The use of certain widely prescribed drug therapies for chronic conditions such as hypertension, high cholesterol and diabetes have been hypothesized to influence Alzheimer’s disease and related dementia (ADRD) risk. Few randomized control trials to evaluate these relationships have been conducted for several reasons including cost, time and lack of financial incentive. Given high rates of therapeutic drug use to treat myriad health conditions prevalent among older adults, analyses of data collected on drug use and health conditions from large, and broadly representative samples of older Americans may be used to understand how these treatments for non-ADRD health conditions affect ADRD risk.
Lack of representation of racial and ethnic minorities in clinical trials further implores use of data sources that have large samples of racial and ethnic minority persons. Analyses on the potential benefits of switching drug treatments for a targeted non-ADRD health condition, initiating treatment or achieving better adherence, or reducing use of drugs that increase risk of dementia provide valuable information for patients, providers and support drug repurposing efforts. Alongside traditional drug development efforts to identify disease risk modifiers, a data-driven, hypothesis-informed approach to identify target drugs and test effects on dementia risk in diverse populations may provide needed knowledge for reducing racial and ethnic disparities in dementia risk and achieving population health equity.
The Evidence Gap Between non-ADRD Drugs and ADRD Risk
In a comprehensive scoping review of 404 studies, our research team identified 29 drug classes across 11 therapeutic areas associated with dementia risk. The review revealed that multiple drug classes with strong scientific evidence for mechanism of action on ADRD risk have had few or no studies, and that studies generally grouped drugs with different mechanisms of action together (e.g. multiple types of antihypertensives or statins), and did not assess heterogeneity in drug effects across sex, and race and ethnicity. Tackling these gaps is a good opportunity for informing dementia prevention and risk reduction efforts in diverse populations of older Americans.
A USC Schaeffer Center research team led by Julie Zissimopoulos and Geoffrey Joyce is evaluating the association of ADRD risk with use of drugs to treat high cholesterol, high blood pressure, overactive bladder and type II diabetes. This research agenda utilizes Medicare claims data to analyze and test the pathways between drug treatments for chronic conditions and dementia risk as drivers of disparities – pathways that have not been systematically examined. Below, this body of literature is summarized.
The Link Between Cholesterol-Fighting Drugs and AD Risk
Prior studies have shown a link between cholesterol and beta-amyloid plaques in the brain, a hallmark of AD. There has been discussion about whether statins could have protective qualities for AD as well as lowering cholesterol. Prior studies compared statin users to non-statin users with inconclusive findings on the association with dementia risk. Zissimopoulos, Barthold, Brinton and colleagues improved on this study design by focusing on statin users with different lengths of drug use over time, and tested for disparate effects of lipophilic statins with higher ability to enter cells compared to hydrophilic statins. They also estimated separate effects for non-Hispanic white, black and Hispanic persons. The study of 400,000 Medicare beneficiaries from 2006 to 2013 showed that incidence of AD was reduced for individuals with high use and over longer periods of time compared to low use. Among women who were high users, the incidence rate was 15% lower and among men, the rate was 12% lower. The greatest drop in incidence of AD was among Hispanic men at 29%. Among white men, high users of statins had an 11% lower risk of incidence of the disease. A similar reduction in risk — 12% — was found among Hispanic women.
Different types of statins differentially affected risk of AD for non-Hispanic white, Black and Hispanic men and women. For example, Hispanics were more likely to use the statin, rosuvastatin (a hydrophilic statin), than whites or Blacks yet rosuvastatin was not associated with reduced AD risk for Hispanics although both simvastatin and atorvastatin (lipophilic) were associated with reduced risk. Pravastatin and rosuvastatin results showed a statistically significant reduction of Alzheimer’s risk for only white women. This study underlined the importance of considering type of statin and racial and ethnic differences in effect.
A separate study of statins and risk of age-related neurodegenerative diseases found exposure to statins was associated with slightly lower incidence of AD, dementia, multiple sclerosis, Parkinson’s disease, and amyotrophic lateral sclerosis.
Press Release: Cholesterol-Fighting Drugs Lower Risk of Alzheimer’s Disease
Alzheimer’s and Dementia Study: Statin Therapy and Risk of Alzheimer’s and Age-Related Neurodegenerative Diseases
The Link Between Blood Pressure Drugs and AD Risk
Hypertension is one of the most common chronic conditions in the United States, affecting almost two-thirds of adults over the age of 60. Like statins, research is building on how antihypertensives mediations (AHTs) may reduce risk of dementia. Although there is agreement that lowering blood pressure reduces dementia, some classes of AHTs are hypothesized to be more protective than others. Angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II AT1-receptor blockers (ARBs) are two classes of AHTs, renin-angiotensin system (RAS) acting, that may have added dementia risk reduction benefits beyond simply lowering blood pressure.
In the first study to compare the association between multiple types of blood pressure medications and risk of acquiring AD across diverse racial and ethnic populations, co-authors Barthold, Joyce, Wharton, Kehoe and Zissimopoulos, find RAS-acting AHTs, in particular angiotensin-II receptor blockers (ARB), confer more protection against AD than other AHTs. The study, which compared AD risk among 1,300,000 Medicare beneficiaries using AHTs between 2007 and 2013, found protective effects varied depending on the race and sex of the patient. Use of angiotensin-II receptor blockers (ARB) was associated with reduced risk of acquiring AD compared to use of other AHTs for Black women, white women and white men. The reduction in risk was strongest for white males, who showed an 18% lower risk when using ARBs compared to those using other non RAS-acting classes of drugs.
Statin/Antihypertensive Combinations and AD Risk
Approximately one in four adults over age 65 use both antihypertensives and statins to manage their high blood pressure and high cholesterol. Combined use of AHTs and statins may reduce dementia risk; however, hypothesized mechanisms suggesting some classes, or subclasses, of these drugs may be more protective than others indicates concurrent use of different combination of AHTs and statins reduce risk more than others. In the first study to examine combination use, Barthold, Joyce, Brinton, Wharton, Kehoe, and Zissimopoulos analyzed claims data from 700,000 Medicare beneficiaries between 2007 to 2014 to quantify incidence of ADRD diagnosis associated with concurrent use of different statins and AHT drug classes. The study found the use of cholesterol lowering drugs pravastatin and rosuvastatin, combined with ACE inhibitors or angiotensin II receptor blockers (ARBs) for high blood pressure, were associated with a reduced risk for dementia compared to other combinations of drugs.
Like use of statins and AHTs alone, combination use of AHTs and statins and subsequent dementia risk varied across racial and ethnic background. Among Black users, ACE inhibitors combined with rosuvastatin conferred a large risk reduction, about 33%, while no combination of AHTs and statins were associated with reduced risk among Hispanic beneficiaries.
Overactive Bladder Medications and Risk of AD
Drugs with anticholinergic properties are associated with increased risk of ADRD. A drug class used for overactive bladder (Bladder antimuscarinic or BAM drugs) has known anticholinergic properties, but studies hypothesize certain drugs within this class – those that selectively bind to a specific receptor in the brain, M3-receptors – may have less of an impact on cognition.
A novel study by Barthold, Marcum, Gray and Zissimopoulos compared ADRD risk for 72,000 users of non-selective and M3-selective BAMs between 2007-2009 and examined ADRD risk associated with overall BAM use. They found no difference in dementia risk between non-selective and M3-selective BAM users across sex and racial/ethnic groups. Yet, long-term use of any BAM drug was associated with higher likelihood of ADRD compared to short-term use thus caution may be warranted for persons using these drugs for multiple years.
Pharmacoepidemiology & Drug Safety Study: Alzheimer’s disease and related dementias risk: Comparing users of non-selective and M3-selective bladder antimuscarinic drugs
Medicines for Type II Diabetes and Risk of AD
The pathology of AD is defined by two abnormal features in the brain: Increased amyloid beta plaques and tau proteins. Type II diabetes and AD share several pathophysiological features, making persons with diabetes at higher risk of AD. While insulin has a very important role in digestion, in the brain it preforms many of the functions that are impaired with AD. For example, insulin protects again the accumulation of amyloid beta that leads to plaques. Thus, there is a line of thinking to suggest that insulin-sensitizing agents used to treat type II diabetes (T2DM) may also prove useful in reducing the risk of AD. One class of medications typically used as a second-line treatment for T2DM, glucagon-like peptide-1 (GLP-1), has been hypothesized to have additional neuroprotective properties due to its ability to cross the blood brain barrier.
Zhou, Zissimopoulos, Nadeem, Crane, Goldman and Romley leveraged data from a sample of 340,000 Medicare beneficiaries with T2DM between 2007 to 2008 and measured subsequent AD risk between 2009 and 2013. The study found that use of exenatide (a GLP-1), was associated with a significant reduction in incidence of AD among Medicare beneficiaries aged 65 and older, and was stronger for women than men.
Alzheimer’s & Dementia Study: Association Between Exenatide Use and Incidence of Alzheimer’s Disease