INTERNATIONAL SYMPOSIUM ON OLFACTION AND TASTE

Epidemiological Studies of Smell

Discussion and Perspectives

Wendy Smitha and Claire Murphya,b

aUniversity of California, San Diego Medical Center and bSan Diego State University,San Diego, California, USA

The critical epidemiological data for estimating the prevalence of chemosensory dis-orders in the United States are lacking. Several reasons for this will be discussed,including the time-consuming nature of many existing tests, stimulus delivery in alarge-scale study, and the rationale for inclusion in a large-scale epidemiological study.The opportunity to include measures of chemosensory function in ongoing population-based studies has greatly facilitated the collection of recent data that establish the highprevalence of olfactory impairment in older adults in the U.S. population and the inabil-ity of self-report measures to capture this impairment. Epidemiological studies of thecomplete range of the population that involve chemosensory testing pose considerablechallenges, but are critical to establishing prevalence rates. These studies have the po-tential to suggest prevention or intervention strategies for chemosensory impairment.Key issues, including cross-cultural issues in stimulus design, testing of special popu-lations, cohort effects, and optimal analyses of population-based chemosensory data,are considered.

Key words: olfaction; olfactory impairment; smell; odor; prevalence; epidemiology;population studies

U.S. epidemiological data for estimating theprevalence of chemosensory disorders havebeen less available than such data for othermodalities. A large-scale epidemiological studyof smell in the United States is crucial for es-timating the public health burden of olfactoryimpairment in the general population and foridentifying factors that may exacerbate or, con-versely, mitigate smell problems, such as partic-ular medications or comorbidities.

The undertaking of such a project presentsseveral challenges. First, a representative pop-ulation sample, encompassing a wide variety ofages and ethnicities, must be recruited or beavailable for study. This requires a significantcommitment of time and financial resources.Second, a rapid, reliable assessment of olfac-

Address for correspondence: Claire Murphy, Ph.D., SDSU/UCSDJoint Doctoral Program, 6363 Alvarado Ct., Suite 101, San Diego,CA 92120-4913. Voice: +619 594 4559; fax: +619 594 3773.cmurphy@sciences.sdsu.edu

tion is required. Self-report alone is not suffi-cient, since this method has been demonstratedto significantly underestimate prevalence ratesobtained by olfaction testing.1 Ideally, the testshould be easy to administer, inexpensive, andacceptable to participants. It should span cul-tural differences in odor familiarity, as well as liftlanguage barriers, so that it can be used acrossa global population. Additionally, the needs ofspecial populations, such as young children andsubjects with cognitive impairment, must betaken into account.

Dr. Dalton’s presentation1a highlights thespecial requirements involved in testing olfac-tion in children. In fact, many of the same issuesthat challenge epidemiological studies will chal-lenge any study with small children: the needfor rapid administration of tests that presentstimuli that are familiar odors in a format thatminimizes adaptation and maximizes reliabil-ity and validity in this population. A number

International Symposium on Olfaction and Taste: Ann. N.Y. Acad. Sci. 1170: 569–573 (2009).doi: 10.1111/j.1749-6632.2009.04483.x c© 2009 New York Academy of Sciences.

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of tests have been successfully used with chil-dren. Generally, children aged 5 years andabove require some accommodation but canproduce reliable, valid data. For example, theSan Diego Odor ID test showed a test–retestreliability of 0.86 in children and in adultswith Down syndrome.2 Dr. Dalton’s study inprogress, designed to test the feasibility of anodor-identification test for children beginningat age 3, is a major undertaking, and the resultswill be welcome and informative. It incorpo-rates the features of earlier tests and is sensi-tive to the issues relevant to testing very youngchildren.

Dr. Wysocki’s presentation raises the impor-tant consideration of individual differences inolfactory function and specifically ethnic/racialdifferences. His research group has been focus-ing on specific anosmias, as well as on a subsetof olfactory receptor genes, known as segregat-ing pseudogenes, which vary among individu-als. Such considerations become important inattempts to generalize the data from epidemi-ological studies in specific samples, and theyunderscore the need for epidemiological stud-ies that are broad in scope.

Recently conducted epidemiological studiesof olfaction have focused upon specific subpop-ulations, such as the middle-aged and elderlypopulation in the Beaver Dam study discussedby Ms. Schubert,1 and Japanese-Americanmales in the Honolulu–Asia Aging Study.3 Ineach case, brief olfaction tests were added toa pre-existing project that had been designedto acquire epidemiological data on other vari-ables, such as hearing loss in the Beaver Damstudy and cardiac disease in the Honolulu–Asia Aging Study. In both cases, chemosen-sory tests were administered after training ex-isting project personnel. Such an arrangementallowed for the collection of valuable data withlimited impact on financial and human re-sources. However, it does require collabora-tion between researchers from diverse trainingbackgrounds, who may differ in their termi-nology and data analysis and sharing practices.The addition of chemosensory testing should

TABLE 1. Sensitivity and Specificity of Self-reported Olfactory Impairment in the U.S. OlderAdult Population, Shown as a Function of Ageand Gender, Support the Need for ChemosensoryTesting

Sensitivity Specificity

Women52–59 years 0.33 0.9460–69 years 0.24 0.9570–79 years 0.16 0.9480–97 years 0.12 0.96All women 0.16 0.94

Men52–59 years 0.36 0.9160–69 years 0.25 0.9370–79 years 0.24 0.9580–97 years 0.18 1.00All men 0.24 0.93

All 0.20 0.94

Data from Murphy et al., 2002, Journal of the Ameri-can Medical Association.1

avoid taxing the major study and maximize theapplication of new ideas.

The Epidemiology of Hearing Loss Study(EHLS), a longitudinal population-based studyinvolving Beaver Dam, Wisconsin residents,has provided many significant insights into thisfield. The San Diego Odor Identification Testhas been incorporated into this study, and sub-sequently, taste testing has been adopted. Ms.Schubert presented data from both the EHLSand Beaver Dam Offspring Study (BOSS), astudy of offspring that spans a larger age range.In the EHLS, Murphy and colleagues1 founda mean prevalence of olfactory impairment of24.5% among people older than 50 years ofage, with rates rising exponentially with in-creasing age (See Figure in Hoffman3a). Among80- to 97-year-olds, 62.5% had olfactory im-pairment on the San Diego Odor IdentificationTest. In contrast, self-reported olfactory impair-ment was low, and this measure became lessaccurate with age. Table 1 compares the abil-ity of older adults to accurately report olfactoryloss with measured impairment, illustrating thelow sensitivity of the self-report measure andthus the need for sensory testing. The very high

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specificity suggests that older adults who do re-port loss of function do so accurately.

In this same population, Schubert and co-workers4 recently reported that among 1920participants in the EHLS, olfactory impair-ment at base line was associated with cog-nitive impairment (Mini-Mental State Exam(MMSE) score) at 5-year follow-up (Odds Ratio[OR] = 6.62, 95% CI, 4.36–10.05). The asso-ciation remained significant after adjusting forpossible confounders (MMSE at base line, age,sex, education, and occupation) (OR = 3.33,95% CI, 2.04–5.42). This result is particu-larly interesting since the population is younger(mean [M] = 67 at base line) than in previousstudies indicating an association of olfactoryimpairment with subsequent cognitive impair-ment, and thus the incidence of cognitive im-pairment in this population was low, and posi-tive predictive value low. However, the negativepredictive value was very high, 97.2%, so thatolder adults without olfactory impairment werevery likely to be free of cognitive impairment for5 years.4 Interestingly, preliminary data fromthe BOSS, which involves children of the orig-inal Beaver Dam study participants, indicatea lower prevalence of olfactory impairment inthe BOSS cohort as compared to the EHLScohort at similar ages.

Self- or informant-reported data on smelldisorders has also been gathered throughthe Disability Supplement to the NationalHealth Interview Survey (NHIS), which wasdistributed to 42,000 randomly selected house-holds in 1994. Adjusted national estimates sug-gested a prevalence of 1.4% for self-reportedolfactory disorders among U.S. adults. Approx-imately 40% of those who reported chronicsmell problems were 65 years or older. Sig-nificant associations were found between ratesof smell disorders and the individual’s overallhealth status, functional limitations, depression,and trouble hearing.5 The relatively low preva-lence rates in this study are likely underesti-mates of actual prevalence, given the use ofself-report only, with no opportunity for clini-cal testing of olfaction.

Epidemiological studies assessing olfactionare critical for accurate determination of preva-lence and potential cohort effects, as well asfor investigating the health implications ofchemosensory disorders. Smell disorders have asignificant impact on dietary habits and weight,and may also affect blood pressure and otherrisk factors for cardiovascular disease and di-abetes. The prevalence of obesity has reachednearly epidemic levels, partially due to dietarymodifications with higher intake of saturatedfats and sugars. Obesity serves as a risk fac-tor for many health problems, including heartdisease, hypertension, stroke, and certain typesof cancer. Obesity is also a significant risk fac-tor for diabetes, with a threefold increase indiabetes risk seen in moderately obese middle-aged men.6 The prevalence of this disease hasbeen accelerating rapidly since 1990; currently,over 18 million people in the United States havebeen diagnosed with diabetes.7

Increasing evidence indicates that cognitivestatus in old age is closely linked to health sta-tus in middle age. A recent study demonstratedthat the risk of dementia is increased by 74% inobese middle-aged individuals, while this risk isincreased 35% in overweight middle-aged indi-viduals.8 Strong evidence supports glucose dys-regulation as a predictor for cognitive impair-ment. A nearly twofold increase in the risk ofdeveloping cognitive impairment has beenshown in postmenopausal women with dia-betes, as well as those with impaired fast-ing glucose.9 Moreover, levels of glycosylatedhemoglobin, a marker of long-term glucosecontrol, have been linked to the risk of develop-ing mild cognitive impairment or dementia.10

Older patients with poor diabetes control havea high risk of undiagnosed cognitive dysfunc-tion.11 Some evidence of olfactory impairmenthas also been seen in diabetics.12 An increasedrisk of Alzheimer’s disease (AD) has been asso-ciated both with diabetes13 and the metabolicsyndrome, which is manifest by large waist cir-cumference, elevated glucose levels, and lipiddysregulation.14

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Olfactory loss has been closely linked to cog-nitive decline, particularly in neurodegenera-tive diseases, such as AD15 and Parkinson dis-ease (PD).3 Some 4.5 million Americans sufferfrom AD, and the number is projected to rise to5.7 million by 2020. The disease is expected toquadruple by 2050, absent treatment or curefor AD. Estimates of the indirect and directhealth costs of AD approach $150 billion. PDaffects at least 500,000 Americans, or approx-imately 2% of those older than 65. Activityin the pharmaceutical sector to develop effec-tive treatments has increased significantly. Be-cause of its potential to serve as an early markerof prodromal AD or PD, population studiesof olfactory function that assess the sensitivityand specificity of olfactory impairment com-bined with other measures of dementia maybe very important in establishing the potentialfor olfactory testing, in conjunction with otherneuropsychological testing, to signal preclini-cal disease in those who are potential candi-dates for pharmaceutical intervention. Recentresults from a number of population studies arepromising. Wilson and colleagues16 reportedthat impaired olfaction at base line predictedmild cognitive impairment at 5-year follow-up.Similarly, participants in the Beaver Dam pop-ulation study showed a strong association be-tween olfactory impairment at base line andthe 5-year incidence of cognitive impairment.4

Ross and colleagues3 reported that odor iden-tification impairment at base line was stronglyassociated with PD at 5-year follow. In all ofthese studies, specificity was high and sensitivityless so, suggesting the potential utility of com-bining olfactory assessment with other mea-sures in a dementia battery. Novel populationstudies that assess the influence of environmen-tal and genetic influences on the developmentof cognitive impairment and dementia maybe very informative and suggest avenues forprevention.

The advent of specific medications mayhave positive cohort effects if their use protectsagainst olfactory impairment. For instance, in-creased use of nasal steroids and oral antibi-

otics for nasal inflammation and paranasalsinus disease over recent decades could poten-tially reduce the insult of inflammatory diseaseson the peripheral olfaction system, therebylessening the risk of permanent olfactory im-pairment. The use of hormone replacementtherapy in postmenopausal women mayalso protect against olfactory loss, as hasbeen demonstrated in individuals with theApolipoprotein epsilon 4 allele.17 The BeaverDam study demonstrated a decreased risk ofolfactory impairment in subjects taking oralsteroids or statins, a widely used cholesterol-lowering medication. Olfactory impairment iscommon in aging and may serve as a usefulmarker for other age-related disorders. Oppor-tunities may exist for both prevention and treat-ment of these diseases if modifiable risk factorscan be identified. Cohort effects related to birthyear, medication use, and comorbidities, such asobesity and diabetes, are areas of particular in-terest for future research utilizing a large-scaleepidemiological study.

In summary, self-report, cross-sectional stud-ies and research on age-limited cohorts sug-gest that there is significantly high prevalenceof olfactory impairment in the U.S. popula-tion. The opportunity to include measures ofchemosensory function in ongoing population-based studies has greatly facilitated the collec-tion of recent data. Epidemiological studies ofthe complete range of the population pose con-siderable challenges, but are critical. Absentepidemiological studies focused on testing thechemical senses, incorporation of chemosen-sory assessment into existing large-scale cohortstudies will advance knowledge and open op-portunities for prevention.

Acknowledgment

Supported by NIH Grant #AG04085 toC.M.

Conflicts of Interest

The authors declare no conflicts of interest.

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References

1. Murphy, C., C.R. Schubert, K.J. Cruickshanks, et al.2002. Prevalence of olfactory impairment in olderadults. JAMA (J. Am. Med. Assoc.) 288: 2307–2312.

1a. Dalton, P., J. Mennella, B. Cowart, et al. 2009. Evalu-ating the prevalence of olfactory dysfunction in a pe-diatric population. Ann. N. Y. Acad. Sci. InternationalSymposium on Olfaction and Taste. 1170: 537–542.

2. Murphy, C., J.A. Anderson & S. Markison. 1994. Psy-chophysical assessment of chemosensory disordersin clinical populations. In Olfaction and Taste XI . K.Kurihara, N. Suzuki & H. Ogawa, Eds.: 609–613.Springer-Verlag. Tokyo.

3. Ross, G.W., H. Petrovitch, R.D. Abbott, et al. 2008.Association of olfactory dysfunction with risk for fu-ture Parkinson’s disease. Ann. Neurol. 63: 167–173.

3a. Hoffman, H.J., K.J. Cruickshanks & B. Davis. 2009.Perspectives on population-based epidemiologicalstudies of olfactory and taste impairment. Ann. N.

Y. Acad. Sci. International Symposium on Olfactionand Taste. 1170: 514–530.

4. Schubert, C.R., L.L. Carmichael, C. Murphy, et al.2008. Olfaction and the 5-year incidence of cogni-tive impairment in an epidemiological study of olderadults. J. Am. Geriatr. Soc. 56: 1517–1521.

5. Hoffman, H.J., E.K. Ishii & R.H. MacTurk. 1998.Age-related changes in the prevalence of smell/tasteproblems among the United States adult population.Results of the 1994 disability supplement to the Na-tional Health Interview Survey (NHIS). Ann. N. Y.

Acad. Sci. 855: 716–722.6. Thompson, D., J. Edelsberg, G.A. Colditz, et al. 1999.

Lifetime health and economic consequences of obe-sity. Arch. Intern. Med. 159: 2177–2183.

7. National Institute of Diabetes and Digestive and Kid-ney Diseases. 2008. National Diabetes Statistics, 2007

fact sheet. U.S. Department of Health and Human

Services, National Institutes of Health. Bethesda,MD.

8. Whitmer, R.A., E.P. Gunderson, E. Barrett-Connor,et al. 2005. Obesity in middle age and future risk ofdementia: a 27-year longitudinal population basedstudy. BMJ 330: 1360.

9. Yaffe, K., T. Blackwell, A.M. Kanaya, et al. 2004.Diabetes, impaired fasting glucose, and developmentof cognitive impairment in older women. Neurology

63: 658–663.10. Yaffe, K., T. Blackwell, R.A. Whitmer, et al. 2006.

Glycosylated hemoglobin level and development ofmild cognitive impairment or dementia in olderwomen. J. Nutr. Health Aging 10: 293–295.

11. Munshi, M., L. Grande, M. Hayes, et al. 2006. Cog-nitive dysfunction is associated with poor diabetescontrol in older adults. Diabetes Care 29: 1794–1799.

12. Le Floch, J.P., G. Le Lievre, M. Labroue, et al. 1993.Smell dysfunction and related factors in diabetic pa-tients. Diabetes Care 16: 934–937.

13. Arvanitakis, Z., R.S. Wilson, J.L. Bienias, et al. 2004.Diabetes mellitus and risk of Alzheimer disease anddecline in cognitive function. Arch. Neurol. 61: 661–666.

14. Razay, G., A. Vreugdenhil & G. Wilcock. 2007. Themetabolic syndrome and Alzheimer disease. Arch.

Neurol. 64: 93–96.15. Murphy, C., M.M. Gilmore, C.S. Seery, et al. 1990.

Olfactory thresholds are associated with degree ofdementia in Alzheimer’s disease. Neurobiol. Aging 11:465–469.

16. Wilson, R.S., J.A. Schneider, S.E. Arnold, et al. 2007.Olfactory identification and incidence of mild cogni-tive impairment in older age. Arch. Gen. Psychiatry 64:802–808.

17. Sundermann, E.E., P.E. Gilbert & C. Murphy. 2008.The effect of hormone therapy on olfactory sensitivityis dependent on apolipoprotein E genotype. Horm.

Behav. 54: 528–533.