Statins for Alzheimer's Disease? Not so fast...
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There have been many tantalizing headlines heralding breakthroughs in Alzheimer's disease research. The short video highlights that all of the advances aren't necessarily medical. A recent retrospective study using data from a nationwide cohort of the National Health Insurance Research Database in Taiwan followed a cohort of patients with type 2 diabetes (T2DM) with regular use of statins for approximately 8 years. Multivariate cox-proportional hazards regression model estimated the association between statin use and incidence of Alzheimer's disease and non-Alzheimer dementia after adjusting for several potential confounders. 
Among 28,321 patients diagnosed with T2DM age above 50 and without history of dementia before 2000/1/1, 15,770 patients who had never used statin and 2,400 patients who regularly used statin drugs were enrolled. After adjusting for age group, gender, CCI (Charlson-Deyo comorbidity index) group, stroke types and anti-diabetic drugs, regular statin use was associated with a decreased risk of developing incident Alzheimer's disease dementia (adjusted HR: 0.48, 95% CI 0.30 - 0.76, p<0.001), but not in non-Alzheimer dementia (adjusted HR: 1.07, 95% CI 0.54-2.12 p = 0.844) in patients with T2DM. Further analysis showed significant protective effects of the use of atorvastatin and simvastatin.
A recent post in Alzheimer's & Dementia Weekly reported findings suggesting a promising link between statins and AD prevention. The same Taiwan database identified 57,669 patients aged >65 years who had no history of dementia in 1997 and 1998. The analysis included pre-senile and senile dementia excluding vascular dementia.
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So what do we actually know? First we need to look at study design. Observational studies such as these two retrospective studies can suggest a potential association between a drug and an outcome but they are unable to prove cause-and-effect. The robust, gold standard of clinical research design is the randomized controlled trial (RCT).
The Cochrane Collaboration reviewed available data on statins for treatment of dementia and stated:
“There is insufficient evidence to recommend statins for the treatment of dementia. Analysis from the studies available, including one large RCT, indicate statins have no benefit on the outcome measures ADAS-Cog [Alzheimer’s Disease Assessment Scale- cognitive subscale] or MMSE [Mini Mental State Examination].”
The Cochrane Collaboration reviewed available data on statins for treatment of dementia and stated:
“There is insufficient evidence to recommend statins for the treatment of dementia. Analysis from the studies available, including one large RCT, indicate statins have no benefit on the outcome measures ADAS-Cog [Alzheimer’s Disease Assessment Scale- cognitive subscale] or MMSE [Mini Mental State Examination].”
Key Take-Aways...
An analytic review of statins in the brain and what these findings add provides an interesting context for continuing dialogue in prevention of Alzheimer's Disease. The role of statins in cholesterol metabolism includes non-lipid lowering pleiotropic effects that demonstrate the complexity of specific targets in the brain. Importantly, lipophilic statins (those that can cross the blood brain barrier) are not uniformly effective or thought to have CNS-related effects. These mechanisms aren't trivia because effects not specific to reduction of cholesterol may help explain a few of the extra benefits being investigated (anti-inflammatory for example). The ability to identify the details of cholesterol metabolism in the brain will clarify the role in pathology.
Although cholesterol circulating systemically is unable to cross the blood brain barrier, an oxidized product 27-hydroxycholesterol (27-OHC) is able to reach the brain. This has been theorized to be a potential link from elevated cholesterol to the risk of Alzheimer's disease. Elevated cholesterol may increase reactive oxygen species (ROS) formation which may promote amyloid beta deposits in the brain. There is a lot of data to cover so detailed descriptions are not really the point here but many of the mechanisms have not actually been evaluated in actual patients. The majority of models have been cultured tissues and animal models. These findings have been contradictory and ongoing research is needed to determine if there is a safe and efficacious place for statins in the treatment or prevention of neurodegenerative diseases like Alzheimer's disease.
Although cholesterol circulating systemically is unable to cross the blood brain barrier, an oxidized product 27-hydroxycholesterol (27-OHC) is able to reach the brain. This has been theorized to be a potential link from elevated cholesterol to the risk of Alzheimer's disease. Elevated cholesterol may increase reactive oxygen species (ROS) formation which may promote amyloid beta deposits in the brain. There is a lot of data to cover so detailed descriptions are not really the point here but many of the mechanisms have not actually been evaluated in actual patients. The majority of models have been cultured tissues and animal models. These findings have been contradictory and ongoing research is needed to determine if there is a safe and efficacious place for statins in the treatment or prevention of neurodegenerative diseases like Alzheimer's disease.
