Abstract
IMPORTANCE
To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD), markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk.
OBJECTIVE
To examine associations of impaired olfaction with incident MCI subtypes, and progression from MCI subtypes to AD dementia.
DESIGN, SETTING, AND PARTICIPANTS
Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging were clinically evaluated at baseline and every 15-months thereafter, and classified as having normal cognition, MCI (amnestic, aMCI and nonamnestic, naMCI), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function.
MAIN OUTCOMES AND MEASURES
Mild cognitive impairment, AD dementia, longitudinal change in cognitive performance measures.
RESULTS
Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by decrease in number of correct responses in B-SIT score, and an increased risk of aMCI. Compared to the upper B-SIT quartile (Q4, best scores), hazard ratios (HR) were 1.12; P = 0.68 for Q3; HR, 1.95; P =0.003 for Q2; and HR, 2.18; P = 0.001 (worst scores; p for trend <0.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD, with a significant dose-response with worsening B-SIT quartiles. Compared to Q4, HR estimates were 3.02, P = 0.038 for Q3; HR, 3.63; P = 0.024 for Q2; and HR, 5.20; P = 0.001 for Q1. After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10; p < 0.001), and improved the model concordance.
CONCLUSIONS AND RELEVANCE
Olfactory impairment predicts incident aMCI and progression from aMCI to AD. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life, and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress.
Loss of odor identification has been associated with plaques and tangles in the olfactory bulb, entorhinal cortex and the CA1 regions of the hippocampus in autopsy studies.1 Consistent with this, several clinic-based, case-control, cross-sectional or selected participant studies have demonstrated associations of olfactory loss with AD dementia, cognitive decline or mild cognitive impairment (MCI).2-6 This suggests that impairment in odor identification may be a marker for risk of amnestic MCI (aMCI) due to AD or may predict progression from aMCI to AD dementia. In addition, anosmia has been associated with Lewy bodies, suggesting that impaired olfaction may also be a marker for Lewy Body Dementia7 and with vascular dementia.8 There are several longitudinal studies on olfactory impairment and progression from MCI to dementia,3,9-13 but fewer on the association with MCI,2,4,5,10 Studies on olfaction and MCI have often been conducted in cross-sectional or clinic-based studies, and in studies of small sample size or short duration of follow-up.4,14-16 Furthermore, few studies have investigated the associations of olfaction with MCI subtypes, or with progression from MCI to AD dementia or non-AD dementia in a large population-based cohort. Thus we sought to replicate previous findings on the association of olfactory impairment with risk of MCI (and MCI subtypes) and progression from MCI and its subtypes to AD or non-AD dementia in a large, prospective, population-based study.
Methods
Study Design and Participants
The Mayo Clinic Study of Aging (MCSA) was established in 2004 to study risk factors for MCI and dementia.17-19 The initial cohort consisted of Olmsted County, Minnesota residents aged 70 – 89 years on October 1, 2004 who were randomly selected from an enumeration of the county population using the Rochester Epidemiology Project (REP) medical records linkage system. In 2008, we began ongoing recruitment using the same protocols as at baseline. This study includes participants who were enrolled between 2004-2010 and were evaluated in-person. All protocols were approved by the institutional review boards of the Mayo Clinic and the Olmsted Medical Center, and participants provided written informed consent.
In-person Evaluation and Assessment of Cognitive Function
At baseline, each participant and an informant were interviewed using questions about memory (participant), Beck's Depression Inventory, Beck's Anxiety Inventory, the Clinical Dementia Rating (CDR) scale,20 Functional Activities Questionnaire (FAQ)21 and Neuropsychiatric Inventory Questionnaire (NPI) (informant). Participants were evaluated by a physician to obtain a medical history, assess global cognition using the Short Test of Mental Status (STMS),22 complete a modified Unified Parkinson's Disease Rating Scale (UPDRS),23 and perform a neurological examination. Participants underwent neuropsychological testing to assess performance in 4 cognitive domains: memory (Auditory Verbal Learning Test Delayed Recall Trial; WMS-R Logical Memory-II and Visual Reproduction-II),24-26 2) executive function (Trail Making Test B, WAIS-R Digit Symbol Substitution),27-29 3) language (Boston Naming Test, category fluency test),30-32 and 4) visuospatial skills (WAIS-R Picture Completion, Block Design).29 The raw test scores were age-adjusted using normative data, summed and scaled to compute domain z scores.33
The data for each participant were reviewed for a diagnosis of MCI (amnestic [aMCI] and nonamnestic [naMCI], single and multidomain) as previously defined;17-19 dementia including AD dementia;34,35 or normal cognition.17,18,33 Participants were followed at 15-month intervals for incident diagnoses of MCI or dementia using the same protocols as at baseline.
Assessment of Olfactory Function
Olfaction was assessed using the Brief Smell Identification Test (B-SIT)36 which consists of six food-related and six nonfood-related smells (banana, chocolate, cinnamon, gasoline, lemon, onion, paint thinner, pineapple, rose, soap, smoke, and turpentine). Participants were required to scratch, sniff and select one of 4 possible tests. The B-SIT score was computed as the sum of the correct responses for persons with ≤2 missing responses; a score of 0.25 was assigned for each missing response.2,6
Statistical Analyses
Proportional Hazards Models
Follow-up time was computed from the time of administration of the B-SIT (baseline) to the midpoint between the last assessment as cognitively normal (or MCI) and the date of the incident event MCI (or dementia). Persons who died or were lost to follow-up prior to an event were censored at their last follow-up. The association of B-SIT score with 1) incident MCI and 2) progression from MCI to dementia was examined using Cox proportional hazards models. Olfaction was characterized as the continuous or categorical B-SIT score; categories were based on B-SIT quartiles for cognitively normal participants; osmia categories: anosmia (score <6), microsmia (men 6-10, women 6-10.25), normosmia (men 10.25-12; women 10.5-12) as previously describe;4 and dichotomized as < 9 (impaired) vs. ≥ 9.3 The basic models were adjusted for sex and education, with age as the time scale. Potential confounding by type 2 diabetes, hypertension, stroke, apolipoprotein E (APOE) ε4 allele, self-reported alcohol problem and ever smoking, baseline cognitive domain scores, and STMS was examined in separate models, but there was no confounding by these covariates and the data are not reported. Interaction of the B-SIT score with sex and with each of the above covariates was examined.
We determined whether B-SIT score predicts MCI and improves model fit for MCI after adjusting for predictors of MCI included in a risk score for MCI developed in our cohort.37 For each participant, we computed a risk score from 1) a basic risk prediction model using variables obtainable in the outpatient setting (education, subjective memory complaints, alcohol problems, stroke, diabetes, atrial fibrillation, smoking, dyslipidemia or hypertension in midlife, maximum adult BMI, marital status; 2) the basic model plus the STMS, and 3) the augmented model including variables in the basic model, STMS, informant-based measures (FAQ, CDR), UPDRS, gait speed, and neuropsychiatric symptoms [from NPI, BDI, BAI],).37 We ran separate Cox models to predict MCI including the risk scores with and without the B-SIT score, and computed the differences in model fit assessed as the C-statistic (concordance).
Mixed Effects Models
Among cognitively normal participants, we used linear mixed effects models to investigate the association of B-SIT score with decline in cognitive z-scores and the STMS during follow-up. All the analyses were performed using SAS version 9.3 (Cary, NC).
Results
Characteristics of Cognitively Normal Participants
Of 1,630 participants who were cognitively normal at the time of the smell test, 33 died before follow-up and 167 were lost to follow-up. Among 1,430 cognitively normal participants included, the mean (SD) age was 79.5 (5.3) years, 49.4% were men, mean education was 14.3 years, and 25.4% were APOE ε4 carriers (Table 1). Over a mean 3.5 years of follow-up, there were 250 incident MCI cases; the frequency of incident MCI decreased with increasing B-SIT scores.
Table 1.
Characteristics of Cognitively Normal Participants by B-SIT Score Quartiles at Baseline
| Characteristics* | All N=1430 | Q1 N=298 | Q2 N=409 | Q3 N=294 | Q4 N=429 | P for Trend† |
|---|---|---|---|---|---|---|
| Smell score range | 1-12 | 0-7.5 | 8-9 | 9.25-10.5 | 11-12 | |
| Male, n (%) | 706 (49.4) | 181 (60.7) | 215 (52.6) | 139 (47.3) | 171 (39.9) | <0.001 |
| Age y, | 79.5 (5.3) | 81.3 (5.4) | 80.1 (5.3) | 78.9 (5.2) | 78.0 (4.8) | <0.001 |
| Education y, | 14.3 (2.8) | 14.3 (3.1) | 14.1 (2.7) | 14.1 (2.7) | 14.7 (2.7) | 0.024 |
| APOE ε 4 | 362 (25.4) | 74 (24.9) | 115 (28.3) | 71 (24.2) | 102 (23.8) | 0.451 |
| Diabetes | 274 (19.2) | 49 (16.4) | 84 (20.5) | 69 (23.5) | 72 (16.8) | 0.072 |
| Hypertension | 1120 (78.3) | 241 (80.9) | 328 (80.2) | 229 (77.9) | 322 (75.1) | 0.194 |
| Stroke | 57 (4.0) | 13(4.4) | 18 (4.4) | 13 (4.4) | 13 (3.0) | 0.691 |
| Smoking, ever | 678 (47.4) | 153 (51.3) | 193 (47.2) | 139 (47.3) | 193 (45.0) | 0.776 |
| Alcohol problem | 53 (3.7) | 13 (4.5) | 14 (3.4) | 13 (4.4) | 13 (3.1) | 0.689 |
| Follow-up, yr | 3.5 (1.1) | 3.4 (1.2) | 3.6 (1.1) | 3.5 (1.1) | 3.6 (1.1) | 0.058 |
| Incident MCI‡ | 250 (17.5) | 72 (24.2) | 84 (20.5) | 42 (14.3) | 52 (12.1) | <0.001 |
| Cognitive domain z-score | ||||||
| Memory | 0.0 (1.0) | −0.2 (1.0) | 0.0 (1.0) | 0.0 (1.0) | 0.2 (1.0) | <0.001 |
| Exec Function | 0.0 (1.0) | −0.3 (1.1) | −0.1 (1.0) | 0.1 (0.9) | 0.2 (1.0) | <0.001 |
| Language | 0.0 (1.0) | −0.3 (1.1) | −0.1 (1.0) | 0.1 (0.9) | 0.3 (1.0) | <0.001 |
| Visuospatial | 0.0 (1.0) | −0.1 (1.0) | −0.1 (1.1) | 0.0 (1.0) | 0.1 (1.0) | 0.182 |
| Global | 0.0 (1.0) | −0.3 (1.0) | −0.1 (1.0) | 0.1 (0.9) | 0.2 (1.0) | <0.001 |
| Cognitive test scores | ||||||
| AVLT | 7.7 (3.4) | 6.9 (3.4) | 7.6 (3.3) | 7.9 (3.6) | 8.1 (3.4) | <0.001 |
| Logical Memory II | 18.7 (7.3) | 18.1 (7.1) | 18.2 (7.0) | 18.9 (7.2) | 19.6 (7.7) | 0.038 |
| Visual Reprod II | 22.4 (8.0) | 21.0 (8.2) | 22.2 (8.1) | 22.5 (7.7) | 23.6 (7.9) | 0.001 |
| DSS | 43.7 (10.0) | 41.1 (9.8) | 42.8 (10.4) | 44.7 (9.3) | 45.7 (9.8) | <0.001 |
| TMTB | 195.4(48.2) | 185.7 (54.4) | 193.5 (46.3) | 197.7 (49.1) | 202.4 (43.7) | <0.001 |
| BNT | 55.1 (4.2) | 54.4 (5.0) | 55.0 (4.2) | 55.3 (3.7) | 55.6 (3.8) | 0.020 |
| Category Fluency | 43.3 (9.3) | 39.7 (8.6) | 42.2 (8.9) | 43.8 (9.0) | 46.4 (9.5) | <0.001 |
| Picture Completion | 13.4 (3.1) | 13.4 (2.8) | 13.1 (3.3) | 13.5 (3.1) | 13.6 (3.0) | 0.215 |
| Block Design | 23.6 (8.1) | 22.9 (8.3) | 23.4 (8.2) | 23.7 (7.7) | 24.2 (8.1) | 0.378 |
| STMS | 34.7 (2.3) | 34.4 (2.4) | 34.5 (2.3) | 34.7 (2.1) | 35.0 (2.3) | 0.001 |
APOE, apolipoprotein E; B-SIT, Brief Smell Identification Test; Exec Function, executive function; AVLT, Auditory Verbal Learning Test; Visual Reprod, Visual Reproduction; DSS, Digit symbol Substitution; TMTB, Trail Making Test B; BNT, Boston Naming Test; STMS, Short Test of Mental Status.
Estimates are reported as mean (standard direction) or number (percent).
P for trend based on chi-squared test for categorical variables and Kruskal Wallis test for continuous variables.
MCI subtype was unknown for 38 participants who participated only by telephone at the time of MCI diagnosis and did not undergo neuropsychological testing.
Characteristics of Participants with Prevalent MCI
Of 317 participants with prevalent MCI, 75 had no follow-up and 21 died. Of the 221 included (aMCI, 185; naMCI, 36), the frequency of MCI decreased with increasing B-SIT score (Table 2). Over a mean 3.1 years of follow-up, there were 64 incident dementia cases. The frequency of any or AD dementia decreased, and cognitive performance increased with increasing B-SIT scores.
Table 2.
Characteristics of Prevalent MCI Cases by B-SIT Scores at Baseline
| Characteristics* | All N=221 | Q1 N=59 | Q2 N=45 | Q3 N=54 | Q4 N=63 | P for Trend† |
|---|---|---|---|---|---|---|
| Smell score range | 1-12 | 1-5 | 5.25-7.5 | 8-9.5 | 10-12 | |
| Male, n (%) | 122 (55.2) | 34 (57.6) | 31 (68.9) | 26 (48.1) | 31 (49.2) | 0.136 |
| Age, y | 82.1 (6.0) | 84.0 (5.0) | 82.8 (6.2) | 81.5 (5.7) | 80.4 (6.4) | 0.005 |
| Education, y | 13.4 (2.9) | 13.2 (3.2) | 14.1 (3.2) | 13.3 (2.7) | 13.1 (2.6) | 0.289 |
| APOE ε 4† | 73 (33.2) | 18 (31.0) | 19 (42.2) | 17 (31.5) | 19 (30.2) | 0.550 |
| Diabetes | 63 (28.5) | 14 (23.7) | 16 (35.6) | 17 (31.5) | 16 (25.4) | 0.514 |
| Hypertension | 189 (85.5) | 54 (91.5) | 35 (77.8) | 48 (88.9) | 52 (82.5) | 0.184 |
| Stroke | 29 (13.1) | 7 (11.9) | 8 (17.8) | 6 (11.1) | 8 (12.7) | 0.768 |
| Smoking, ever | 101 (45.7) | 28 (47.5) | 18 (40.0) | 24 (44.4) | 31 (49.2) | 0.802 |
| Alcohol problem | 11 (5.0) | 3 (5.1) | 1 (2.3) | 3 (5.6) | 4 (6.5) | 0.802 |
| Follow-up, y | 3.1 (1.1) | 2.9 (1.2) | 2.9 (1.0) | 3.2 (1.1) | 3.2 (1.2) | 0.343 |
| Incident dementia‡ | 64 (29.0) | 26 (44.1) | 10 (22.2) | 19 (35.2) | 9 (14.3) | 0.002 |
| Incident AD | 54 (24.4) | 23 (39.0) | 9 (20.0) | 14 (25.9) | 8 (12.7) | -- |
| Cognitive domain z-scores | ||||||
| Memory | −1.9 (0.9) | −2.1 (0.8) | −2.0 (0.8) | −1.9 (1.0) | −1.6 (0.8) | 0.004 |
| Executive function | −1.4 (1.4) | −1.7 (1.3) | −1.5 (1.4) | −1.5 (1.5) | −1.1 (1.3) | 0.180 |
| Language | −1.6 (1.4) | −1.9 (1.4) | −1.6 (1.5) | −1.7 (1.3) | −1.2 (1.3) | 0.028 |
| Visuospatial | −1.0 (1.1) | −1.2 (1.2) | −0.8 (1.1) | −1.1 (1.3) | −1.0 (1.0) | 0.414 |
| Global | −1.9 (1.1) | −2.3 (1.1) | −1.9 (1.0) | −2.1 (1.0) | −1.6 (0.8) | 0.015 |
| Cognitive test scores | ||||||
| AVLT | 2.8 (3.0) | 2.1 (2.4) | 2.2 (2.8) | 2.8 (3.0) | 4.1 (3.2) | 0.002 |
| Logical memory II | 8.8 (6.3) | 8.4 (6.5) | 7.8 (4.8) | 9.4 (6.7) | 9.4 (6.7) | 0.684 |
| Visual Reprod II | 9.6 (7.9) | 8.1 (7.6) | 9.3 (8.8) | 8.4 (7.4) | 12.0 (7.4) | 0.006 |
| DSS | 33.9 (10.2) | 30.3 (8.2) | 33.5 (9.4) | 34.8 (11.8) | 36.6 (10.1) | 0.018 |
| TMTB | 125.2 (76.3) | 118.5(79.1) | 123.2 (77.0) | 115.9 (77.9) | 139.3 (72.1) | 0.390 |
| BNT | 49.1 (7.3) | 47.5 (7.4) | 48.8 (8.1) | 49.4 (6.8) | 50.4 (6.7) | 0.128 |
| Category Fluency | 33.0 (9.0) | 31.6 (8.9) | 33.0 (9.2) | 31.4 (8.3) | 35.6 (9.1) | 0.025 |
| Picture Completion | 10.4 (3.7) | 10.1 (3.9) | 10.9 (3.6) | 10.1 (4.0) | 10.5 (3.5) | 0.694 |
| Block Design | 17.5 (8.2) | 16.3 (8.6) | 19.3 (8.3) | 17.3 (8.7) | 17.7 (7.2) | 0.322 |
| STMS | 30.1 (2.7) | 30.1 (2.3) | 29.8 (2.9) | 30.1 (2.7) | 30.5 (2.7) | 0.637 |
AVLT, Auditory Verbal Learning Test; APOE ε4, apolipoprotein E; B-SIT, Brief Smell Identification Test; Visual Reprod, Visual Reproduction; DSS, Digit Symbol Substitution; TMT B, Trail Making Test B; BNT, Boston Naming Test; STMS, Short Test of Mental Status; AD, Alzheimer's disease.
Estimates represent mean (standard deviation) or number (percent)
P for trend; chi-squared test for categorical variables and Kruskal Wallis test for continuous variables.
Dementia type was unknown for 2 subjects; only 8 subjects had non-Alzheimer's type dementia
Impaired Olfaction and Incident MCI
The risk of MCI increased with decreasing B-SIT scores (Table 3). There was a significant dose-response association across worsening olfaction categories. The associations remained significant after adjustment for or exclusion of persons with a history of stroke (data are not presented). There was no significant interaction of smell with sex or with APOE ε4 allele. However, the hazard ratio (HR [95% confidence interval]) for MCI in men with B-SIT scores <9 (vs. ≥ 9) was higher (HR, 2.35 [1.59, 3.49]; p < 0.001] than that for women with scores <9 (HR, 1.54 [1.10, 2.18]; p = 0.013; p for interaction = 0.11). Similarly, HR in APOE ε4 carriers with BSIT scores <9 were higher (2.09 [1.35, 3.24]) than for ε4 non-carriers with scores <9 (HR, 1.72 [1.26, 2.36], both p <0.001; p for interaction = 0.47).
Table 3.
Association of B-SIT Scores with Risk of Any MCI, MCI Subtypes, Any Dementia, and Alzheimer's Disease
| Incident MCI* | Incident Amnestic MCI | Incident Non-amnestic MCI | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Smell test score | N/events | HR 95% CI | P | N/events | HR 95% CI | P | N/events | HR (95% CI) | p |
| Continuous† | 1430/250 | 1.10 (1.05, 1.16) | <0.001 | 1392/162 | 1.13 (1.06, 1.20) | <0.001 | 1392/50 | 0.97 (0.85, 1.11) | 0.68 |
| Quartiles | |||||||||
| Q4 (11-12) | 429/52 | 1.00 (reference) | 425/30 | 1.00 (reference) | 425/18 | 1.00 (reference) | |||
| Q3 (9.25-10.5) | 294/42 | 1.07 (0.71, 1.61) | 0.76 | 283/24 | 1.12 (0.65, 1.92) | 0.68 | 283/7 | 0.55 (0.23, 1.32) | 0.18 |
| Q2 (8-9) | 409/84 | 1.47 (1.03, 2.09) | 0.033 | 402/62 | 1.95 (1.25, 3.03) | 0.003 | 402/15 | 0.73 (0.36, 1.48) | 0.38 |
| Q1 (1-7.5) | 298/72 | 1.82 (1.26, 2.64) | 0.001 | 282/46 | 2.18 (1.36, 3.51) | 0.001 | 282/10 | 0.73 (0.32, 1.64) | 0.45 |
| P for trend | <0.001 | <0.001 | 0.46 | ||||||
| Categorical | |||||||||
| Normosmia | 431/52 | 1.00 (reference) | 427/30 | 1.00 (reference) | 427/18 | 1.00 (reference) | |||
| Microsmia | 863/164 | 1.39 (1.01, 1.91) | 0.043 | 836/111 | 1.70 (1.13, 2.57) | 0.011 | 836/26 | 0.65 (0.35, 1.20) | 0.17 |
| Anosmia | 136/34 | 1.82 (1.16, 2.86) | 0.009 | 129/21 | 2.15 (1.21, 3.81) | 0.009 | 129/6 | 0.92 (0.34, 2.47) | 0.87 |
| P for trend | 0.007 | 0.004 | 0.46 | ||||||
| Dichotomized | |||||||||
| ≥ 9 | 953/130 | 1.00 (reference) | 935/79 | 1.00 (reference) | 935/33 | 1.00 (reference) | |||
| <9 | 477/120 | 1.85 (1.43, 2.39) | <0.001 | 457/83 | 2.21 (1.61, 3.03) | <0.001 | 457/17 | 1.01 (0.55, 1.86) | 0.96 |
| Any MCI to Dementia‡ | aMCI to AD | |||||
|---|---|---|---|---|---|---|
| Continuous† | 221/64 | 1.15 (1.05, 1.26) | 0.002 | 185/49 | 1.19 (1.07, 1.32) | <0.001 |
| Quartiles | ||||||
| Q4 (10-12) | 63/9 | 1.00 (reference) | 47/5 | 1.00 (reference) | ||
| Q3 (8-9.5) | 54/19 | 2.61 (1.17, 5.86) | 0.020 | 49/13 | 3.02 (1.06, 8.57) | 0.038 |
| Q2 (5.25-7.5) | 45/10 | 1.89 (0.75, 4.75) | 0.18 | 35/9 | 3.63 (1.19, 11.1) | 0.024 |
| Q1 (0-5) | 59/26 | 3.48 (1.59, 7.61) | 0.002 | 54/22 | 5.20 (1.90, 14.2) | 0.001 |
| P for trend | 0.004 | 0.001 | ||||
| Dichotomized | ||||||
| ≥9 | 94/20 | 1.00 (reference) | 77/14 | 1.00 (reference) | ||
| <9 | 127/44 | 1.82 (1.05, 3.16) | 0.032 | 108/35 | 2.17 (1.14, 4.15) | 0.019 |
B-SIT, Brief Smell Identification Test; MCI, mild cognitive impairment; aMCI, amnestic MCI, naMCI, nonamnestic MCI; Q1, Q2, Q3, Q4, 1st to 4th quartiles; AD Alzheimer's disease.
Estimates are adjusted for sex and education, with age as the time scale. MCI subtype was unknown for 38 participants who participated only by telephone evaluation at the time of MCI diagnosis and did not undergo neuropsychological testing.
B-SIT score here represents the number of incorrect responses. Alternatively, with B-SIT scored as the number of correct responses, the corresponding estimate (HR, 95% confidence intervals) for risk of incident MCI is 0.91 (0.86, 0.96), p < 0.001. This estimate is comparable to estimates for baseline cognitive test scores in predicting incident MCI: Auditory Verbal Learning Test: 0.81(0.78, 0.85), p <0.001; Logical Memory II: 0.91 (0.89, 0.93), p <0.001; Visual Reproduction II: 0.93 (0.91, 0.94), p <0.001; Picture completion: 0.92 (0.88, 0.95), p <0.001; Block Design: 0.93 (0.92, 0.95), p < 0.001; Digit Symbol Substitution: 0.93 (0.92, 0.95), p < 0.001; Trail Making Test B: 0.99 (0.99, 0.99), p <0.001; Boston Naming Test: 0.90 (0.88, 0.92), p < 0.001; Category Fluency: 0.93 (0.91, 0.95), p < 0.001.
Estimates are not reported for osmia groups because there were no dementia events among the normosmia group for comparison.
Impaired Olfaction and MCI Subtypes
Impaired olfaction was associated with any MCI and with aMCI (Table 3). With additional adjustment for baseline global z score and APOE ε4 allele, the risk of aMCI for the worst B-SIT categories remained significantly elevated for Q1 versus Q4: HR, 1.67, [1.03, 2.73]; p = 0.039, p for trend = 0.022) and for B-SIT < 9 vs. ≥ 9: 1.91 [1.37, 2.66], p < 0.001), and marginally significant for anosmia versus normosmia: HR, 1.69 [0.93, 3.05], p = 0.084, p for trend = 0.072). HRs for the intermediate categories were non-significantly elevated (data not presented). B-SIT score was not associated with naMCI.
Impaired Olfaction and changes in Cognitive Z-Scores
In linear mixed effects models, each unit decrease in B-SIT score was correlated with worse performance in domain z scores at baseline (Table 4). Longitudinally, each unit decrease in baseline B-SIT score was significantly associated with decline in performance in memory (β = −0.013, p < 0.001), executive function (β = −0.016, p < 0.001), language (β = −0.013, p < 0.001), and in global z scores (β = −0.015, p < 0.001). Similar cross-sectional and longitudinal associations patterns were present for the individual test scores, except for Picture Completion.
Table 4.
Cross-Sectional and Longitudinal Associations of Smell Test Scores with Cognitive Domain Z-Scores in Cognitively Normal Individuals (Mixed Effect Models)
| Cognitive scores | Baseline β(SE) | P | Time β(SE) | P | Smell*time β(SE) | P |
|---|---|---|---|---|---|---|
| Domain z scores | ||||||
| Memory | −0.036 (0.01) | 0.001 | −0.043 (0.01) | <0.001 | −0.013 (0.002) | <0.001 |
| Exec function | −0.022 (0.01) | 0.041 | −0.117 (0.01) | <0.001 | −0.016 (0.003) | <0.001 |
| Language | −0.065 (0.01) | <0.001 | −0.074 (0.01) | <0.001 | −0.013 (0.002) | <0.001 |
| Visuospatial | −0.009 (0.01) | 0.42 | −0.037 (0.01) | 0.004 | −0.003 (0.002) | 0.23 |
| Global | −0.043 (0.01) | <0.001 | −0.091 (0.01) | <0.001 | −0.015 (0.002) | <0.001 |
| Test z-scores | ||||||
| AVLT | −0.024 (0.01) | 0.025 | −0.041 (0.01) | <0.001 | −0.009 (0.003) | <0.001 |
| Log Memory II | −0.024 (0.01) | 0.030 | −0.019 (0.01) | 0.005 | −0.009 (0.003) | 0.002 |
| Visual Reprod II | −0.030 (0.01) | 0.006 | −0.034 (0.01) | <0.001 | −0.009 (0.003) | 0.003 |
| DSS | −0.027(0.01) | 0.013 | −0.087 (0.01) | <0.001 | −0.008 (0.002) | <0.001 |
| TMTB | −0.011 (0.01) | 0.31 | −0.114 (0.01) | <0.001 | −0.017 (0.003) | <0.001 |
| BNT | −0.043 (0.01) | <0.001 | −0.036 (0.01) | <0.001 | −0.013 (0.002) | <0.001 |
| Cat Fluency | −0.063 (0.01) | <0.001 | −0.084 (0.01) | <0.001 | −0.008 (0.002) | 0.001 |
| Pic Completion | −0.007 (0.01) | 0.52 | 0.008 (0.01) | 0.22 | −0.000 (0.003) | 0.90 |
| Block Design | −0.005 (0.01) | 0.63 | −0.071 (0.01) | <0.001 | −0.006 (0.002) | 0.007 |
| STMS | −0.023 (0.03) | 0.36 | −0.113 (0.02) | <0.001 | −0.033 (0.009) | <0.001 |
Models are adjusted for age, sex, education, and test naïve (i.e. whether the participant was at baseline or not). Baseline represents the cross-sectional association between smell test score and cognitive performance; time (refers to the annual change in the cognitive z score (the outcome), and smell*time refers to the annual rate of change in the cognitive z score for each unit decrease in the smell score.
Impact of B-SIT Score on Risk Prediction Models for MCI
The B-SIT score (continuous) was significantly associated with MCI in a model with the basic risk scores (HR, 1.10 [1.04, 1.16]; p<0.001); the C-statistic improved from 0.590 to 0.620. In the basic plus STMS model, the B-SIT remained significant (HR, 1.10 [1.04, 1.16]; p<0.001); the model C-statistic improved modestly from 0.704 to 0.717. Similarly, in the augmented model, the B-SIT score remained significant (HR, 1.09 [1.03, 1.16]; p=0.002) and model C-statistic improved from 0.716 to 0.726.
Impaired Olfaction and Progression from MCI to Dementia
Among 221 prevalent MCI cases (122, single domain aMCI; 63, multidomain aMCI; and 36, naMCI), the risk of dementia increased with decreasing B-SIT, with a significant dose-response across B-SIT categories (Table 3). The worst B-SIT categories strongly predicted progression from aMCI to AD dementia. In multivariable models, the estimates for the worst olfaction categories remained significant even after additional adjustment for baseline global z score (Q1 versus Q4: HR, 3.32 [95% CI 1.16, 9.44]), p =0.025); <9 versus ≥ 9: 2.07 (HR, [95% CI 1.01, 4.25); p = 0.048), and after further adjustment for stroke (data not presented).
Discussion
In this elderly cohort, impaired olfaction was associated with incident MCI and aMCI and with greater decline in cognitive performance during follow-up. After accounting for several established risk factors for MCI, the smell score remained significantly associated with MCI and improved the model fit for predicting MCI. Impaired olfaction was associated with progression from MCI to dementia, and from aMCI to AD dementia.
Clinical implications of our findings are that odor identification tests may have utility for early detection of persons at risk of cognitive outcomes. The B-SIT is easily administered in the outpatient setting, does not require administration or interpretation by trained personnel, has normative data, is relatively inexpensive, and non-invasive. Thus, the B-SIT could be beneficial for screening to identify cognitively normal persons and MCI cases who could benefit from early interventions to prevent or modulate risk for progression. The findings also suggest that a combination of the B-SIT with other predictors of AD dementia may have utility for identifying persons who should undergo expensive or invasive diagnostic testing to detect AD dementia pathology or for recruitment to primary or secondary prevention trials. The latter, however, requires further evaluation.
The results from mixed models for continuous cognitive outcomes are consistent with the results for the dichotomous outcome of MCI risk. They suggest that impaired olfaction is associated with worse cognitive performance among cognitively normal individuals, and predicts decline in cognitive performance in nearly all cognitive domains. The greater declines in memory, executive function, and language suggest that brain regions that mediate performance in these domains may be involved early in the disease process.
Potential mechanisms for the present findings may involve neurodegenerative changes in the olfactory bulb and tracts, and central brain regions that involve memory and olfaction.38 The olfactory bulb is thought to be involved since smell loss occurs only in neurodegenerative conditions where there is olfactory pathology such as AD and Parkinson's disease.39 Markers of AD pathology (neurofibrillary tangles) have been observed in the olfactory bulb and tracts prior to onset of AD dementia-related symptoms, suggesting that olfactory deficits may be early markers of AD risk.38,40,41 Presence of AD pathology in the entorhinal cortex, hippocampus and other temporal regions, lead to an inability to store and retrieve memories of smell, and thereby to correctly identify odors.42,43 Cholinergic deficits resulting from several mechanisms including damage to the nucleus basalis (a key cholinergic nucleus that projects to brain regions involved in olfaction) are involved in olfactory loss in AD dementia and Parkinson's disease, and helps distinguish between neurodegenerative diseases with (Parkinson's disease, AD) and without (progressive supranuclear palsy, corticobasal syndrome) impairment in olfaction.39 Reduced levels of choline acetyl transferase and dopamine in the olfactory tubercle and other brain regions,44 and decreased norepinephrine related to damage or neurodegeneration in the locus coeruleus (a key source of norepinephrine to the olfactory bulb) and have been hypothesized to play a role in impaired olfaction in AD.
Our findings replicate those from other longitudinal studies on olfaction and incident MCI or cognitive decline. In a multi-ethnic urban community, impaired olfaction was a stronger predictor of incident MCI than episodic memory.10 In the Rush Memory and Aging study, worse olfaction was associated with incident MCI and declines in cognitive outcomes.2 In other studies, impaired olfaction was associated with declines in verbal and visual memory,5 and in global cognition.4
Cross-sectional and case-control studies have also reported associations of impaired olfaction and MCI or cognitive measures. In a case-control study of MCI and AD cases recruited from a neuropsychology clinic, cases had significantly worse scores than controls.14 In a cross-sectional study of MCI cases, severe hyposmia was associated with worse performance on memory tests and executive function.15 Among middle-aged participants, impaired olfaction was associated with worse performance on tests of executive function.45 In the Rush Memory and Aging study, worse olfaction was associated with worse cognitive performance at baseline,2 and in a Chinese sample, impaired olfaction was associated with MCI.16
The association of impaired olfaction with MCI progression to dementia is consistent with longitudinal findings from other studies.9-11 Among patients from a memory clinic and volunteer controls, a combination of markers (smell test scores, functional measures, cognitive test scores, imaging measures), more strongly predicted progression from MCI to dementia than age and MMSE.12 In one prospective study, worse smell scores from a 10-item test predicted conversion from MCI to AD dementia,3 and in another, the B-SIT performed highly in distinguishing between AD dementia cases and controls.13 Cross-sectionally, impaired olfaction was associated with AD in a Japanese cohort.46
Relatively few investigators have specifically examined the associations of MCI subtypes with AD dementia. The strong association for transition from aMCI to AD dementia is consistent with an underlying AD pathophysiology. Consistent with our findings, one study reported a stronger association of impaired olfaction with progression from aMCI to AD dementia than from naMCI to AD dementia, and a combination of the smell test score and memory impairment improved prediction of AD dementia compared to memory scores alone.10 We did not detect an association of impaired olfaction with risk of naMCI due to lack of power (50 incident naMCI cases); we also did not have power to examine associations of prevalent naMCI with risk of non-AD dementias (only 10 incident non-AD dementia cases). By contrast, other investigators have reported associations of impaired olfaction with vascular dementia,8 and with Parkinson's disease and presence of Lewy bodies, with implications for Lewy Body Dementia.7 In contrast to the present findings, one study did not observe an association of impaired olfaction with declines in global cognition (MMSE) or with executive function.5 In a recent study, however, impaired olfaction was associated with AD biomarkers including elevated cortical amyloid, and thinner entorhinal cortex.47
The present findings were robust to changes in cutpoints for olfaction, and the associations persisted even after adjustment for or exclusion of persons with a history of stroke. Despite the absence of a significant interaction with sex and APOE ε4 allele, the estimates and direction of risk were consistent with studies reporting stronger associations of impaired olfaction with cognitive impairment in APOE ε4 allele carriers than non-carriers.4,16,48,49 Consistent with the present study, however, another study did not find a significant interaction of B-SIT score with APOE genotype.5
There are some potential limitations to our study. We did not directly assess odor detection; however, this is unlikely to bias our findings since the odor detection tests correlate highly with odor identification tests, and patients with AD demonstrate deficits in both detection and identification,44,50 and in a number of other neurodegenerative diseases. We excluded 23 participants with Parkinson's disease and 12 with alcoholism (CAGE stage 4),51 but were unable to identify and exclude people with a history of head trauma, allergies, nasal condition or nasal diseases that could impact olfaction if present.52 The predominant northern European ancestry of participants raised questions about generalizability. Nevertheless, studies in multi-ethnic and non-Caucasian cohorts have reported similar associations.10,16,46 The utility of the B-SIT compared to the longer 40-item University of Pennsylvania Smell Identification Test has been questioned.14 However, the B-SIT has been shown to reliably predict cognitive decline and MCI, to distinguish between AD cases and controls in other studies,2-6,13 and to have a test-retest reliability coefficient of 0.71 consistent with the expected estimate for a 12-item test.36,53
There are several strengths of our study. The study was population based, reducing the potential for selection bias. The study included a large cohort of cognitively normal participants and MCI cases with equal representation of both sexes. Reliable and valid information on covariates were abstracted from the community medical records rather than by self-report. Participants were comprehensively characterized for MCI and dementia at each evaluation using previously published criteria and without consideration of previous diagnoses, thereby reducing the potential for bias in ascertainment of diagnoses. The prospective design allowed us to assess the role of impaired olfaction as a marker for early detection of persons at risk for MCI and dementia.
Conclusions
Conclusions Our findings suggest that impaired olfaction is associated with incident aMCI and with progression from aMCI to AD dementia, and may be useful as a marker for early detection of persons at risk for aMCI or AD dementia.
Acknowledgement
Funding/Support: The study was supported by the National Institute on Aging (U01 AG006786, P50 AG016574), the Mayo Foundation for Medical Education and Research, and was made possible by the Rochester Epidemiology Project (R01 AG034676). Dr. Roberts had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Authors’ Contributions:
Study concept and design: Roberts, Petersen
Acquisition, analysis, or interpretation of data: Roberts, Mielke, Machulda, Knopman, Petersen, Vassilaki, Alhurani, Kremers, Christianson
Drafting of the manuscript: Roberts
Critical revision of the manuscript for important intellectual content: Roberts, Mielke, Knopman, Petersen, Vassilaki, Alhurani, Kremers, Christianson, Machulda, Geda
Statistical analysis: Kremers, Christianson
Obtaining funding: Petersen, Roberts, Mielke, Knopman
Administrative, technical, or material support: Petersen, Roberts
Study supervision: Roberts, Kremers, Petersen,
Conflict of Interest Disclosures:
Dr. Roberts receives research funding from the National Institutes of Health (NIH).
Ms. Christianson, Drs. Kremers, Vassilaki and Alhurani report no disclosures.
Dr. Mielke receives research grants from the NIH/NIA, Alzheimer Drug Discovery Foundation, Lewy Body Association, and the Michael J. Fox Foundation.
Dr. Machulda receives research support from the NIH/NIA & NIDCD
Dr. Geda reports no disclosures
Dr. Knopman serves as Deputy Editor for Neurology®; serves on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and for the DIAN study; is an investigator in clinical trials sponsored by TauRX Pharmaceuticals, Lilly Pharmaceuticals and the Alzheimer's Disease Cooperative Study; and receives research support from the NIH.
Dr. Petersen serves on data monitoring committees for Pfizer, Inc., Janssen Alzheimer
Immunotherapy, and is a consultant for Roche, Inc., Merck, Inc. and Genentech, Inc.
Biogen, Inc. Eli Lilly and Co.; receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003), and receives research support from the National Institute of Health.
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