Using a Smell Test to Diagnose Alzheimer’s Disease

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Alzheimer’s disease (AD) pathology appears to start in the part of the brain that handles smell before subsequently spreading to additional brain regions and then, ultimately, taking over much of the rest of the brain. This led some to speculate that Alzheimer’s disease may begin in the nose. Perhaps there’s some environmental agent that might enter the brain through some portal in the nostrils?

This is the so-called olfactory vector hypothesis. The anatomy of the nose is well suited for the transfer of things directly into the brain, since the olfactory nerves that stick out into the nose project directly into the brain, bypassing the blood-brain barrier. The nose was actually a major infection route for the polio virus. Public health officials started cauterizing the nasal passages of schoolchildren by spraying caustic chemicals up their noses in an effort to prevent the disease.

The concern is if people breathe in some ionized metals like aluminum dust, for example, it could be transported into the brain through these olfactory nerves at a rate of about 2 millimeters an hour, which is practically 2 inches a day. Doubt has been cast on this theory, however, by a case report of a woman born with a birth defect in which she had no smell nerves yet still developed Alzheimer’s-like pathology. And so, to date, all the supporting evidence is really just circumstantial. It is clear, though, that changes in the sense of smell are among the first clinical signs of Alzheimer’s, occurring during the preclinical phase—that is, before there’s any noticeable cognitive decline. Could we use these changes to predict or diagnose the disease?

For years, researchers have been trying to find markers of brain illness hidden in people’s ability to smell using all sorts of fancy gadgets. For example, functional MRI scans can detect differences in brain activation in response to an odor. In my video, Peanut Butter Smell Test for Alzheimer’s, you can see the responses to lavender. You’ll see a representation of a normal brain’s responses to the odor versus an Alzheimer’s brain. This unequivocally demonstrates that we can pick up changes in smell function due to Alzheimer’s. But, do we really need a million-dollar machine?

An ingenious group of researchers at the University of Florida discovered all we may need is some peanut butter and a ruler.

Considering that the left side of the brain primarily processes what we smell through our left nostril and the right side of our brain covers the right nostril, and understanding that Alzheimer’s strikes the left side more than the right, what if you performed the following experiment: Close your eyes and mouth, breathe normally through the nose, then close one nostril, and hold a foot-long ruler out from the open nostril. Once your eyes, mouth, and one nostril are closed, open a container of peanut butter at the bottom of the ruler (one foot away from your open nostril). Move the peanut butter closer by 1 centimeter upon each exhale until you can detect the odor. Then, repeat the whole procedure again using your other nostril.

This is exactly what the University of Florida researchers did with their subjects. What did they find? The normal elderly control subjects in the study smelled the peanut butter as soon as it came within an average of 18 centimeters (about 7 inches) from either nostril. It was about the same, roughly 7 inches, in the right nostrils of Alzheimer’s patients. But in their left nostrils, it was a mere 2 inches! The peanut butter had to be only 2 inches away before the Alzheimer’s patients could detect it through their left nostrils. This happened every single time. Indeed, the researchers found that a “left nostril impairment of odor detection was present in all the patients with probable AD.” There was no left-right difference in the control group; they could smell the peanut butter when it was the same distance away from both their left and right nostrils. In the Alzheimer’s group, however, there was a 12-centimeter difference.

The disparity was so great that we may be able to set a cutoff value for the diagnosis of Alzheimer’s. The researchers reported that “[c]ompared to patients with other causes of dementia this nostril asymmetry of odor detection…was 100% sensitive and 100% specific for probable AD,” meaning no false positives and no false negatives. Compared to healthy people, it was 100% sensitive in picking up cases of probable Alzheimer’s and 92% specific. What exactly does that mean? In this study, if you had Alzheimer’s, there was a 100% chance of having that wide left-right discrepancy. But, if you did have that discrepancy, the chance of having Alzheimer’s was only 92%. This means there were some false positives.

The reason it’s only “probable” Alzheimer’s is because the only way we can really confirm someone has the disease is on autopsy. The current criteria for diagnosing Alzheimer’s require an extensive evaluation, combined with fancy positron emission tomography (PET) scans and spinal taps. All of these tests are expensive and hard to get, can be invasive, and can have potential complications. On top of that, they are neither highly sensitive nor specific. The left-right nostril / peanut butter odor detection test, however, was fast, simple, non-invasive, and inexpensive. They concluded that may make peanut butter an ideal instrument for the early detection of Alzheimer’s disease.

Does all this sound a bit too good to be true? It may be. A University of Pennsylvania research team was unable to replicate the results. Click here to read their paper. So, at this point, the data are mixed. I’ll do another post once more studies are published and we have a better handle on whether it’s useful or not.

Of course, it’s better to prevent Alzheimer’s in the first place. Check out these videos for more information.

In health,

Michael Greger, M.D.

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