Loss of smell may be an early sign of Alzheimer’s in at-risk people


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Losing the sense of smell may be an indicator of later cognitive decline in people who are genetically at-risk of Alzheimer’s

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People who are genetically predisposed to develop Alzheimer’s disease may experience a decline in their sense of smell before any change to their cognitive function. Testing for changes to someone’s sense of smell could therefore improve Alzheimer’s diagnoses and allow treatments to be started earlier.

“The sense of smell is one of the most ancient senses,” says Jayant Pinto at the University of Chicago, Illinois. “As the nervous system evolved, it remained closely connected to other brain functions like emotion, pleasure, memory etc. Because memory problems are a key feature of Alzheimer’s, we focused on the connection between smell and cognition.”

A gene called APOE is highly expressed in parts of the sensory system that relate to smell. One of its variants, APOE4, has been linked with an increased risk of Alzheimer’s. People who carry a single copy of this variant are around three times more likely to develop Alzheimer’s than those without this variant, with the risk more than doubling among people who have two copies of the variant.

To understand any link between APOE4 and a person’s sense of smell, Pinto and his colleagues looked at data that was collected as part of the US National Social Life, Health, and Aging Project (NSHAP). In 2010, more than 800 of the project’s participants – aged 62 to 85 – were genetically screened to identify those with the APOE4 variant. That same year, they were tested on their cognition, namely their thinking and memory skills. None of the participants had dementia symptoms at the start of the study.

They also completed tests on their ability to differentiate between different concentrations of the same odour, known as odour sensitivity, and their ability to differentiate one odour from another, known as odour identification, which were ranked on a scale of zero to six. The cognition and smell tests were repeated in 2015.

Among the 323 participants who carried either one or two APOE4 variants, odour sensitivity showed signs of weakening from between the ages of 65 and 69, when those with the APOE4 variant scored on average 3.2 on the scale, compared with 3.9 for the non-carriers. It may sound like a small difference but a statistical analysis suggests it wasn’t a chance finding.

The odour identification abilities of those with the variant also declined more quickly compared with the non-carriers, but at an older age range, 75 to 29, than the fall in odour sensitivity.

Thinking and memory skills were similar between the carriers and non-carriers at the start of the study, but declined more rapidly in those with APOE4 than those without.

Since the decline in odour sensitivity emerged before the decline in odour identification, and before any cognitive differences between the two groups emerged, testing this may be a useful way to predict if someone may develop Alzheimer’s symptoms within the next five years if they are already genetically susceptible to the condition, according to the researchers.

Team member Matthew GoodSmith, also at the University of Chicago, says a drawback of the study is that it didn’t track who went on to develop Alzheimer’s or any signs of it in the brain. “However, our results help clarify the interplay between smell loss and cognitive decline in patients at high genetic risk for developing Alzheimer’s,” he says.

The next step is to see if testing a person’s odour sensitivity could aid Alzheimer’s diagnoses and allow treatments to be started earlier, says Pinto. The team wants smell testing to be as widely available for older people as vision and hearing tests, he says.

“Early detection of brain health abnormalities are important to implementing therapies as soon as possible in the disease course,” says Mark Albers at Massachusetts General Hospital. “Treatment earlier in the disease course generally has a larger impact. This principle is beginning to emerge in the AD [Alzheimer’s disease] field with the advent of therapeutics, and olfactory screening may be an important component of the annual wellness visit.”



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