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. 2016 May-Jun;113(3):207–214.

Over-Prescribed Medications, Under-Appreciated Risks: A Review of the Cognitive Effects of Anticholinergic Medications in Older Adults

Daniel M I Britt 1, Gregory S Day 2,✉
PMCID: PMC5125613  NIHMSID: NIHMS829916  PMID: 27443047

Introduction

Dementia refers to an acquired syndrome of intra-individual decline in cognitive performance that ultimately interferes with daily functioning. Although the syndromic label of “dementia” may be widely applied, specific etiological diagnoses are reserved for patients meeting well-defined clinicopathological criteria. Of these, Alzheimer disease (AD) represents the most common cause of dementia in individuals over the age of 65,1 most often manifesting with the gradual onset and progression of memory and other cognitive impairment (characterized as AD dementia).2 The prevalence of AD dementia3 is predicted to rise in line with longevity,4 reflecting the strong association between age and AD. An estimated 5.1 million Americans over 65 years are currently affected with AD dementia. This number is expected to swell to 5.8 million by 2020,5 plateauing by 2030, at which point all surviving “baby boomers” (persons born between the years 1946 and 1964) will be 65 years or older, and thus at greater risk of AD.3 In the state of Missouri alone, the number of individuals with AD dementia is expected to grow by 20% by 2030,6 with wide-reaching implications for family members, caregivers, support organizations and health systems.1

Beyond AD, advancing age is also associated with multiple chronic illnesses, including heart disease, arthritis, diabetes and cancer.7 Aggressive medical management of these conditions and related risk factors is encouraged to reduce long-term morbidity and mortality.8 As a result, elderly individuals are increasingly likely to be prescribed multiple medications for their therapeutic benefits.9,10, A secondary consequence of this strategy is that risks of medication non-compliance, adverse drug reactions and mortality also increase.11 The potential cognitive adverse effects of medications in older individuals, with and without dementia, is of particular concern, recognizing that acute declines in cognition may further contribute to negative outcomes associated with medication misuse. Of the medications known to associate with cognitive impairment,12 those with anticholinergic properties pose the greatest risk in older individuals because of the broad indications for their use (e.g., treatment of allergic rhinitis, cold and flu symptoms, nausea and vomiting, urinary incontinence and insomnia), the high frequency with which they are encountered in over-the-counter and prescription preparations, and the potential for age-related changes in pharmacokinetics and pharmacodynamics to increase susceptibility to adverse effects. We review the available literature concerning anticholinergic medication use in older adults, with the goals of qualifying their potential adverse cognitive effects and of clarifying strategies for anticholinergic prescribing in this high risk population.

We searched PubMED and Google Scholar databases for English-language studies including the terms Alzheimer(’s) disease or dementia; AND anticholinergic medication OR serum anticholinergic activity; AND cognitive function, cognition OR cognitive decline. Additional sources were extracted from study references. Studies were reviewed in detail and included in this review if they met the following inclusion criteria: (1) enrolled older participants ≥50 years old; (2) reported exposure to anticholinergic activity or anticholinergic medication; (3) measured cognitive function; and, (4) reported on cognitive outcomes or change in outcomes following exposure to anticholinergic medications. Fifteen publications met these criteria.

Polypharmacy and Alzheimer Disease: An Aging Problem

Medication use is on the rise in older populations.10,13 As many as 50% of Americans over 65 years of age are currently prescribed five or more medications,14 meeting even the most conservative definitions of polypharmacy. Individuals with AD dementia are no exception. A cross-sectional study of community-dwelling elders in Chicago found that older individuals with AD dementia on average were prescribed more medications than those without dementia, including medications known to worsen cognitive impairment (4.9±2.6 versus 3.9±2.5; p<0.001).15 The risk of polypharmacy may be even higher in individuals with greater utilization of health care resources. A retrospective study considering the outcomes of 644 older adults receiving home care services in the St. Louis area, demonstrated that individuals requiring hospitalization were exposed to a higher overall number of medications than those returning to self- or family-directed care.16 Forty-six percent (87/189) of older adults requiring hospitalization were taking seven or more medications at the time of hospitalization, with 21% (40/189) exposed to 10 or more medications.16 These observations suggest that increasing numbers of medications associate with poorer health outcomes. One mechanism through which this may occur is by induction of a ‘prescribing cascade’ (See Figure 1), in which increasing numbers of medications result in adverse drug reactions, which are misinterpreted as new medical conditions, prompting prescribing of additional medications (and conveying even greater risks of medication adverse effects).9 The risks of improper prescribing may be highest in individuals receiving care from multiple physicians and in those within environments where medication changes may be rapidly implemented (i.e., inpatient or skilled-nursing settings). Individuals with AD dementia commonly fulfil both of these criteria, conveying additional risk in this vulnerable population.

Figure 1.

Figure 1

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Model illustrating the prescribing cascade. Misinterpretation of medication adverse effect as a new symptom (e.g., worsening confusion, new visual hallucinations and agitation—compatible with anticholinergic-induced delirium) leads to prescribing of additional medications, contributing to polypharmacy, and further increasing the risk of additional medication adverse effects (black). Terminating the prescribing cascade requires recognition of new symptoms as adverse effects and discontinuation of offending medications (gray).

The prevalence of anticholinergic use in older individuals is as high as 37%10, 17–20 and is expected to be even higher in individuals taking multiple medications. Common anticholinergic side effects include dry mouth, constipation, visual impairments, confusion and delirium.21 Older individuals may be more vulnerable to these effects, owing to age-related decreases in brain muscarinic receptor density,22 acetylcholine transmission23 and blood-brain barrier integrity, and age-related changes in drug metabolism and volume of distribution.24 Accordingly, anticholinergic use in the elderly has been linked to increases in functional and cognitive decline,17, 18, 23, 25–29 risks of institutionalization, length of hospital stay,30 and morbidity and mortality.31 The potential risks may be further compounded in individuals with AD due to disease-associated deficits in central nervous system acetylcholine levels32 and reductions in cognitive reserve.33 As a result, anticholinergic use may potentiate the symptoms associated with AD dementia, altering disease expression.34 There is even the suggestion that anticholinergic use may directly alter the progression of AD neuropathologic change, contributing to an earlier age of onset of AD dementia.35 Recognizing this, anticholinergic medications may represent a potentially reversible contributor to cognitive impairment and progression of AD pathology,12, 36–38 raising the possibility that outcomes in patients with AD dementia could be improved by reducing anticholinergic use.

Anticholinergic Medications and Dementia Expression

The cholinergic hypothesis posits that brain levels of the neurotransmitter acetylcholine are critical for learning and memory.39 This assertion is supported by animal studies demonstrating a marked decline in performance in navigational learning tasks in rats with pharmacologically-induced lesions targeting the cholinergic projection system (i.e., the nucleus basalis magnocellularis);40 and by studies in patients with AD dementia that report an inverse association between acetylcholine levels, and short-term memory and learning.38, 41, 42 In humans, this relationship has been attributed to a reduction in central nervous system acetylcholine-synthesizing neurons, and muscarinic and nicotinic acetylcholine receptors, owing to early AD neuropathologic change in chief cholinergic nuclei.43, 44 This line of evidence has been used to justify current approved symptomatic therapeutic strategies in patients with AD dementia, emphasizing prescribing of cholinesterase inhibiting medications (i.e., donepezil, rivastigmine, galantamine) in an attempt to increase central nervous system levels of acetylcholine.45–47

Anticholinergic medications may contribute to memory and learning impairment through central blockade of cholinergic (nicotinic and muscarinic) receptors.39 Scopolamine, a central cholinergic antagonist, has a well-recognized potential to mediate reversible amnesia in cognitively normal individuals.26, 48 Such effects can be blocked through the administration of cholinesterase inhibitors.48 In addition to central-acting agents, anticholinergic medications prescribed for their effects on peripheral nervous system targets may inadvertently alter central acetylcholine levels.49 Oxybutynin is one such “peripherally-acting” medication that is commonly prescribed for the symptomatic management of overactive bladder in adults,50 yet is associated with adverse cognitive outcomes in cognitively normal and impaired older adults.51–53 The magnitude of adverse cognitive effects and potential exacerbating factors associated with anticholinergic medications remain to be determined, with the potential that anticholinergic medications may unmask or exacerbate cognitive dysfunction in patients with preclinical (i.e., AD neuropathologic change in the absence of symptoms) or very mild AD dementia.34, 54, 55

We summarize the results of 15 studies that considered the cognitive impact of anticholinergic medications in older adults, with and without AD dementia (See Table 1). Ten studies considered the overall effect of anticholinergic medications on cognition; the remaining five studies evaluated the cognitive consequences associated with specific anticholinergic medications, versus placebo. Aggregate results from over 22,000 participants are presented, including 7,903 (34.6%, 7903/22821) participants exposed to anticholinergic medications.

Table 1.

Summary (abbreviated) of studies considering the cognitive impact of anticholinergic medications in older adults.*

Study Design Exposure Summary
1 64 Prospective observational study of community-dwelling adults with ADD85 High vs. low anticholinergic burden score No increased cognitive decline in participants with ADD receiving established doses of anticholinergic medications
2 28 Prospective observational study of community-dwelling and institutionalized older adults Definite vs. possible anticholinergic medications, vs. no exposure Anticholinergic medication use increased cumulative risk of cognitive impairment and mortality
3 29 Prospective observational study of community-dwelling cognitively normal older African Americans Definite anticholinergic medications vs. no exposure Anticholinergic medication use associated with an increased risk of cognitive impairment
4 55 Cross-sectional study of participants with probable ADD85 referred to a psycho-geriatric Unit SAA positive vs. negative Positive SAA was associated with lower global cognitive performance
5 56 Prospective observational study of community-dwelling and institutionalized older adults Exposure to anticholinergic medications vs. no exposure Anticholinergic medication use was associated with decreased cognitive performance in older females
6 53 RCT, placebo controlled trial in institutionalized older adult females with mild-to-severe dementia Oxybutynin ER 5 mg QD vs. placebo Oxybutynin was safe and well-tolerated for the short-term treatment of urinary incontinence
7 17 Prospective observational study in community-dwelling and institutionalized older adults Anticholinergic medications vs. no exposure Adults exposed to anticholinergic medications had significant declines in cognitive performance, and were more likely to be classified as MCI
8 51 RCT, placebo controlled trial in cognitively normal older adults Oxybutynin ER 20 mg QD vs. Darifenacin 15 mg QD, vs. placebo Oxybutynin was associated with significant impairment in delayed recall; darifenacin was not
9 41 Cross-sectional study in patients with moderate-to-severe dementia admitted to a psycho-geriatric Inpatient Unit SAA positive vs. negative Higher SAA associated with lower cognitive performance
10 54 Retrospective cohort study in participants with ADD85 selected from ADC database Anticholinergic medications vs. no exposure Anticholinergic medication use was associated with a greater decline in global cognitive performance
11 27 Cross-sectional study in community-dwelling cognitively normal older adults High vs. low, vs. undetectable SAA Higher SAA was associated with lower MMSE scores
12 52 RCT, placebo controlled cross-over study in cognitively normal older adults Oxybutynin 10 mg vs. diphenhydramine 50 mg, vs. placebo Oxybutynin and diphenhydramine caused impairment of cognition within 90 minutes of administration
13 57 Cross-sectional study in cognitively normal older adults with major depressive disorder SAA positive vs. negative SAA was associated with lower delayed recall scores, even at very low levels
14 26 RCT, placebo controlled cross-over study in cognitively normal adults Scopolamine 0.5 mg IV vs. placebo Older participants were more sensitive to the cognitive effects of scopolamine
15 34 Dose-response trial, placebo controlled in individuals with ADD86 vs. age-matched controls Scopolamine IV titration (0.1, 0.25, 0.5 mg and placebo) Patients with ADD were more sensitive to the cognitive effects of cholinergic blockade
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SD = standard deviation; RCT = randomized control trial; ADD = Alzheimer disease dementia; MMSE = Mini Mental State Examination 62; ADC = Alzheimer Disease Center; SAA = serum anticholinergic activity; MCI = Mild Cognitive Impairment

*

A detailed summary of Table 1 results is available upon email request (lfleenor@msma.org)

Overall, 13 (87%, 13/15) studies reported consistent declines in objective measures of cognitive function (e.g. measures of delayed recall such as Name-Face Association, and of general cognition, such as the Mini-Mental State Examination 17, 26–29, 34, 41, 51, 52, 54–57), with performance in tests of delayed recall most profoundly affected. The adverse effects of anticholinergic medications on recall may be disproportionately higher in older individuals with baseline cognitive impairment. This assertion is supported by three studies including over 13,000 participants: All reported an increased risk of cognitive impairment in participants with AD dementia who were exposed to anticholinergic medications.28, 34, 54 A similar effect, albeit of smaller magnitude, was noted in young cognitively normal participants,26 emphasizing the robust and pervasive effects of anticholinergic medications across populations of community-dwelling adults. Of particular concern, adverse effects on cognition may be under-recognized or under-reported. Although objective deficits in delayed recall were measured in healthy participants ≥60 years of age taking oxybutynin, no between-treatment differences were detected in self-rated memory, suggesting that participants were unaware of memory deterioration.51 Thus anticholinergic medications may represent a covert risk for cognitive impairment, with potentially important implications for individuals living independently, in whom medication-induced changes in cognition could go unchecked.

The adverse cognitive effects of anticholinergic medications appear to be dose-related. Four studies utilizing a biochemical measure of serum anticholinergic activity 58 reported an inverse relationship between serum anticholinergic activity and cognitive performance in over 200 cognitively normal participants,27, 57 and 100 individuals with AD dementia.41, 55 This dose-effect relationship may be further exacerbated by aging-related changes in pharmacokinetics and pharmacodynamics,59 hormonal changes (e.g., associated with estrogen treatment in females,60, 61 and other age-associated factors (e.g., simultaneous use of other medications which impair metabolism or prolong the effect of anticholinergic medications), resulting in higher serum anticholinergic activity and potentially contributing to the greater magnitude of cognitive effects observed in this vulnerable population.26, 56

Two studies (13%, 2/15) reported no increased cognitive decline in association with anticholinergic medications. The largest of these enrolled 224 participants with AD dementia who were receiving stable doses of medications. Although baseline performance on bedside cognitive tests (including the Mini Mental State Examination62 and Alzheimer’s Disease Assessment Battery, Cognitive subsection63) were significantly lower in individuals with an elevated ‘anticholinergic burden score’ (ABS ≥1; for information on calculation of the ABS see 23, 29), no significant correlation was observed between ABS scores and cognition at baseline, or at 6 or 18 month follow-up assessments.64 The other study reported no diminution in cognitive function in 50 females with mild-to-moderate dementia who were prescribed oxybutynin for the short-term management of urinary incontinence.53 Although the findings of these studies may be interpreted to suggest that anticholinergic medications may be tolerated in select populations, both studies included a majority of participants with prominent cognitive impairment, as evidenced by average Mini Mental State Examination scores below 15 in individuals taking anticholinergic medications,53, 64 and high overall rates of institutionalization (33%64 and 100%53). Thus, an alternate explanation may be that the impact of anticholinergic medications was harder to measure in individuals with moderate-to-severe AD dementia (owing to limitations in testing patients with more severe AD dementia—a so called ‘floor effect’). Further study is required before drawing conclusions concerning the efficacy and safety of anticholinergic medications in older populations with moderate-to-severe dementia.

Anticholinergic Medications and Alzheimer Disease

The neuropathological hallmarks of AD include the progressive accumulation of insoluble aggregates of amyloid-β peptide (forming amyloid plaques), and misfolded tau protein (forming neurofibrillary tangles) within cortical and subcortical structures.2 Although AD neuropathologic change may be suspected in patients with AD dementia, antemortem diagnosis of AD requires the use of neuroimaging or cerebrospinal fluid biomarkers of amyloid-β and tau.4, 65–67 Although many treatments targeting AD neuropathologic change have been and continue to be formally investigated,68, 69 none have succeeded in halting disease progression in humans. This finding exemplifies the importance of developing symptomatic treatments that can be applied to patients with AD dementia, and the importance of avoiding therapies and exposures that may promote disease expression or exacerbate AD neuropathologic change.

Systemic administration of cholinergic muscarinic agonists has been shown to reduce levels of amyloid-β in the cerebrospinal fluid and cerebral cortex of guinea pigs, with no significant effect on amyloid precursor protein levels.70, 71 Similarly, chronic nicotine treatment has been found to reduce amyloidosis in the mouse brain.72 Together these observations suggest that activation of central muscarinic and nicotinic cholinergic receptors may limit brain amyloid-β accumulation or promote clearance. It follows therefore, that cholinergic blockade may promote development of AD neuropathologic change, increasing the risk of development of AD dementia.

This hypothesis has been tested in a number of human observational studies (See Table 2), including three studies that considered the potential relationship between high cumulative use of anticholinergic medications and AD dementia.35, 38, 56 Collectively these studies reported a greater incidence of AD dementia in 4172 (32.2%, 4172/12951) individuals exposed to anticholinergic medications for three years or more. Individuals exposed to higher potency anticholinergics exhibited the highest incidence of AD dementia,35, 38 although higher rates of AD dementia diagnosis were still noted in individuals taking lower potency anticholinergics compared to those not exposed to anticholinergic medications (HR 1.8, P<0.001).38 Similar findings were reported in a postmortem study of participants with Parkinson’s disease, where a higher burden of AD neuropathology was observed in the brains of study participants with a history of long-term exposure (≥2 years) to anticholinergic medications.73

Table 2.

Summary (abbreviated) of studies considering the impact of anticholinergic medications on AD pathology.*

Study Design Exposure Summary
1 35 Prospective observational study in community-dwelling cognitively normal older adults Stratified participants by anticholinergic TSDD Higher cumulative use of anticholinergic medications was associated with an increased risk of dementia (HR 1.54, 95% CI 1.21–1.96) and ADD (HR 1.63, 95% CI 1.24–2.14)
2 38 Prospective observational study in cognitively normal older individuals from a primary care registry Anticholinergic medications vs. no exposure Anticholinergic medication use was associated with an increased risk of dementia (HR 2.081, p<0.001)
3 74 Retrospective study in cognitively normal older adults Anticholinergic medications vs. no exposure Anticholinergic medication use was not associated with an increased amyloid-β plaque burden (measured with amyloid imaging)
4 56 Prospective observational study in community-dwelling and institutionalized older adults Anticholinergic medications vs. no exposure Continuous anticholinergic medication use was associated with an increased risk of dementia (HR 1.65, 95% CI 1.00–2.73) and ADD (HR 1.94, 95% CI 1.01–3.72)
5 73 Retrospective study in patients with Parkinson disease, selected from a pathological database Anticholinergic medication use and duration Anticholinergic use was associated with increased amyloid-β plaque and neurofibrillary tangle density
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TSDD = Total Standard Daily Dose; ADD = Alzheimer disease dementia; HR = Hazard Ratio; CI = Confidence Interval

*

A detailed summary of Table 2 results is available upon email request (lfleenor@msma.org)

The pathological mechanisms through which anticholinergic medications promote development of AD dementia remain unknown. The application of biomarkers measuring amyloid-β may provide an opportunity to consider the long-term effect of anticholinergic medications on AD neuropathologic change, and to visualize this effect in vivo. To this end, we previously considered whether anticholinergic exposure was associated with elevated amyloid-tracer binding in asymptomatic (i.e., preclinical) and symptomatic individuals with AD evaluated at the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Although a correlation was not confirmed, this study was only powered to detect a large magnitude effect of anticholinergic medications on amyloid deposition.74 Future studies recruiting additional participants are required to address this important question.

Clinical Applications

Anticholinergic medications are commonly prescribed for the treatment of cold or flu symptoms, allergic rhinitis, atopic dermatitis, nausea and vomiting, and urinary incontinence. In treating each of the above conditions, the goal is to antagonize peripheral cholinergic receptors. However, the vast majority of anticholinergic medications lack sufficient specificity for peripheral receptors. The American Geriatric Society lists potentially inappropriate medications that are commonly used in older adults (Beers Criteria).75 Anticholinergic medications that exert marked central cholinergic effects are prominently featured on this list, including first-generation antihistamines, antispasmodics, antimuscarinics, tricyclic antidepressants, antipsychotics, antiparkinsonian agents and skeletal muscle relaxants.

Five distinct muscarinic receptors are recognized throughout the nervous systems, labelled M1–M5.76 Of these, the central M1 and M2 receptors exert the most direct effect on cognition, with antagonism contributing to memory impairment in animals.77–79 The M3 receptor, in contrast, is predominantly distributed throughout the peripheral nervous system,76 with important genitourinary implications. Stimulation of M3 receptors promotes detrusor muscle contractility and urinary voiding,80 with minimal central effects. This selectivity presents an opportunity for pharmacologic intervention for the treatment of urinary incontinence—a common and debilitating problem in older adults. Darifenacin is marketed as a selective M3 muscarinic-antagonist, with minimal effect on central M1/M2 receptors.81 Accordingly, a single randomized control trial showed no change in delayed recall in participants taking darifenacin compared to placebo for a three week period.51 Additionally, a single-center, randomized, double-blind, placebo-controlled study found that solifenacin, another selective M3 antagonist,82 did not cause a significant decline in cognitive function compared to placebo.83 Thus, it may be possible to effectively modulate peripheral cholinergic receptors, while limiting the cognitive consequences commonly associated with anticholinergic medications.

Recommendations derived from review and interpretation of the relevant literature are combined with basic prescribing principles to devise a strategy for anticholinergic prescribing in older adults (See Figure 2). Providers are advised to carefully consider the indications, potential contraindications and alternative therapeutic options before prescribing anticholinergic medications. Additional scrutiny should be considered when making clinical recommendations in individuals with suspected or confirmed AD dementia, acknowledging greater susceptibility to adverse cognitive effects,28, 34, 41, 54, 55 particularly diminution of short-term memory. When indicated, anticholinergic medications should be prescribed at the lowest effective dose, emphasizing the use of peripheral-acting agents, whenever possible. Subsequent dose titrations should be performed while monitoring for efficacy and screening for evidence of subjective or objective change in clinical signs or symptoms. Objective measurement of cognitive performance should be prioritized whenever possible, given the potential for under-recognition or under-reporting of memory deficits in otherwise healthy individuals taking anticholinergic medications.51 If changes are noted, strong consideration should be given to discontinuing the potentially offending medication, thereby avoiding the prescribing cascade. Prescribing indications should be frequently reevaluated, and anticholinergic medications tapered or discontinued at the first opportunity, in the interest of avoiding prolonged exposure to risks associated with anticholinergic use— including the potential for cholinergic blockade to contribute to AD neuropathologic change.35, 73

Figure 2.

Figure 2

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Suggested strategy for anticholinergic medication prescribing and monitoring in older adults with (black) and without dementia (gray).

Future Directions

Studies evaluating the effect of anticholinergic medications in older individuals have largely focused on medication effects in individuals presumed to be “cognitively normal” or those with AD dementia. The recent emergence of biomarkers of AD neuropathologic change that can be measured in living individuals has provided great insight into the timeline and progression of AD dementia,4, 65–67 demonstrating that characteristic changes of AD may precede the onset of symptomic disease by decades.2, 4 This discovery presents an opportunity to identify individuals with AD before the onset of progressive impairment of memory that characterizes the symptomatic phase of disease (i.e., “preclinical AD”). Future studies considering the cognitive effects of anticholinergic medications in individuals with preclinical AD are warranted, with the possibility that this population may exhibit similar vulnerability to anticholinergic-mediated cognitive impairment as reported in participants with AD dementia. It is even possible that anticholinergic use in this population may contribute disproportionately to the cognitive impairment observed in populations of “cognitively normal” older adults reviewed herein (similar to the confounding effect of preclinical AD observed in studies of “normal” aging84).

Conclusions

The balance of existing evidence suggests that anticholinergic medications are associated with adverse cognitive effects in cognitively normal and impaired individuals, with a greater magnitude of effect observed in individuals with preexisting cognitive impairment due to AD. Judicious prescribing of anticholinergic medications to at risk individuals is recommended, with the goal of improving cognitive outcomes in elders with and without AD. Additional attention is required to further clarify the contributions of anticholinergic medications to the expression of AD dementia and AD neuropathologic change.

Acknowledgment

Study funding: This project was supported by a Clinical and Translational Science Award (DB) through Washington University in St. Louis (a program of the National Center for Advancing Translational Sciences of the National Institutes of Health; UL1 TR000448, TL1 TR000449). GSD is a recipient of the Eugene M Johnson, Jr. Weston Brain Institute Postdoctoral Fellowship, and the Neiss-Gain Family Endowment for Alzheimer Disease Research.

The authors are grateful for ongoing mentorship support provided from Dr. Terry Seaton, Professor, St Louis College of Pharmacy; and Dr. John C Morris, Director, Knight Alzheimer Disease Research Center at Washington University in St. Louis.

Biography

Daniel M. I. Britt, (left), is with the St. Louis College of Pharmacy, St. Louis. Gregory S. Day, MD, MSC, FRCPC, (right), is with Washington University, Department of Neurology, St. Louis. Both are with the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University.

Email: dayg@wustl.edu

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Footnotes

Disclosure

None reported.

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