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Loss of Sense of Smell Linked to Genetic Alzheimer’s Risk

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A study has found that people who carry a genetic variant linked to Alzheimer’s disease (AD) may begin to lose their sense of smell – a possible sign of future memory problems – earlier than those who do not have the variant. The research is published in Neurology.

Loss of sense of smell: A harbinger of Alzheimer’s?

The loss of one’s sense of smell has previously been suggested to be a possible early warning sign of AD, arising months or even years before the onset of cognitive symptoms such as memory loss.

Roughly half of people diagnosed with AD carry a variant of a gene called apolipoprotein E (APOE) ε4, which is also linked to a declining sense of smell. APOE ε4 is associated with a faster decline in odor identification – i.e., recognizing and naming odors. However, not much is known about the relationship between this variant and simply detecting an odor (i.e., sensitivity to an odor).

Researchers in the current study sought to understand how APOE ε4 may be linked to loss of odor sensitivity and if this could be linked to cognitive decline and AD.

Genetic variant influences changes in olfaction

The team, led by researchers from the University of Chicago, used data from the National Social Life Health and Aging Project (NSHAP), a representative survey study of home-dwelling (i.e., not in a nursing home) older US adults. The researchers analyzed data gathered from at-home surveys and genetic tests involving 865 participants.

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Tests to measure participants’ sense of smell (olfaction) were taken at 5-year intervals and assessed two aspects of olfaction – their ability to detect as well as identify odors. These were scored from zero to six according to the different concentrations of odors they could smell. Thinking and memory skills were also assessed, and participants provided DNA samples to identify those with the APOE ε4 variant associated with increased risk of developing AD.

The findings showed that people with the APOE ε4 variant were almost 40% less likely to have good odor detection and began to experience a small loss of odor detection ability between the ages of 65–69. In this age group, those who carried the variant detected 3.2 smells on average, compared to 3.9 smells for non-carriers.

In terms of odor identification, those with the APOE ε4 variant showed no deficits in correctly identifying the odor until they reached 75–79 years of age, at which point their odor identification ability began to decline more quickly than those without the variant.

At the beginning of the study, thinking and memory skills were similar for both carriers and non-carriers – however, thinking skills declined more rapidly over time for the carriers compared to the non-carriers.

Predictions of future cognition problems

Overall, the results show that APOE ε4 affects odor sensitivity earlier than odor identification or cognition, suggesting that monitoring odor sensitivity may be useful to predict cognitive problems. “Identifying the mechanism underlying these relationships will elucidate the key role of olfaction in neurodegeneration during aging,” the authors wrote in the paper.

“Testing a person’s ability to detect odors may be a useful way to predict future problems with cognition,” said Dr. Matthew S. GoodSmith, of the University of Chicago. “While more research is needed to confirm these findings and determine what level of smell loss would predict future risk, these results could be promising, especially in studies aiming to identify people at risk for dementia early in the disease.”

Reference: GoodSmith MS, Wroblewski KE, Schumm LP, McClintock MK, Pinto JM. Association of APOE ε4 status with long-term declines in odor sensitivity, odor identification and cognition in older US adults. Neurology. 2023. doi: 10.1212/WNL.0000000000207659

This article is a rework of a press release issued by the American Academy of Neurology. Material has been edited for length and content.