Declined Odor Sensitivity Observed in APOE ε4 Carriers


Between ages 65 to 69, gene carriers of APOE ε4 could detect an average of about 3.2 of the smells presented, compared with about 3.9 smells for noncarriers of the gene variant.

Matthew S. GoodSmith, MD, internal medicine and pediatrics resident physician at University of Chicago

Matthew S. GoodSmith, MD

According to a recent study published in Neurology, findings showed that patients who carried apolipoprotein (APOE) ε4, the gene variant associated with the strongest risk for Alzheimer disease (AD), were 37% less likely to have good odor detection compared with noncarriers at a single timepoint. In addition, results showed that APOE ε4 impacts decline of odor sensitivity earlier than odor identification deficits or cognition and thus assessing odor sensitivity may be useful to predict future impaired cognitive function.1,2

In the study, odor sensitivity (participants, n = 865), assessed over a 5-year period, did not decline more rapidly with aging among APOE ε4 carriers compared with noncarriers (OR, 1.44; 95% CI, 0.94-2.19; P = .092) whereas odor identification (n = 1156) did decline (OR = 0.26; 95% CI; 0.13-0.52, P <.001). Similar to odor identification, cognition (n = 864) declined more rapidly in APOE ε4 carriers compared with those who did not have the gene variant (OR, 0.55; 95% CI, 0.34-0.89; P = .015). Odor sensitivity deficits in APOE ε4 carriers were apparent between 65 and 69 years of age, whereas odor identification deficits did not appear until between 75 and 79 years of age.

“Testing a patient’s ability to detect odors may be a useful way to predict future problems with cognition,” lead author Matthew S. GoodSmith, MD, internal medicine and pediatrics resident physician at University of Chicago, said in a statement.1 “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 patients at risk for dementia early in the disease.”

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GoodSmith and colleagues determined when APOE ε4 affects decline in odor sensitivity, odor identification, and cognition using data from the National Social Life Health and Aging Project (NSHAP), a nationally representative survey study of home-dwelling older adults in the US. Patients’ sense of smell, including measuring odor identification and odor sensitivity, was assessed at 5-year intervals between 2005 and 2015. In addition, researchers measured cognition with a modified version of the Montreal Cognitive Assessment from 2010 to 2015.

Using DNA samples collected in 2010, genotyping was performed to give researchers information about who carried the gene associated with an increased risk of AD. Odor sensitivity and identification, scored on a range from 0 to 6 on how many odor concentrations could be smelled, were compared among APOE ε4 carriers and noncarriers and stratified by age. The relationships between APOE ε4, odor sensitivity, odor identification, and cognition were assessed in a cross section fashion using ordinal logistic regression and longitudinally using mixed effects models that were adjusted for confounders.

“Identifying the mechanisms underlying these relationships will help us understand the role of smell in neurodegeneration,” GoodSmith said in a statement.1 Goodsmith and authors also noted that a limitation of the study was that patients with severe dementia were excluded, suggesting that further research is needed with a more diverse population of patients with dementia.

1. People with increased genetic risk of Alzheimer’s may lose sense of smell first. News Release. American Academy of Neurology. Published July 26, 2023. Accessed September 22, 2023.
2. 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;10.1212/WNL.0000000000207659. doi:10.1212/WNL.0000000000207659
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