03 Oct 2014

Death may be wafting around the corner, but you might not smell it coming. According to a study published September 24 in PLOS One, people who lost their sense of smell had more than triple the chance of dying within five years than did people with a fully functioning proboscis. In fact, olfactory dysfunction better correlated with impending death than many other chronic ailments, including cancer and heart failure. Because the study did not take into account the cause of death, the reasons behind the correlation are unclear. However, olfactory malfunction frequently precedes neurodegenerative disease. Smell tests could serve as screening tools that may prompt clinicians and caregivers to look for deeper problems, first author Jayant Pinto of the University of Chicago told Alzforum.

The study, led by Martha McClintock at the University of Chicago, is not the first to identify waning sense of smell as a harbinger of disease or death, but it is one of the largest. While one previous study linked loss of olfaction to subsequent mortality in 1,162 elderly people living in retirement communities and subsidized housing (see Wilson et al., 2011), Pinto and colleagues wanted to see if the effects held true within a larger, slightly younger cohort that more closely represented the general population.

The researchers tapped data from the National Social Life, Health, and Aging Project. This is a cohort of community-dwelling people aged 57-85 who have been tested for sensory functions and other measures of health (see Schumm et al., 2009). Pinto and colleagues measured olfactory function in nearly 3,000 participants with a simple test. Volunteers were asked to identify five common scents—rose, leather, orange, fish, and peppermint. Zero errors or one error was considered normal, two to three errors hyposmic, and four to five anosmic. Four percent of participants scored in the latter category. Five years later, the researchers had one simple question: Who was still alive?

They found that nearly 40 percent of the people who had bombed the smell test had died, versus 19 percent of hyposmic people and 10 percent of people with normal olfaction. After controlling for the potentially confounding factors of age, gender, and education, the researchers determined that anosmic people were more than three times as likely to die within the next five years as those who could smell normally. People with hyposmia were 1.5 times more likely to die. These numbers held steady when researchers controlled for common chronic health problems known to beckon the grim reaper, such as heart attack, diabetes, stroke, cancer, and severe liver damage. Each of these factors did indeed boost mortality; however, none of them lessened the contribution of olfactory dysfunction. Interestingly, only severe liver damage correlated more highly with five-year mortality than anosmia did.

Because olfactory loss is associated with prodromal neurodegenerative disease, the researchers also considered the participants’ cognitive function. The study used the Short Portable Mental Status Questionnaire, and controlling for low scores on it reduced anosmia’s mortality boost from 3.24- to 2.80-fold. This drop suggested that cognitive impairment at baseline may have partially contributed to anosmia’s association with mortality, but could not explain all of it.

The underlying cause of the association between olfactory loss and mortality may become clearer after researchers look at cause of death, Pinto told Alzforum. They are planning to conduct this follow-up soon, he said.

What could possibly be at play here? It may be that neural stem cells that replenish olfactory neurons throughout life reach the end of their rope. “Maybe when these cells lose that ability to regenerate, that’s a sign that overall, your cells are entering a senescent phase, where they can’t respond to insults or repair themselves, and that puts you at an increased risk of death,” Pinto said. Stem cells in other parts of the body, such as the gut, could also be growing haggard. “When the clock is up for your olfactory stem cells, maybe the same is thing is happening in all parts of your body,” he said.

Waning olfaction has been shown to precede or accompany the onset of Alzheimer’s and Parkinson’s diseases, and may even predict disease severity (see Bacon et al., 1998; Ross et al., 2008; and Jan 2010 news story). Upon autopsy, researchers have found amyloid plaques and neurofibrillary tangles lurking within the olfactory bulbs of people who had not yet displayed signs of disease (see Wilson et al., 2007).

Mark Albers of Massachusetts General Hospital in Charlestown commented that more information, including the cause of death and autopsy data, would be needed to clarify the link between olfactory dysfunction and mortality, but even now the data mesh with the notion that neurodegenerative disease is involved. “The findings are consistent with the idea that [olfactory dysfunction] is a marker for preclinical neurodegenerative disease that then manifests itself in increased mortality over the next five years,” Albers said. He noted an important difference between odor-detection tests and odor-identification tests such as the one used by Pinto and colleagues: The latter measure both olfactory function and cognitive functions such as episodic memory, which are required to process and identify the odor. Therefore, anosmic people may have deficits in other parts of the brain, such as the hippocampus, in addition to or instead of damage to the olfactory bulb. Tests that separate these two factors could be useful, he said.

Richard Doty of the University of Pennsylvania in Philadelphia called for caution in interpreting the link between olfaction and mortality. He said that waning olfaction can be related to many age-related problems (see Doty and Kamath, 2014). For example, repeated viral infections such as the common cold can damage the nasal epithelium and impair olfaction. Olfactory dysfunction could be a measure of the cumulative viral lashings one has received throughout life, which could be a proxy for immune function and overall health. However, Doty added, “Olfactory dysfunction is probably a pretty good marker of damage going on in the brain.”

Should clinicians whip out smell tests, and if so, to what end? Pinto suggested that the tests could nudge clinicians and caregivers to pay extra attention to patients or perhaps look more deeply into potential health problems. Doty suggested that smell tests may even help clinicians distinguish between different neurodegenerative diseases. The vast majority of people with PD, for example, have serious losses in olfaction (see Haehner et al., 2011), whereas those with progressive supranuclear palsy, a disorder sometimes mistaken for PD, do not, he said (see McKinnon et al., 2007). “In this case, a smell test would be useful to tell the doctor which disease this person likely has,” he said. Both Doty and Albers disclosed that they are involved in efforts to develop commercial smell tests.

The strengh of the association between olfactory function and mortality warrants more research into this area, Birgit Westermann of the University of Basel, Switzerland, wrote in an email to Alzforum. “Considering that olfactory impairment is a stronger risk factor for death than heart failure, diabetes and stroke, research and clinical routine should be more focused on olfactory decline, which is expected to give important insight to into age-related physiological processes.”—Jessica Shugart

Comments

1. • Birgit Westermann
     University of Basel
   • Posted: 03 Oct 2014

   In this newsworthy study, Pinto and colleagues investigated the hypothesis that olfactory dysfunction could be an early indicator of death in older adults. The most remarkable feature of the olfactory system is its unique capacity for neurogenesis and replacement of degenerating olfactory receptor neurons long after development. Aging does impair this capacity and results in reduced olfactory function in older adults. In addition, the intimate links between neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), and olfactory function, which have been established by clinical, postmortem, and functional and structural imaging data support the idea that impaired olfactory function may be a candidate biomarker, indicative of impaired cellular regeneration and physiological decline.

   One of Pinto et al.'s  most interesting findings was that the likelihood of death is significantly increased for anosmic and hyposmic older adults even after controlling for several potentially confounding variables, such as age, gender, race, education, and known comorbidities. Intriguingly, the five-year mortality was three times higher in anosmic and still 1.5 times higher in hyposmic subjects compared to normosmic subjects. The effect of higher mortality was present in all age groups and was not driven by subjects with a severe olfactory deficit.   

   The results shed completely new light on the significance of olfactory impairment in older subjects as it pertains to cellular processes related to aging. However, it has to be noted here that olfactory function is reduced in the elderly as a consequence of normal aging. Whether this process can be accelerated by toxic environmental exposure needs to be investigated in further studies. In the same vein, I agree with the authors that a more extensive clinical test of olfactory function might help differentiate subjects with normal age-related decline of olfaction from those with severe impairment. Furthermore, although statistical analyses controlled for cognitive deficits, subjects in the study group were in an age range at which PD or AD may develop. Such potential confounds were additionally considered by excluding subjects with severe olfactory deficits, as it is known that even in early, pre-clinical stages of PD, olfaction is often dramatically reduced. 

   In summary, the article by Pinto et al. shows clearly that olfactory dysfunction is a strong predictor for five-year mortality in elderly subjects. The study has important implications for future research. Considering olfactory impairment is a stronger risk factor for death than heart failure, diabetes, and stroke, research and routine clinical care should be more focused on olfactory decline, because it may provide important insight to into age-related physiological processes.

   View all comments by Birgit Westermann

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References

News Citations

1. Blunted Sense of Smell Parallels Pathology in AD, PD 20 Jan 2010

Paper Citations

1. Wilson RS, Yu L, Bennett DA. Odor identification and mortality in old age. Chem Senses. 2011 Jan;36(1):63-7. Epub 2010 Oct 5 PubMed.
2. Schumm LP, McClintock M, Williams S, Leitsch S, Lundstrom J, Hummel T, Lindau ST. Assessment of sensory function in the National Social Life, Health, and Aging Project. J Gerontol B Psychol Sci Soc Sci. 2009 Nov;64 Suppl 1:i76-85. Epub 2009 Jun 23 PubMed.
3. Bacon AW, Bondi MW, Salmon DP, Murphy C. Very early changes in olfactory functioning due to Alzheimer's disease and the role of apolipoprotein E in olfaction. Ann N Y Acad Sci. 1998 Nov 30;855:723-31. PubMed.
4. Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, Launer L, White LR. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol. 2008 Feb;63(2):167-73. PubMed.
5. Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA. The relationship between cerebral Alzheimer's disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry. 2007 Jan;78(1):30-5. PubMed.
6. Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol. 2014;5:20. Epub 2014 Feb 7 PubMed.
7. Haehner A, Hummel T, Reichmann H. Olfactory loss in Parkinson's disease. Parkinsons Dis. 2011;2011:450939. Epub 2011 Apr 21 PubMed.
8. McKinnon JH, Demaerschalk BM, Caviness JN, Wellik KE, Adler CH, Wingerchuk DM. Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders?. Neurologist. 2007 Nov;13(6):382-5. PubMed.

Further Reading

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