Olfactory Dysfunction Linked to Amnestic MCI and AD

Pauline Anderson

November 23, 2015

A new study has added more detail to what is known already about the connection between olfactory dysfunction and cognitive decline.

Results show that in elderly patients, impaired olfaction was associated with incident amnestic mild cognitive impairment (aMCI) and with progression from aMCI to Alzheimer's disease (AD) dementia.

"We found that impaired smell or impaired olfaction is a marker for progressing from normal cognition to MCI, particularly for the amnestic type, where we found a two-fold increased risk, and for progression from having amnestic MCI, which we think is a precursor for Alzheimer's disease, to actually developing Alzheimer's disease, where we had a five-fold increased risk," said lead study author Rosebud Roberts, MB, ChB, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minnesota.

Their results were published online November 16 in JAMA Neurology.

Previous studies have investigated the link between altered sense of smell and dementia, but many of them were small and included volunteers or patients at memory clinics.

This new study was larger, included randomly selected participants, and didn't look just at dementia.

"A lot of other studies of olfactory function have focused on dementia; fewer have focused on MCI," said Dr Roberts. "We wanted to take it a step earlier and ask about the predementia stage; is it also a marker for developing incident cognitive impairment?"

As well, unlike other studies, this new one distinguished between aMCI and nonamnestic MCI (naMCI).

"For these reasons, I think this study provides new and interesting insights," said Dr Roberts.

The study included 1630 cognitively normal participants enrolled in the population-based prospective Mayo Clinic Study of Aging between 2004 and 2010.

Investigators evaluated these participants clinically at baseline and every 15 months to 2014. They assessed olfaction using the Brief Smell Identification Test (B-SIT).

Scratch and Sniff

This test consists of six food-related and six non–food-related smells (banana, chocolate, cinnamon, gasoline, lemon, onion, paint thinner, pineapple, rose, soap, smoke, and turpentine). Study participants were asked to scratch, sniff, and select one of four possible responses.

The B-SIT score was the sum of the correct responses for participants with no more than two missing responses. A score of 0.25 was assigned for each missing response.

Of the initial 1630 participants, 33 died and 167 were lost to follow-up. Among the 1430 remaining, the mean age was 79.5 years and 49.4% were male. Their mean duration of education was 14.3 years, and 25.4% were APOE ε4 carriers.

During a mean of 3.5 years of follow-up, there were 250 incident MCI cases. Impaired olfaction was associated with any MCI and with aMCI after adjustment for sex and education.

Table. Risk for Incident aMCI by Increasing Olfactory Impairment

Quartile Hazard Ratio (95% Confidence Interval) P Value
Quartile 4 (best score) Reference  
Quartile 3 1.12 (0.65 - 1.92) .68
Quartile 2 1.95 (1.25 - 3.03) .003
Quartile 1 2.18 (1.36 - 3.51) .001


The researchers didn't detect an association of impaired olfaction with risk for naMCI, but this was likely because the study had few such patients, said Dr Roberts. The study also lacked power to examine associations of prevalent naMCI with risk for non-AD dementia.

Dr Roberts noted, though, that other studies have suggested an association with neurodegenerative conditions, such as Lewy body dementia and Parkinson's dementia, which develop from naMCI.

During a mean of 3.1 years, there were 64 incident dementia cases. Among the 221 prevalent MCI cases, the risk for dementia increased with decreasing B-SIT scores, with a significant dose-response across B-SIT categories.

The worse B-SIT categories strongly predicted progression from aMCI to AD dementia: Compared with quartile 4, the hazard ratio for quartile 1 was 5.20 (95% confidence interval, 1.90 - 14.20; P = .01).

The strong association for transition from aMCI to AD dementia is consistent with an underlying AD pathophysiology, said the authors. Possible mechanisms may involve neurodegenerative changes in the olfactory bulb and tracts and central brain regions that involve memory and olfaction.

The presence of AD pathology in the entorhinal cortex, hippocampus, and other temporal regions leads to an inability to store and retrieve memories of smell and thereby to correctly identify odors, according to the authors.

Important Marker

The new findings imply that smell is an important marker, said Dr Roberts. "It's not a diagnostic marker, but it's a marker for risk, so if you're trying to figure out if someone is at risk of progression, maybe this is something you could add to your diagnostic armamentarium."

Olfactory function could be a tool added to risk factors already being investigated, including history of hypertension or type 2 diabetes, and can be used by family physicians, geriatricians, and neurologists. said Dr Roberts. "People will eventually start to think about developing a risk score and include this smell test."

Dr Roberts and her colleagues used the shorter B-SIT instead of the longer University of Pennsylvania Smell Identification Test (UPSIT) in the study. As she explained, the B-SIT is a validated, noninvasive, relatively inexpensive test that can easily be administered by nontrained personnel in the outpatient setting.

"It's an efficient, reliable, and sensitive marker of impairment," said Dr Roberts. "It's important to have a shorter test because patients aren't going to sit around for 40 minutes in the clinic to do a test" as they have already been there for 3 hours.

"You don't want something that burdensome yet you want something that's reliable and that's why we chose the brief test."

Many conditions, such as head trauma, could affect olfactory function and therefore the results of such tests.

"That's not what we're talking about; we're talking about a situation where we think there is some pathology in the brain," said Dr Roberts. "Typically some pathology associated with AD starts in the olfactory bulb, so for people who don't have a history of impaired olfaction, it may be a marker that they are beginning to develop protein deposits in the brain that will subsequently lead to cognitive impairment."

Real and Reliable

Asked to comment, D.P. Devanand, MD, professor of psychiatry and neurology, and director of geriatric psychiatry, Columbia University Medical Center, New York, New York, noted that the study includes many variables but that the main findings replicate those of other studies, including his own (Neurology. 2015;84:182-188).

"The findings are therefore real and reliable," said Dr Devanand, adding that he knows of no large epidemiologic studies that contradict these new results.

"So it should be viewed as a well-replicated finding and not a fluke, which can happen with some findings with other biomarkers that are in the literature and have not been replicated, for example pupillary diameter as an early marker of Alzheimer's disease."

The full 40-item UPSIT scale, which takes 15 to 25 minutes to administer, may be "marginally better" than the 12-item B-SIT used in the study, which takes only 5 to 7 minutes to administer and may be "more practical" but less sensitive to change, said Dr Devanand.

However, he stressed that this has not been proven.

Dr Devanand did not feel that the study's exclusion of persons with a history of head trauma and nasal diseases — conditions that may affect olfactory function — had an impact on the results. He pointed out that most olfaction studies exclude such patients.

"It becomes an issue if the exclusion is very rigorous, for example, if any head injury including a concussion suffered decades earlier is excluded. This would lead to many people being excluded and then the value of the test for the general population decreases."

Nasal disease, he added, is "tricky" when determining what threshold will lead to exclusion from a study. "Many people have chronic mild nasal disease."

Asked whether the study makes the argument that all older patients should have their sense of smell tested, Dr Devanand, stressed that if such testing is carried out, results need to be interpreted carefully.

"It should not be the sole measure for diagnosis or to predict cognitive decline over time because there can be a fair number of false-positives and some false-negatives."

The tests should be done as an "add-on" to a careful clinical and cognitive evaluation and not as a screening test by itself, he said.

The study was supported by the National Institute on Aging and the Mayo Foundation for Medical Education and Research. It was made possible by the Rochester Epidemiology Project. Dr Roberts received research funding from the National Institutes of Health. Dr Roberts has disclosed no relevant financial relationships.

JAMA Neurol. Published online November 16, 2015. Abstract



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