shown to protect against stroke damage and death from strokes. (6)
Carnosine deficiency is a dietary factor implicated in premature aging, diabetes, and Alzheimer’s Disease, and is derived from animal meat.
Not only did the study fail to address the role of these, and other hidden factors, that can influence dementia, it also failed to answer the question as to whether statins would have protected those with vascular disease from developing dementia, had they been included in the study.
ABSENT DATA :
The data from the study is insufficient to determine whether candidates in either of the 2 groups had risk factors for dementia, as quoted above, leaving the question of risk status unanswered, for those who did develop dementia, while not taking a statin, and for who were taking a statin, and were found to be at lower risk for dementia.
THE HIGHER INCIDENCE OF DEMENTIA ( The non – statin Group )
If undiagnosed diabetes, for example, was present amongst those who had developed dementia, they would have been without medication, including statins, and exposed to the risk of vascular disease, resulting in diminished blood flow to the brain and resultant dementia.
Diabetes is a disease of the arteries, and diabetic patients are at greater risk of developing cardiovascular or cerebrovascular disease, followed by compromised cerebral function, as a result of restricted blood flow to the brain.
In a separate Taiwanese study, involving 3717 newly diagnosed diabetic patients, reported in 2012, there was a 63% higher risk of dementia in the newly diagnosed diabetic patients, compared to those who did not have diabetes. (7)
In another recent study, researchers concluded “diabetes may increase the risk of Alzheimer’s Disease in both sexes and in all ages, with a greater risk for Alzheimer’s Disease in diabetic people over the age of 65 years”. (8)
So, in the group who had the higher risk for dementia, was there a nest of candidates with pre-diabetes, and who had not yet developed vascular disease, but subsequently developed atherosclerosis ?
We do not know.
THE LOWER INCIDENCE OF DEMENTIA GROUP : (The statin Group )
Amongst those who had been taking a statin drug, and for whom a lowered risk of dementia was recorded at the conclusion of the study, there might have been additional therapy in use, such as blood pressure lowering drugs, anti-inflammatory drugs, or nutritional supplements like fish oil, which are known to reduce arterial inflammation and improve cerebral circulation, thereby reducing the risk for dementia.
The dietary habits within this group of participants may have been modified for health purposes, given that they were already medicated with powerful statins for pre-existing medical conditions.
It is unlikely that patients would be given only a statin, since poly-pharmacy is a common practice in persons judged to be at risk of cardiovascular disease.
Any of these factors may have provided protection against dementia in the group who happened to be taking statins.
We cannot be sure as to whether the statins alone, or other protective factors present, were responsible for the lower incidence of dementia at the conclusion of the study.
THE PARADOX :
In several Statin trials an increased risk for newly developed diabetes has been identified, suggesting that statin users are at risk of developing diabetes, and the resulting effects of vascular disease.
In a meta-analysis of 13 statin randomized controlled trials from 1994 to 2009, involving 91,140 participants, statin use was associated with a 9% increased risk for incident diabetes. (9)
Other researchers believe that the risk is much higher than 9%.
It would, therefore, be expected that a higher incidence of diabetes, with its adverse vascular consequences, would emerge in the group which used high potency statins.
Surprisingly, this potential adverse effect of statins was not observed, or recorded, according to the study report.
An FDA report in October 2012, mandated that statin packages include the following warning about statin use. “ Certain cognitive (brain related) effects have been reported with statin use. Statin labels will now include information about some patients experiencing memory loss and confusion”. (10)
Again, this potential adverse effect was not observed, according to the study report.
NEUROTOXICITY OF STATINS :
Numerous studies have reported the neurotoxicity of statins in the laboratory and clinical setting.
Because statins are widely prescribed for purposes of lowering serum cholesterol in persons with high cholesterol levels, there exists the likelihood of more widespread neurological impairment than anticipated, or reported, in statin users.
Subtle behavioural changes and mood alterations, frequently observed in persons using statins, may be wrongfully attributed by their physicians to the normal aging process, or to other factors, rather than to the statin in use.
Beatrice Golomb and her associates described 171 patients who had reported cognitive disturbances after taking statins (11), and
Wagstaff and associates reported their analysis of 60 cases in which memory loss was linked to statin use. (12)
In a separate study, Attentiveness and Daytime Performance was evaluated in a randomized, double blind study in 1992, comparing healthy young males who were taking the statin, Lovastatin, with those who were not on a statin. (13)
Two measures of performance were used in this study to assess the effect of Lovaststin on daytime performance by these healthy candidates, compared to the performance of the non statin users.
In this study, Divided Attention and Vigilance were both reported to be worsened in those taking Lovastatin, indicating an adverse neurological effect from statin use.
Dr. Duane Graveline, a former USA Astronaut and Family Physician, was prescribed Lipitor (atorvastatin) by his military physician, and subsequently experienced severe memory loss, which he described in his book, “Lipitor, Thief of Memory”. (14)
His memory returned upon cessation of the statin, and once again disappeared when his physician urged him to resume taking Lipitor.
Since discontinuing the drug his memory has returned to normal. His condition was described as Transient Global Amnesia, (TGA) caused by Lipitor.
While the Taiwan study claimed a benefit for statins in reducing dementia, a population based study in 2005 showed that statin users increased their risk of developing Alzheimer’s Disease by two and half tomes more than those not taking statins. (15)
This finding contradicts the findings of the Taiwan Study.
CHOLESTEROL AND NEURONAL FUNCTION:
Researchers at the University of Arizona investigated the link between statin use and cognitive decline, and discovered a possible mechanism in the form of swellings on nerve axons, having the appearance of “beads-on-a-string” effect, directly caused by statin drugs, and which disappeared when the statin drug was removed.
These swellings were shown to disrupt the normal function of the neurons, and were not caused by any of the many other drugs used in the laboratory experiment. (16)
Furthermore, the protective role of cholesterol, in the healthy transmission of nerve impulses across nerve cell synapses, was demonstrated by researchers Smith and Barnes.
They demonstrated that certain nerve cells, called astrocytes, produce cholesterol, which is then utilized in nerve synapses as a vehicle for transmitting information across the synapses. ( 17)
Thus 2 mechanisms have been identified whereby neuronal function can be impaired, or compromised, by statin use.
On the one hand, direct toxicity of neurons, as demonstrated, can be caused by statins, and secondly, cholesterol reduction by statin use can impair neuronal function.
( Whether statins reduce astrocyte formation of cholesterol in addition to the liver synthesis of cholesterol is not clear )
PLEIOTROPIC EFFECTS OF STATINS:
Statins block the normal synthesis of cholesterol in the liver, resulting in reduced serum levels of cholesterol.
Numerous studies demonstrate that low levels of serum cholesterol disrupt normal neuronal function, resulting in cognitive impairment and memory loss. Low levels of cholesterol may thus contribute to dementia.
It is paradoxical that statins were associated with reduced incidence of dementia in the Taiwanese study, considering the biochemical and clinical evidence which contradicts this association.
While statins have been shown to exhibit several different properties, apart from their capacity to block the synthesis of cholesterol, they have also demonstrated additional properties, known as pleiotropic effects (18), (anti-inflammatory, anti-oxidant, profibrinolytic) whereby they have been reported, in some studies , to improve cardiovascular outcomes through improvement in vascular endothelial function (19) , a benefit noted which was unrelated to cholesterol lowering. (20)
Experimental evidence indicates that the statin, rosuvastatin, possesses favourable pleiotropic effects in respect of human airway smooth muscle contractions, via the eicosanoid agents thromboxane A2 (TxA2) (21)
The degree to which these pleiotropic benefits have been promoted in the outcomes of some clinical studies is controversial, since evidence is quite clear that often where clinical benefits have been claimed to be substantial, they have in fact been meager, and the absolute benefits, in fact, quite marginal when compared with relative risk reductions. (MRFIT, JUPITER ) (22)
NO BENEFIT FOR STATIN THERAPY IN DEMENTIA:
Following a review of 3 statin studies, Cochrane Researchers concluded that “ there is insufficient evidence to recommend statins for the treatment of dementia. The studies showed no benefit on the outcome measures, Alzheimer’s Disease Assessment Scale- Cognitive Substrate (ADAS-Cog) or MMSE. (23)
A geriatric study in 2012 reported the effects of statins on the cognition levels of elderly people with Alzheimer’s dementia.
They noted that when statin treatment was stopped in these elderly subjects, their brain function improved, and when the statin treatment was resumed, their brain function worsened. (24)
In another statin study, seeking to evaluate the clinical benefit of atorvastatin therapy, circulating cholesterol was lowered, but not free radical activity, and thus no clinical benefit for AD was noted. (25)
In a separate study, 5 years later, researchers again reported that atorvastatin does not slow cognitive decline in patients with mild to moderate Alzheimer’s Disease. (26)
In the PROSPER study, no cognitive benefit was reported for statin therapy in 5804 men and women between the ages of 70 and 82. (27)
The LEADe study, likewise, looking at Lipitor’s Effect in Alzheimer’s Dementia, in 641 subjects, failed to show any protective effect for Lipitor against AD and dementia. ( 28)
A 2013 Review of the potential therapeutic role of statins in the treatment of Alzheimer’s Disease lists the main interventive trials that have failed to show an improvement in cognitive function with statins.
The Review also list several smaller studies that have likewise failed to show global benefit for statin therapy on cognition. (29)
Included in these negative studies was the LORD study, in 2007, which likewise, showed no benefit for statin therapy, and similar findings by Beatrice Golomb in a 2004 report. (30)
THE HEALTH HAZARDS OF LOW CHOLESTEROL :
Since cholesterol has been shown to be protective of healthy neuronal function, it is likely that clinical evidence of neuronal impairment may be the consequence of unnecessary lowering of cholesterol by statin use.
People who suffer from Alzheimer’s Disease have been shown to have low levels of cholesterol and low levels of LDL cholesterol. (31)
In this 2011 epidemiological study by Presecki et al, those people with high levels of cholesterol correlated with better scores of mental functioning, as assessed by a test known as the Mini Mental State Exam (MMSE).
The results that emerged from this study, show correlations between low cholesterol and Alzheimer’s Disease, and while they do not prove a cause and effect relationship, such a relationship is quite plausible, given the protective role of cholesterol for neurons and neuronal activity.
The impairment of neuronal activity can be expressed as severe memory loss, personality change, or in less obvious ways, as slow responses to stimuli, or slow reaction time when faced with the need to make urgent and rapid decisions.
The slowing effects of statins on human reaction time was described by Muldoon and his team, showing that the average total reaction time of men whose cholesterol levels had been reduced, was slower than those with high cholesterol levels.
The difference in reaction time between these 2 groups was greater than that expected after 3 decades of aging ! (32)
Similar results emerged from a UK study in which College students with low cholesterol levels produced slower movement and slower reaction time than those with normal cholesterol levels. (33)
DO STATINS PROTECT AGAINST DEMENTIA ?
While the outcome reports from the TAIWAN study suggest that statin medication may have a role to play in preventing or treating dementia, the bulk of biochemical and clinical evidence is not supportive of this conclusion.
The 2013 review of the potential therapeutic role of statins in the treatment of Alzheimer’s Disease concludes that “statin therapy has failed to show a clear general effect on the treatment or prevention of AD” (29)
More data is required from the Taiwan study before recommendations can be made to offer statins to people with dementia.
Current evidence suggests that to do so would aggravate, rather than improve, their mental condition and their cognitive functions.
Dr. Neville Wilson.
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