Older adults with dementia have been found in cross‐sectional studies to have a greater prevalence of olfactory dysfunction than those without dementia, 1 but in the few longitudinal studies that have assessed whether olfactory dysfunction precedes the development of Alzheimer's disease (AD), the most‐common type of dementia, 2 - 7 not all found a significant predictive relationship. Moreover, subjects in these longitudinal studies were from at‐risk groups, relatively small samples, or homogenous populations. In some studies, it was also possible that the apparent predictive power of olfaction was an artifact of its association with cognitive abilities at baseline and did not have predictive power in addition to the predictive effects of baseline cognition itself. Thus, it is uncertain whether olfactory dysfunction is a predictive marker of subsequent dementia in the diverse general population of older U.S. adults. We investigated the relationship between olfactory dysfunction and a diagnosis of dementia within 5 years in the National Social Life, Health, and Aging Project (NSHAP), a nationally representative probability sample of home‐dwelling Americans aged 57 to 85.

We tested the association between baseline olfactory dysfunction and an interval dementia diagnosis using multivariate logistic regression, controlling for age, sex, race and ethnicity, education, comorbidities, and baseline cognitive function. We tested the incremental risk attributed to each additional odor identification error using a 1–degree of freedom linear trend test. Results are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical significance was set at P < .05.

NSHAP used a national probability sample of home‐dwelling older U.S. adults (born 1920–1947). Participation rates were considered excellent for surveys of this type: 75.5% at baseline (2005–06) and 74% at follow‐up (2010–11; the conditional response rate among returning respondents was 89%). In addition, NSHAP oversampled blacks, Hispanics, men, and older individuals to obtain roughly equal numbers of sampled individuals in each of six sex‐by‐age categories. 8 Respondent‐level weights were calculated to adjust for differential nonresponse to survey participation and the planned oversampling based on race and ethnicity, sex, and age. This permits estimation of parameters for the U.S. population of older home‐dwelling adults. 10 , 11 All values presented use these respondent‐level weights. Design‐based standard errors were calculated using the linearization method together with the strata and Primary Sampling unit indicators provided with the dataset. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated using standard formulas. All statistical analyses were conducted using Stata version 14.0 (Stata Corp., College Station, TX).

It is likely that baseline cognitive function of respondents may influence subsequent development of dementia. We previously reported in a cross‐sectional analysis that olfaction is associated with cognition within the normal cognitive range. 18 Therefore, cognitive function at baseline was included as a covariate to test the hypothesis that olfactory dysfunction would predict development of dementia after accounting for baseline cognition itself. Cognitive function at baseline was measured using a modified version of the Short Portable Mental Status Questionnaire (SPMSQ; range 0–10).

Our analyses accounted for numerous potential confounders, including age, sex, race and ethnicity, education, comorbidity, and baseline cognition (Supplementary Table S1 ). Age and sex have long been known to be associated with olfactory function. 12 Race, an established olfactory risk factor, 17 was measured according to self‐report using standard National Institutes of Health questions. Respondents were classified as white, black, or Hispanic. (Those who reported their race as black or African American and answered “yes” to Hispanic ethnicity were classified as black.) Small sample sizes necessitated combining those reporting their race as American Indian or Alaskan Native, Asian, or other into a single “other” category. Education was measured according to highest degree or certification earned. Comorbid diseases were measured using the Charlson Comorbidity Index modified for the NSHAP survey.

Proxy interviews were unattainable for 296 respondents (10.2%). We classified these respondents conservatively as normal. We found similar effect sizes and significance levels when we classified all of them as having dementia or excluded them altogether.

At 5‐year follow‐up, we determined physician diagnosis of dementia during home interviews with the respondent, or a proxy if the respondent was too sick to interview or had died. Prior studies have found that proxy reports of date and cause of death match or exceed the accuracy of information from death certificates and that proxy reports of dementia are reasonably accurate when compared with psychometric testing. 14 - 16

Objective odor identification ability was evaluated at baseline using a validated five‐item test. 10 , 11 Odors were presented using odor pens (Sniffin’ Sticks, Burghart Messtechnik, Wedel, Germany), and respondents were asked to identify each odor by choosing from a set of four picture or word prompts. Refusals were coded as incorrect. Using previously validated cutpoints 10 , 11 , respondents who identified four or five odors correctly were classified as normosmic, whereas those who identified three or fewer odors correctly were classified as having some form of olfactory dysfunction. Using these criteria, 22.0% of older U.S. adults had objective olfactory dysfunction, a percentage that aligns with other estimates of olfactory dysfunction in older adults. 12 , 13

We studied 2,906 NSHAP respondents who were interviewed at baseline (2005–06) and reinterviewed at 5‐year follow‐up (2010–11) in their homes by professional interviewers (from NORC at the University of Chicago) after excluding respondents who reported a preexisting physician diagnosis of dementia (0.7%), those who did not complete olfactory testing (2.2%), and those who did not provide complete demographic information (0.4%). Both interviews included assessments of demographic, social, psychological, and biological measures, including olfactory ability. To select its sample, NSHAP followed a standard multistage area probability sample design, covering all geographic areas of the United States. This sample is representative of the U.S. home‐dwelling population aged 57 to 85 (born 1920–1947). 8 Further details regarding study design and data collection are published elsewhere. 9 By design, the population was cognitively intact at baseline (mean Short Portable Mental Status Questionnaire (SPMSQ) score 9.2 ± 1.0 out of 10). Additional baseline characteristics of the population are presented in Table 1 . The institutional review boards at NORC and the University of Chicago approved this study.

As a stronger test of the predictive effects of olfaction independent of baseline cognition, we restricted our analysis to older adults who, at baseline, tested within the normal cognitive range. In case those with impaired cognition at baseline drove the initial findings, we excluded respondents whose baseline SPMSQ scores were below the traditional cutoff for likely dementia (<8). The sensitivity of olfactory dysfunction was similar; 43% of older adults reporting a new dementia diagnosis had had olfactory dysfunction on testing 5 years before. Furthermore, for older adults who tested within the normal cognitive range, poor olfaction continued to strongly predict an interval dementia diagnosis (OR = 2.21, 95% CI = 1.33–3.69, n = 2,677).

As expected, better cognitive function at baseline was associated with lower likelihood of interval dementia diagnosis (OR = 0.73, 95% CI = 0.61–0.87). In addition, dementia was more likely to develop in older adults (OR = 1.06, 95% CI = 1.01–1.11), further supporting the validity of our diagnostic measure. Nonetheless, olfactory dysfunction had a predictive value in addition to that of baseline cognition, equivalent to aging 13 years; each additional odor identification error increased the odds of dementia independent of all of the covariates ( P = .04, Figure 1 ).

At 5‐year follow‐up, 4.1% of older adults reported a new physician diagnosis of dementia (Supplementary Table S2 ). The sensitivity of olfactory dysfunction was 47%; nearly half of older adults reporting a new physician diagnosis of dementia had had olfactory dysfunction on testing 5 years before. Specificity was 79%; more than three‐quarters of older adults without a new dementia diagnosis had had normal olfactory testing 5 years before. The PPV of olfactory dysfunction in predicting a dementia diagnosis 5 years later was 9%, and the negative predictive value was 97%.

Discussion

We show for the first time that home‐dwelling older U.S. adults with more difficulty identifying odors have greater odds of receiving a new physician diagnosis of dementia 5 years later (based on respondent or proxy reports). The strengths of this study include a design that represents the general U.S. population, demographic diversity, the largest sample size to date, and control of important covariates. Specifically, we demonstrate the predictive power of olfaction in addition to cognition by including baseline cognitive function as a covariate in the analyses and by confirming results after excluding individuals with SPMSQ scores indicating high dementia risk. An additional strength that gives this study its broad implications is that olfaction is predictive of dementia even in cognitively intact older adults, extending prior work with high‐risk populations and smaller, more‐homogenous samples.1-7

Why would olfactory dysfunction precede the development of dementia? One potential explanation is that the neuropathology underlying dementia, such as AD (amyloid‐β plaques and paired helical filament tau tangles), may begin earlier in the olfactory system than the cortex.19-21 If so, this type of neuropathology in the olfactory system would impair its function before the detrimental effects in other parts of the central nervous system, including cognition. A postmortem study of brains obtained at autopsy of older adults who had completed olfactory testing before death (mean ± standard deviation of 2.2 ± 1.2 years before death) found that neuropathological findings associated with AD accounted for 12% of the variation in odor identification ability.22 The association between olfactory dysfunction and dementia could also arise from other shared pathological mechanisms to which the olfactory system is more vulnerable, such as decreased age‐related regenerative capacity, reduced physiological repair, or worsening immunopathology. Additional studies will be needed to test and fine‐tune these hypotheses.

On a practical basis for clinicians, a validated five‐item odor identification test10, 11 can potentially serve as an efficient, low‐cost component of the physical examination that provides useful information in assessing older adults at risk of dementia. This tool is a noninvasive biomarker that provides additional information to other relevant clinical information, established risk factors, and neuropsychological testing to aid in an earlier diagnosis of dementia. The ability to identify individuals at risk of dementia before overt cognitive impairment would allow for earlier intervention, with the potential to improve outcomes, and would offer individuals and their families more time to plan ahead.

In addition to olfactory testing, several biomarkers for dementia have been proposed, including cerebrospinal fluid biomarkers (e.g., amyloid‐β and tau concentrations), structural brain imaging (hippocampal volume23), and inflammatory molecules.24 We found that our five‐item odor identification test had a sensitivity of 47% and a specificity 79% 5 years in advance of any evidence of cognitive impairment. These characteristics compare reasonably with other proposed dementia biomarkers when cognitive decline is already in process; for example, a recent Cochrane Review found that, in individuals with mild cognitive impairment, amyloid‐β in cerebrospinal fluid has a sensitivity of 81% at the median specificity of 64% for predicting conversion to AD.25 Mild cognitive impairment is considered to be a precursor to AD, but despite efforts to identify biomarkers for dementia, none of the candidate biomarkers have achieved the appropriate screening characteristics to recommend their use in the general population.26 The U.S. Preventive Services Task Force gives screening for cognitive impairment in older adults an “I” grade, concluding that the current evidence is insufficient to assess the balance of benefits and harms. More‐detailed study of the additional value of olfactory testing in this clinical context is warranted.

We found that the PPV of olfactory dysfunction in predicting a dementia diagnosis within 5 years was 9% in home‐dwelling older Americans, meaning that 91% of older adults who failed our olfactory test did not develop dementia within the 5‐year follow‐up period. The PPV of a test depends on the prevalence of disease in the population studied, indicating that the PPV of olfactory dysfunction will be greater in at‐risk populations. Furthermore, it is likely that the PPV will improve as the follow‐up period increases, given that risk of dementia increases with age.

Further research is needed to determine the test characteristics of olfactory dysfunction in different populations and over different follow‐up periods. Regardless of test characteristics, primary care physicians will need to thoughtfully evaluate when olfactory testing is appropriate for their individual patients, taking into consideration the benefits of early dementia risk stratification given the lack of available therapies and the emotional and financial harms that can result from misdiagnosis.

Beyond aiding in earlier diagnosis of dementia by alerting physicians to consider other factors that may affect disease development, olfactory testing may help distinguish clinically between different dementia subtypes. Cross‐sectional studies have shown associations between olfactory dysfunction and vascular dementia and frontotemporal dementia.27, 28 Prior studies suggest that different types of olfactory disability (e.g., odor identification, odor discrimination, odor threshold) may be associated with different forms of dementia.28 Finally, olfactory testing may be useful in predicting progression of disease and response to treatment.29 This remains to be tested in future work.

Our study has several limitations. As our primary outcome, we rely on interview reports of physician‐diagnosed dementia, and we are therefore most likely underestimating the incidence of new dementia cases, although proxy reports of dementia are reasonably accurate when compared with psychometric testing.14-16 It is likely that psychometric testing would reveal a greater incidence of dementia were it not infeasible in a time‐limited, many‐item, and omnibus nationally representative survey.23 In addition, although we controlled for many known confounders, as in any cohort analysis, there may be additional confounders associated with olfactory function and dementia that are unaccounted for in our analyses, such as smoking and depression.

In summary, older adults with olfactory dysfunction were twice as likely to develop dementia 5 years later as those with normal olfaction. Use of simple olfactory testing in the primary care setting may provide an opportunity for targeted early interventions to reduce the attendant morbidity and public health burden of dementia.