Abstract
Objectives.
Many studies have reported that patients with anosmia exhibit an increased incidence of dementia later in life. However, most of these studies have focused exclusively on individuals aged 65 or older, leaving a gap in research on middle-aged subjects (40–65 years).
Methods.
We conducted a retrospective cohort study using Korea’s National Health Insurance claims data. The study targeted participants aged 40 years and above by randomly selecting 40% of individuals who underwent the 2009 national health check-up. The cohort was divided into two groups: the anosmia group (n=8,023), comprising individuals diagnosed with anosmia between 2006 and 2008, and the control group (n=2,680,534), consisting of the remaining participants. Subsequently, we followed the participants to monitor the occurrence of Alzheimer and vascular dementia from 2011 to 2020.
Results.
After adjusting for various factors, the incidence of Alzheimer dementia was significantly higher in the anosmia group compared to the control group (hazard ratio [HR], 1.15; 95% CI, 1.04–1.28). Stratification by age revealed that the risk of developing dementia was significantly elevated in anosmia patients under 65 years (HR, 1.28; 95% CI, 1.07–1.54), whereas no significant increase was observed in those over 65 years (HR, 1.10; 95% CI, 0.97–1.24). Vascular dementia was not statistically associated with anosmia.
Conclusion.
A diagnosis of anosmia in middle age increases the risk of developing Alzheimer dementia, while no such increase is observed in older individuals.
Keywords: Anosmia, Alzheimer Dementia, Vascular Dementia
INTRODUCTION
Dementia is a clinical syndrome characterized by declines in various cognitive functions, such as memory, language, and judgment, which hinder the performance of daily activities [1]. Among the different types of dementia, Alzheimer disease (AD) is the most common, followed by vascular dementia (VD) [1]. Although various treatments are being explored, no definitive cure exists; thus, early detection and intervention to slow progression are critical [2]. The prevalence of dementia increases with age, affecting 2%–3% of individuals aged 65–69 and doubling every 5 years to exceed 20% in those aged 80 years or older [3]. Recently, early-onset dementia, which occurs in middle adulthood (aged 40–65 years), has been rising and tends to progress more rapidly [4]. Although its precise etiology is unknown, factors such as mental stress, heavy metal exposure, and an irregular lifestyle are suspected [4].
The association between anosmia and AD has been reported since the 1990s [5-14]. In early AD, neurodegenerative changes that lead to anosmia occur via mechanisms such as noradrenergic axon loss, amyloid-beta (Aβ) deposition, and neuroinflammation within the olfactory pathway [15-20]. Numerous clinical studies have demonstrated that older individuals with anosmia are at an increased risk of developing dementia compared to those without anosmia [5-14]. The first large-scale study on this topic, conducted by Graves et al. [7] in 1999, followed 168 anosmia patients and 1,431 controls over 2 years, revealing that the relative risk of developing dementia was 2.92 times higher (95% CI, 1.76–4.86) in the anosmia group. Subsequent studies with similar designs consistently reported significant increases in relative risk [8-14]. Notably, Fischer et al. [10] reported a relative risk as high as 4.18 (95% CI, 2.68–6.51). Given that anosmia has been recognized as an early indicator of dementia in older populations, olfactory tests have been increasingly used for the early diagnosis of AD, with considerable success [21,22]. However, research is lacking on whether anosmia in middle-aged adults can also predict dementia development. If an association exists, closer monitoring of middle-aged individuals with anosmia could facilitate earlier detection of dementia, including early-onset cases. Nevertheless, because early-onset dementia is relatively rare and AD is more common in old age, long-term follow-up of a large number of middle-aged subjects is necessary to obtain reliable results.
We hypothesized that Korea’s National Health Insurance claims data could help answer this question. South Korea, with a population of approximately 52 million, has nearly universal enrollment in its National Health Insurance System, which provides free national health check-ups every 2 years and offers comprehensive claims and health examination data for research purposes [23]. We constructed a retrospective cohort from these data to evaluate the long-term risk of dementia among middle-aged individuals with anosmia and to compare it with that of older adults.
MATERIALS AND METHODS
This study was approved by the Internal Review Board of Konkuk University Medical Center (No. 2023-07-009). Informed consent from individual patients was not required due to the retrospective nature of the study using anonymized insurance claims data.
We designed a retrospective cohort study using Korea’s National Health Insurance claims data and targeted participants aged ≥40 years from 40% of randomly selected individuals who underwent the 2009 national health check-up. The reason for selecting only 40% was based on empirical evidence, which indicated that it significantly reduced computation time while causing minimal loss of statistical power. Those who had been previously diagnosed with any dementia or with missing health examination data were excluded. The participants were categorized into two groups, including those diagnosed with anosmia who visited clinics or hospitals more than twice between 2006 and 2008 in the anosmia group and the rest in the control group.
A variety of information (age, sex, income level, smoking history, alcohol consumption status, physical activity, body mass index [BMI], blood pressure, and lab test) was included in the analysis. Significant comorbidities such as type 2 diabetes, hypertension, hyperlipidemia, and renal failure were defined using the patient’s diagnostic claim code, medication prescription and hospital visit records, blood pressure, and lab tests. Excluding the 1-year lag period, we followed up with the participants and monitored the occurrence of AD and VD from 2011 to 2020. They were censored if they emigrated or died during the follow-up period. The working definitions for all variables are presented in Table 1.
Table 1.
Definitions of variables in the study
| Variable | ICD-10-CM code | Definition |
|---|---|---|
| Anosmia | R43.0 | Two or more outpatient visits under the diagnosis |
| Alzheimer dementia | F00 or G30 | One diagnosis and use of antidementia medications |
| Vascular dementia | F01 | One diagnosis and use of antidementia medications |
| Comorbidity | ||
| Type 2 diabetes | E11–14 | One diagnosis and use of anti-diabetic medications for the past year or serum fasting glucose ≥126 mg/dL |
| Hypertension | I10; I11; I12; I13; I15 | One diagnosis and use of anti-hypertensive medications for the past year or systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg |
| Dyslipidemia | E78 | One diagnosis and use of anti-hyperlipidemic medications for the past year or serum total cholesterol ≥240 mg/dL |
| Renal failure | - | Estimated glomerular filtration rate <60 mL/min/1.73 m2 |
| Sociodemographic | ||
| Drinking | - | Non: no alcohol intake; mild: 0< alcohol intake <30 g/day; heavy: alcohol intake ≥30 g/day |
| Regular exercise | - | Mid-term exercise ≥5 days or vigorous exercise ≥3 days in a week |
ICD-10-CM: International Classification of Diseases, Tenth Revision, Clinical Modification.
Data are presented as a mean±standard deviation for continuous data and proportions for the remaining categorical variables. Comparisons between the anosmia and control groups were performed using the student t-test for continuous variables or the chi-square test for categorical variables. The Cox proportional hazards regression analysis was used to calculate the risk of dementia development in the anosmia group after adjusting for various variables. Additionally, a subgroup analysis was performed to investigate whether the results varied by age (under and over 65 years), sex, BMI (under and over 25 kg/m2), social behaviors (smoking, drinking, and regular exercise), and comorbidities (type 2 diabetes, hypertension, dyslipidemia, and renal failure). The outcomes were the mean and 95% CI. We performed all statistical analyses using SAS version 9.4 (SAS Institute) and R version 3.2.3 (The R Foundation for Statistical Computing).
RESULTS
A total of 2,688,557 subjects (mean age, 54.14±10.34 years) were followed for an average of 9.87 years. The incidence rates for AD and VD were 4.54 and 0.54 per 1,000 person-years, respectively. The enrollment process is depicted in Fig. 1.
Fig. 1.
The enrollment process of participants.
Comparison of the demographic data between the anosmia and control groups
The mean age was similar between the groups; however, there was a significant sex difference, with the anosmia group comprising a higher proportion of females (62.32%) compared to the control group (49.57%) (P<0.001). The anosmia group also exhibited a slightly higher BMI and significantly lower blood pressure. The proportion of individuals in the lowest income quartile was marginally lower in the anosmia group (19.41% vs. 20.3%, P=0.047). Significant differences were observed in smoking status (P<0.001): the anosmia group had a higher percentage of non-smokers (71.62% vs. 63.32%) and a lower percentage of current smokers (13.72% vs. 21.09%). Alcohol consumption also differed significantly (P<0.001), with more non-drinkers in the anosmia group (64.79% vs. 58.28%). Additionally, type 2 diabetes mellitus was less prevalent in the anosmia group (10.64% vs. 11.63%, P=0.006), while dyslipidemia was more common (25.68% vs. 22.68%, P<0.001). Fasting glucose and triglyceride levels were lower in the anosmia group, whereas other blood test results were similar between the groups. Detailed data are summarized in Table 2.
Table 2.
Comparison between anosmia and control groups
| Variable | Anosmia group (n=8,023) | Control group (n=2,680,534) | P-value |
|---|---|---|---|
| Age (yr) | 54.29±9.52 | 54.14±10.34 | 0.180 |
| Sex | <0.001 | ||
| Male | 3,023 (37.68) | 1,351,812 (50.43) | |
| Female | 5,000 (62.32) | 1,328,722 (49.57) | |
| Body mass index (kg/m2) | 24.07±2.92 | 23.97±3.03 | 0.002 |
| Blood pressure (mmHg) | |||
| Systolic | 123.08±14.93 | 124.19±15.51 | <0.001 |
| Diastolic | 76.4±10.09 | 77.2±10.23 | <0.001 |
| Income (lowest quartile) | 1,557 (19.41) | 544,164 (20.3) | 0.047 |
| Smoking | <0.001 | ||
| Non-smoker | 5,746 (71.62) | 1,697,217 (63.32) | |
| Ex-smoker | 1,176 (14.66) | 418,007 (15.59) | |
| Current smoker | 1,101 (13.72) | 565,310 (21.09) | |
| Drinking | <0.001 | ||
| Not drinking | 5,198 (64.79) | 1,562,320 (58.28) | |
| Mild drinking | 2,378 (29.64) | 920,752 (34.35) | |
| Heavy drinking | 447 (5.57) | 197,462 (7.37) | |
| Regular exercise | 1,703 (21.23) | 537,824 (20.06) | 0.009 |
| Comorbidity | |||
| Type 2 diabetes mellitus | 854 (10.64) | 311,667 (11.63) | 0.006 |
| Hypertension | 2,595 (32.34) | 890,780 (33.23) | 0.092 |
| Dyslipidemia | 2,060 (25.68) | 607,977 (22.68) | <0.001 |
| Renal failure | 614 (7.65) | 216,798 (8.09) | 0.154 |
| Blood test | |||
| Fasting glucose (mg/dL) | 98.52±22.13 | 100.04±25.86 | <0.001 |
| Total cholesterol (mg/dL) | 200.76±37.52 | 199.14±37.33 | <0.001 |
| HDL cholesterol (mg/dL) | 56.11±24.49 | 55.79±29.49 | 0.333 |
| LDL cholesterol (mg/dL) | 118.79±38.39 | 117.06±38.81 | <0.001 |
| Estimated GFR (mL/min/1.73 m2) | 85.04±41.87 | 84.97±37.9 | 0.859 |
| Triglycerides (mg/dL) | 113.78 (112.43–115.15) | 117.84 (117.76–117.92) | <0.001 |
Values are presented as mean±standard deviation, number (%), or median (range).
HDL, high-density lipoprotein; LDL, low-density lipoprotein; GFR, glomerular filtration rate.
Comparison of the risk of developing dementia between the anosmia and control groups
The results of the Cox proportional hazards regression analysis are presented in Table 3. Model 1 was adjusted only for age and sex; model 2 included adjustments for BMI, income, smoking history, alcohol consumption, and regular exercise; and model 3 further adjusted for diabetes mellitus, hypertension, dyslipidemia, and renal failure. In all three models, the incidence of AD was significantly higher in the anosmia group compared to the control group. In contrast, no statistically significant increase in VD was observed. In model 3, which included the most comprehensive adjustments, the hazard ratio for AD was 1.15 (95% CI, 1.04–1.28), and for VD was 1.13 (95% CI, 0.85–1.52), with a notably wider confidence interval for VD.
Table 3.
Comparison of the risk of developing dementia between the anosmia and control groups
| Number | Event | Duration (person-years) | Incidence ratea) | Hazard ratio (95% CI) |
|||
|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | |||||
| Alzheimer dementia | |||||||
| Control group | 2,680,534 | 120,256 | 26,478,354 | 4.54 | 1 | 1 | 1 |
| Anosmia group | 8,023 | 365 | 79,885 | 4.57 | 1.14 (1.03–1.26) | 1.15 (1.04–1.27) | 1.15 (1.04–1.28) |
| Vascular dementia | |||||||
| Control group | 2,680,534 | 14,891 | 26,478,354 | 0.56 | Reference | Reference | Reference |
| Anosmia group | 8,023 | 45 | 79,885 | 0.56 | 1.12 (0.83–1.49) | 1.13 (0.84–1.51) | 1.13 (0.85–1.52) |
Model 1 was adjusted only for age and sex; model 2 was further adjusted for body mass index, income, smoking history, alcohol consumption status, and regular exercise; and model 3 was further adjusted for diabetes mellitus, hypertension, dyslipidemia, and renal failure.
Incidence rate per 1,000 person-years.
The risk of developing dementia by age group
Compared to individuals over 65, the incidence rate of AD in those under 65 was substantially lower, approximately 1/20 of that in the older group. Nevertheless, the hazard ratio for developing AD in the anosmia group relative to controls was significantly elevated in individuals under 65 (1.28; 95% CI, 1.07–1.54), but not in those over 65 (1.10; 95% CI, 0.97–1.24). This indicates a greater relative risk in the younger cohort. The difference was statistically significant in the Log-rank test, which compared simple incidence rates (P<0.001) (Fig. 2), although it was not significant in the Cox proportional hazards model after adjustment for multiple confounders (P=0.160). VD accounted for approximately 1/10 of AD cases, and similarly, the risk ratio for VD increased in individuals under 65 (1.36; 95% CI, 0.88–2.12) but did not increase in those over 65 (1.00; 95% CI, 0.68–1.48). However, statistical significance was not reached for VD even in the under-65 group. Detailed results are presented in Table 4.
Fig. 2.
Cumulative incidence of Alzheimer disease in individuals aged 40–64 years. The cumulative incidence of Alzheimer disease in the anosmia group was higher than that in the control group (log-rank, P<0.001).
Table 4.
Comparison of the risk of developing dementia by age group
| Number | Event | Duration (person-years) | Incidence ratea) | Hazard ratio (95% CI) |
P for interaction | |
|---|---|---|---|---|---|---|
| Model 3 | ||||||
| Alzheimer dementia | 0.160 | |||||
| 40–64 yr | ||||||
| Control group | 2,193,351 | 25,379 | 22,306,195 | 1.14 | 1 | |
| Anosmia group | 6,722 | 111 | 68,412 | 1.62 | 1.28 (1.07–1.54) | |
| ≥65 yr | ||||||
| Control group | 487,183 | 94,877 | 4,172,159 | 22.74 | 1 | |
| Anosmia group | 1,301 | 254 | 11,472 | 22.14 | 1.10 (0.97–1.24) | |
| Vascular dementia | 0.300 | |||||
| 40–64 yr | ||||||
| Control group | 2,193,351 | 4,620 | 22,306,195 | 0.21 | 1 | |
| Anosmia group | 6,722 | 20 | 68,412 | 0.29 | 1.36 (0.88–2.12) | |
| ≥65 yr | ||||||
| Control group | 487,183 | 10,271 | 4,172,159 | 2.46 | 1 | |
| Anosmia group | 1,301 | 25 | 11,472 | 2.18 | 1.00 (0.68–1.48) |
Model 3 was adjusted for age, sex, body mass index, income, smoking history, alcohol consumption status, regular exercise, diabetes mellitus, hypertension, dyslipidemia, and renal failure.
Incidence rate per 1,000 person-years.
The risk of developing dementia depending on other factors
Compared to individuals over 65, the incidence rate of AD in those under 65 was substantially lower, approximately 1/20 of that in the older group. Nevertheless, the hazard ratio for developing AD in the anosmia group relative to controls was significantly elevated in individuals under 65 (1.28; 95% CI, 1.07–1.54), but not in those over 65 (1.10; 95% CI, 0.97–1.24). This indicates a greater relative risk in the younger cohort. The difference was statistically significant in the log-rank test, which compared simple incidence rates (P<0.001) (Fig. 2), although it was not significant in the Cox proportional hazards model after adjustment for multiple confounders (P=0.160). VD accounted for approximately 1/10 of AD cases, and similarly, the risk ratio for VD increased in individuals under 65 (1.36; 95% CI, 0.88–2.12) but did not increase in those over 65 (1.00; 95% CI, 0.68–1.48). However, statistical significance was not reached for VD even in the under 65 group. Detailed results are presented in Table 4.
DISCUSSION
In this study, we monitored the development of dementia over approximately 10 years in both the anosmia and control groups using Korea’s National Health Insurance claims data. The primary finding is that a diagnosis of anosmia increases the risk of developing AD in middle-aged individuals, but not in the elderly. Although the overall incidence of AD is considerably higher in older adults, the presence of anosmia in older individuals did not significantly increase the risk of developing AD.
The association between anosmia and AD is supported by several neurodegenerative mechanisms [15-20]. These mechanisms involve both central and peripheral olfactory pathways, with early pathological changes in the olfactory system potentially serving as indicators of AD progression [15-20]. Key contributors to olfactory dysfunction in AD include the loss of noradrenergic axons, deposition of Aβ and tau proteins, and neuroinflammation [15-20]. Collectively, these factors underscore the complex interplay between olfactory impairment and AD pathology. Early degeneration of the locus coeruleus—a primary source of noradrenaline—leads to reduced noradrenergic input to the olfactory bulb (OB), which is associated with impaired olfaction, as observed in both mouse models and human patients with early AD [18]. Moreover, microglial activity in the OB, responsible for clearing hyperactive locus coeruleus axons, further exacerbates olfactory dysfunction and is linked to elevated translocator protein signals that indicate neuroinflammation [15]. Aβ and tau deposition, hallmarks of AD, are closely associated with olfactory deficits. Research indicates that individuals with Aβ-positive mild cognitive impairment and AD experience significant olfactory deficits compared to Aβ-negative individuals [16]. The accumulation of Aβ oligomers and tau in specific regions of the OB and olfactory epithelium results in a decline in olfactory sensory neurons and dopaminergic neurons, further contributing to olfactory impairment [17-20]. Additionally, neuroinflammation driven by Aβ and tau production is implicated in the progressive neurodegeneration of the olfactory system, affecting the structural integrity of olfactory pathways, including the olfactory and orbitofrontal cortex, entorhinal cortex, and hippocampus [18].
Similarly, numerous mechanisms have been identified to explain the relationship between anosmia and AD, and previous clinical studies have reported that elderly individuals with anosmia face an increased risk of developing AD [7-20]. In contrast, our study did not observe an increased risk of AD in individuals aged 65 and older diagnosed with anosmia compared to controls. Although it is challenging to explain this discrepancy precisely, a major contributing factor may be differences in the selection methods used for the anosmia and control groups. Prior studies performed olfactory tests on all subjects and classified them into patient and control groups [7-14]. In our study, however, the population was divided based on a diagnosis of anosmia between 2006 and 2008, with the remaining individuals comprising the control group. Among individuals aged 65 and older, only about 0.3% were diagnosed with anosmia, in stark contrast to Hoffman’s study, which reported a prevalence of 40% [24]. This discrepancy suggests that many undiagnosed cases of anosmia may have been included in the control group, potentially diluting the observed effect.
Another possibility is that, even when diagnosed in individuals aged 65 and older, anosmia is infrequently caused by AD. Most cases of anosmia are attributed to conditions such as chronic rhinosinusitis, post–upper respiratory viral infections, and head trauma [25]. Moreover, olfactory function declines rapidly with age; by 85, approximately 80% of individuals experience some degree of olfactory impairment [26]. In addition, neurodegenerative diseases that contribute to anosmia include not only AD but also Parkinson’s disease, Lewy body dementia, and Huntington’s disease [26]. Consequently, while AD remains a significant cause of anosmia in the elderly, its relative contribution may be lower than previously assumed.
Why was the risk of AD significantly increased only among middle-aged individuals diagnosed with anosmia? Although a definitive explanation is elusive, one possible reason is that middle-aged individuals with anosmia may be more proactive in seeking medical attention compared to their older counterparts. This could result in a lower proportion of undiagnosed anosmia cases in the control group, thereby amplifying the observed association with AD. Furthermore, because age-related anosmia is less common in this group, a greater proportion of anosmia cases may be attributable to neurodegenerative processes, thereby increasing the relative risk of AD. Another possible explanation is an actual increase in early-onset dementia cases within this age group [4].
This study did not detect a significant association between an anosmia diagnosis and the incidence of VD. One hypothesis is that the statistical power was insufficient due to the relatively lower number of VD cases compared to AD. Alternatively, it is possible that the onset of AD, which begins in the olfactory centers of the brain, is more closely linked to anosmia, whereas VD develops independently of the olfactory system [15-20].
This study has several limitations. First, the diagnosis of anosmia was based solely on claim codes, precluding a clinical definition of anosmia and preventing analysis based on severity. Consequently many anosmia cases may have been misclassified within the control group. Second, dementia was also defined solely based on claim codes, which may have introduced inaccuracies. Third, psychiatric disorders such as depression, known to influence dementia risk, were not included as confounding factors. Fourth, to simplify the study design, we considered only anosmia cases that occurred within a specific time period and disregarded any subsequent diagnoses of anosmia.
This study is the first to investigate whether anosmia is a prognostic factor for dementia development in a large cohort of middle-aged individuals. Although AD is more prevalent in older adults, middle-aged patients diagnosed with anosmia may face an increased risk of developing AD compared to age-matched controls.
HIGHLIGHTS
▪ Clinically diagnosed anosmia is associated with an approximately 15% increased risk of progressing to Alzheimer dementia compared to controls.
▪ This increased risk was found to be significant in middle-aged patients, but not in older adults.
▪ Anosmia does not appear to affect the incidence of vascular dementia.
Acknowledgments
This study was supported by grants from the Korean Society of Otorhinolaryngology Head and Neck Surgery (2022).
Footnotes
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conceptualization: JHC, JKK. Data curation: JHC. Formal analysis: JHC. Funding acquisition: JKK. Investigation: JHC. Methodology: JHC. Project administration: JHC, JKK. Resources: JHC. Software: JHC. Supervision: JKK. Validation: JHC. Visualization: JHC. Writing–original draft: JHC. Writing–review & editing: JKK. All authors read and agreed to the published version of the manuscript.
REFERENCES
- 1.Gale SA, Acar D, Daffner KR. Dementia. Am J Med. 2018 Oct;131(10):1161–9. doi: 10.1016/j.amjmed.2018.01.022. [DOI] [PubMed] [Google Scholar]
- 2.Tisher A, Salardini A. A comprehensive update on treatment of dementia. Semin Neurol. 2019 Apr;39(2):167–78. doi: 10.1055/s-0039-1683408. [DOI] [PubMed] [Google Scholar]
- 3.Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol. 2010 Jan;67(1):114–21. doi: 10.1002/ana.21915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kuruppu DK, Matthews BR. Young-onset dementia. Semin Neurol. 2013 Sep;33(4):365–85. doi: 10.1055/s-0033-1359320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Solomon GS. Anosmia in Alzheimer disease. Percept Mot Skills. 1994 Dec;79(3 Pt 1):1249–50. doi: 10.2466/pms.1994.79.3.1249. [DOI] [PubMed] [Google Scholar]
- 6.Chen Z, Xie H, Yao L, Wei Y. Olfactory impairment and the risk of cognitive decline and dementia in older adults: a meta-analysis. Braz J Otorhinolaryngol. 2021 Jan-Feb;87(1):94–102. doi: 10.1016/j.bjorl.2020.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Graves AB, Bowen JD, Rajaram L, McCormick WC, McCurry SM, Schellenberg GD, et al. Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status. Neurology. 1999 Oct;53(7):1480–7. doi: 10.1212/wnl.53.7.1480. [DOI] [PubMed] [Google Scholar]
- 8.Adams DR, Kern DW, Wroblewski KE, McClintock MK, Dale W, Pinto JM. Olfactory dysfunction predicts subsequent dementia in older U.S. adults. J Am Geriatr Soc. 2018 Jan;66(1):140–4. doi: 10.1111/jgs.15048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Devanand DP, Lee S, Luchsinger JA, Andrews H, Goldberg T, Huey ED, et al. Intact global cognitive and olfactory ability predicts lack of transition to dementia. Alzheimers Dement. 2020 Feb;16(2):326–34. doi: 10.1016/j.jalz.2019.08.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Fischer ME, Cruickshanks KJ, Schubert CR, Pinto AA, Carlsson CM, Klein BE, et al. Age-related sensory impairments and risk of cognitive impairment. J Am Geriatr Soc. 2016 Oct;64(10):1981–7. doi: 10.1111/jgs.14308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yaffe K, Freimer D, Chen H, Asao K, Rosso A, Rubin S, et al. Olfaction and risk of dementia in a biracial cohort of older adults. Neurology. 2017 Jan;88(5):456–62. doi: 10.1212/WNL.0000000000003558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lipnicki DM, Sachdev PS, Crawford J, Reppermund S, Kochan NA, Trollor JN, et al. Risk factors for late-life cognitive decline and variation with age and sex in the Sydney Memory and Ageing Study. PLoS One. 2013 Jun;8(6):e65841. doi: 10.1371/journal.pone.0065841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Roberts RO, Christianson TJ, Kremers WK, Mielke MM, Machulda MM, Vassilaki M, et al. Association between olfactory dysfunction and amnestic mild cognitive impairment and Alzheimer disease dementia. JAMA Neurol. 2016 Jan;73(1):93–101. doi: 10.1001/jamaneurol.2015.2952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Stanciu I, Larsson M, Nordin S, Adolfsson R, Nilsson LG, Olofsson JK. Olfactory impairment and subjective olfactory complaints independently predict conversion to dementia: a longitudinal, population-based study. J Int Neuropsychol Soc. 2014 Feb;20(2):209–17. doi: 10.1017/S1355617713001409. [DOI] [PubMed] [Google Scholar]
- 15.Gannon M, Che P, Chen Y, Jiao K, Roberson ED, Wang Q. Noradrenergic dysfunction in Alzheimer’s disease. Front Neurosci. 2015 Jun;9:220. doi: 10.3389/fnins.2015.00220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wang SM, Kang DW, Um YH, Kim S, Lee CU, Lim HK. Olfactory dysfunction is associated with cerebral amyloid deposition and cognitive function in the trajectory of Alzheimer’s disease. Biomolecules. 2023 Aug;13(9):1336. doi: 10.3390/biom13091336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yoo SJ, Lee JH, Kim SY, Son G, Kim JY, Cho B, et al. Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of β-amyloid oligomer. Cell Death Dis. 2017 Aug;8(8):e2977. doi: 10.1038/cddis.2017.349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Son G, Jahanshahi A, Yoo SJ, Boonstra JT, Hopkins DA, Steinbusch HW, et al. Olfactory neuropathology in Alzheimer’s disease: a sign of ongoing neurodegeneration. BMB Rep. 2021 Jun;54(6):295–304. doi: 10.5483/BMBRep.2021.54.6.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Dong Y, Li Y, Liu K, Han X, Liu R, Ren Y, et al. Anosmia, mild cognitive impairment, and biomarkers of brain aging in older adults. Alzheimers Dement. 2023 Feb;19(2):589–601. doi: 10.1002/alz.12777. [DOI] [PubMed] [Google Scholar]
- 20.Klein J, Yan X, Johnson A, Tomljanovic Z, Zou J, Polly K, et al. Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease. J Alzheimers Dis. 2021;80(3):1051–65. doi: 10.3233/JAD-201149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Audronyte E, Pakulaite-Kazliene G, Sutnikiene V, Kaubrys G. Properties of odor identification testing in screening for early-stage Alzheimer’s disease. Sci Rep. 2023 Apr;13(1):6075. doi: 10.1038/s41598-023-32878-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Audronyte E, Pakulaite-Kazliene G, Sutnikiene V, Kaubrys G. Odor discrimination as a marker of early Alzheimer’s disease. J Alzheimers Dis. 2023;94(3):1169–78. doi: 10.3233/JAD-230077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cho JH, Suh JD, Han KD, Lee HM. Uvulopalatopharyngoplasty reduces the incidence of depression caused by obstructive sleep apnea. Laryngoscope. 2019 Apr;129(4):1005–9. doi: 10.1002/lary.27294. [DOI] [PubMed] [Google Scholar]
- 24.Hoffman HJ, Ishii EK, MacTurk RH. Age-related changes in the prevalence of smell/taste problems among the United States adult population: results of the 1994 disability supplement to the National Health Interview Survey (NHIS) Ann N Y Acad Sci. 1998 Nov;855:716–22. doi: 10.1111/j.1749-6632.1998.tb10650.x. [DOI] [PubMed] [Google Scholar]
- 25.Goodspeed RB, Gent JF, Catalanotto FA. Chemosensory dysfunction: clinical evaluation results from a taste and smell clinic. Postgrad Med. 1987 Jan;81(1):251–7. doi: 10.1080/00325481.1987.11699680. [DOI] [PubMed] [Google Scholar]
- 26.Whitcroft KL, Altundag A, Balungwe P, Boscolo-Rizzo P, Douglas R, Enecilla ML, et al. Position paper on olfactory dysfunction: 2023. Rhinology. 2023 Oct;61(33):1–108. doi: 10.4193/Rhin22.483. [DOI] [PubMed] [Google Scholar]