By Brandon R. Peters, M.D.
The news was enough to give you indigestion: Some of the over-the-counter and prescription medications most widely used to treat heartburn and acid reflux are linked to the development of dementia. The research suggesting a possible association is the latest in a string of implicated drugs over the past few years, including medications taken to treat anxiety, seizures, insomnia, and allergies. What is going on? Before emptying out the medicine cabinet, take a moment to consider the role of untreated obstructive sleep apnea.
Scientific research can be difficulty to contextualize, especially when it is splashing around in headlines or restricted to a sound bite. Nuance is lost. The complexity of the topic may not be fully conveyed. Researchers themselves may not fully understand the findings and it often takes the collective wisdom of the scientific community for proper interpretation to occur. Though a full discussion of these issues is unnecessary, it is important to understand the meaning of an "association" in studies.
Scientists are careful to point out that association does not prove causation. Two conditions or characteristics may be observed without one causing the other. Statistical analysis may demonstrate that something is occurring within an exposed population more often than one would expect based on chance. This is called an association or correlation. Many times a third, unknown element may be associated with the initial measured characteristic and be causative of the observed outcome.
The recent study in JAMA Neurology entitled "Association of Proton Pump Inhibitors With Risk of Dementia" by Willy Gomm, PhD and associates explored the potential relationship by reviewing a health insurance database within Germany (1). A total of 73,679 subjects aged 75 years and older were identified and about 3 in 4 were women. Though initially free of dementia, after following these people from 2004 to 2011, cognitive changes were noted among those who took proton pump inhibitor medications. These medicines are both over-the-counter and prescription drugs used to treat heartburn and gastro-esophageal reflux disease (GERD), including: omeprazole (Prilosec), pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), and rabeprazole (AcipHex). Regular use of the drugs was associated with a 44% increased risk of developing dementia.
This result made headlines for two reasons: these drugs are some of the most widely used of all medicines - and people really don't want to get dementia. There are few things more fear-inducing than the prospect that something you are doing is increasing your risk of developing a condition that steadily robs you of your independence, your personality, and your memory. Why might such an association exist with a seemingly unrelated stomach medication?
The jury is still out on a potential explanation. The accompanying editorial explored some of the possible contributions: medication crossing the blood-brain barrier and increasing amyloid levels and plaques or reduced vitamin B12 levels, known risk factors for dementia (2). The population was older and perhaps sicker, with comorbid diseases that may increase the risk of both heartburn and dementia. One condition that was curiously left off the list as a possible cause of both the symptom instigating the use of a medication - and dementia - was sleep apnea. It wasn't the first time.
Obstructive sleep apnea is too often the ugly stepchild of medicine. It gets blamed for a lot, but it is so common that its importance may be dismissed. There are a few distinguishing features:
1. Its symptoms may be inappropriately attributed to other conditions.
2. It leads to major health consequences (including dementia).
3. Effective treatment can reverse both these categories of impacts.
In the context of heartburn, the collapse of the upper airway that occurs as part of obstructive sleep apnea creates a negative intra-thoracic pressure that draws the contents of the stomach (including acid and food) into the esophagus (3). This results in nocturnal heartburn and occasionally even reflux, coughing, or choking episodes. It may also weaken the effectiveness of the lower esophageal sphincter and contribute to daytime symptoms. It can be expected that anyone presenting to a doctor with such complaints would be started on a proton pump inhibitor posthaste.
Consider another example of two very distinct classes of medications used to treat insomnia: benzodiazepines and antihistamines. The former includes prescription medication also taken to treat anxiety and seizures, including lorazepam (Ativan), clonazepam (Klonopin), diazepam (Valium), and alprazolam (Xanax). The latter are the most common over-the-counter sleep aids containing diphenhydramine (Benadryl): Tylenol PM, Advil PM, Aleve PM, and ZzzQuil. One group acts to enhance GABA and the other contradicts the effects of histamine, yet both have been linked to an increased risk of dementia in the past several years (4, 5). Why?
Fragmented sleep and early morning awakenings frequently occur in sleep apnea. Disturbed breathing may provoke an arousal that moves the affected person from deep to light sleep and even to wakefulness. This may occur hundreds of times over the night. Difficulty returning to sleep may occur, resulting in insomnia complaints. Some may go to bed earlier to get more sleep and they may soon develop difficulty falling asleep at the beginning of the night as they extend their time in bed beyond their actual sleep needs. This insomnia may lead to the inappropriate use of sleeping pills.
If you take a medication that promotes a depressed level of consciousness, but you don't address the underlying trigger of the awakenings, the consequences of untreated sleep apnea can still develop. Over time, decreased oxygen levels during sleep may affect vulnerable cell populations in the brain. The hippocampus, the seat of the memory system, is highly dependent on oxygen: when someone suffers from an anoxic brain injury, it may be one of the first areas of the brain destroyed. Chronic oxidative stress that occurs in sleep apnea may slowly degrade this structure (6). It may not be the sleeping pills that cause dementia - it may be the untreated sleep apnea.
Sleep apnea is clearly a risk factor for the development of dementia (7,8). It likely explains the relationship between those who have unrefreshing sleep (or are "long sleepers") and the associated decline of physical health (9). Treatment with continuous positive airway pressure (CPAP) can effectively reverse its effects and preserve long-term memory function (10). We must not underestimate the impact of this common disorder on numerous aspects of health, including cognitive function.
If researchers have the interest and the resources to examine the issue, it becomes possible to predict the next medications that will be associated with the development of dementia. Prescription drugs used for the treatment of nocturnal urinary frequency, especially benign prostate hypertrophy in men, are the next low-hanging fruit. Urologists will be shocked to learn that sleep apnea causes nocturia, too, and treatment with CPAP can greatly reduce its occurrence. Those who don't know this can look and, sure enough, there will be an association.
Why stop with medications? Curious minds will discover that mouth guards to treat teeth grinding may have a similar link to dementia. (Grinding and clenching in sleep is often due to untreated sleep apnea.) Nasal strips, valves, chinstraps, and every imaginable contraption and contrivance to treat snoring will also be implicated in memory loss. We will face a stampede to rid ourselves of dementing pills, potions, and devices.
It is not now nor has it ever been these treatments -- no matter the nature or scope of the intervention -- it is the fact that we focus on symptoms without treating the cause. The cause, time and time again, is sleep apnea. We miss it, our most trusted doctors and researchers miss it, and we face interminable suffering and decline when we don't get it right.
1. Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, Doblhammer G, Haenisch B. "Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis." JAMA Neurology. 2016 Feb;10.1001/jamaneurol.2015.4791.
2. Kuller LH. "Do Proton Pump Inhibitors Increase the Risk of Dementia?" JAMA Neurology. 2016 Feb;10.1001/jamaneurol.2015.4931.
3. Orr WC, Heading R, Johnson LF, Kryger M. "Review article: sleep and its relationship to gastro-oesophageal reflux." Aliment Pharmacol Ther. 2004 Dec;20 Suppl 9:39-46.
4. Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B. "Benzodiazepine use and risk of Alzheimer's disease: case-control study." BMJ. 2014 Aug;349:g5205.
5. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB. "Cumulative Use of Strong Anticholinergics and Incident Dementia." JAMA Intern Med. 2015;175(3):401-407.
6. Daulatzai MA. "Evidence of neurodegeneration in obstructive sleep apnea: Relationship between obstructive sleep apnea and cognitive dysfunction in the elderly." J Neurosci Res. 2015 Dec;93(12):1778-94.
7. Pan W, Kastin AJ. "Can sleep apnea cause Alzheimer's disease?" Neurosci Biobehav Rev. 2014 Nov;47:656-69.
8. Yaffe K, Falvey CM, Hoang T. "Connections between sleep and cognition in older adults." Lancet Neurol. 2014 Oct;13(10):1017-28.
9. Hall MH, Smagula SF, Boudreau RM, Ayonayon HN, Goldman SE, Harris TB, Naydeck BL, Rubin SM, Samuelsson L, Satterfield S, Stone KL, Visser M, Newman AB. "Association between sleep duration and mortality is mediated by markers of inflammation and health in older adults: the Health, Aging and Body Composition Study." Sleep. 2015 Feb;38(2):189-95.
10. Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ. "Sleep-disordered breathing advances cognitive decline in the elderly." Neurology. 2015 May;84(19):1964-71.
Brandon R. Peters, M.D., is the author of an upcoming book chapter entitled "Sleep and Dementia: The Aging Brain in Rest and Decline" and the writer on sleep for About.com, a board-certified neurology-trained sleep medicine specialist at Pulmonary and Sleep Associates of Marin in Novato, Calif., and consulting assistant professor at the Stanford Center for Sleep Sciences and Medicine. This Center is the birthplace of sleep medicine and includes research, clinical, and educational programs that have advanced the field and improved patient care for decades. To learn more, visit us at: sleep.stanford.edu.