Odor sensitivity deficits may predict cognitive decline in older adults who carry the apolipoprotein E (APOE) gene ε4 allele, according to study findings published in Neurology.

As the number of Americans affected with Alzheimer disease (AD) is estimated to nearly double by the year 2060, early identification and intervention mechanisms remain essential. Despite its predictive value for AD development and protein’s high expression in areas involved in olfaction, the APOE genotype’s effects on olfactory performance remain largely unknown. Considering these relationships, researchers sought to examine olfactory function in patients with a high genetic risk for AD and the prodrome of AD.

Using the National Social Life Health and Aging Project, the researchers conducted a longitudinal, epidemiological study investigating odor sensitivity, odor identification, and cognition among older adults in the US who are APOE ε4 genotype carriers and noncarriers. Through multistage sampling, the researchers selected a sample balanced across age and gender subgroups.

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The researchers extracted respondents’ APOE genotype from saliva samples collected in 2010.

The Olfactory Function Field Exam examined odor sensitivity (ability to identify increasing concentrations of odor) and odor identification (ability to accurately identify common odorants) at baseline and a 5-year follow-up, with an additional 10-year follow-up on odor identification.

The researchers measured cognition with an adapted version of the Montreal Cognitive Assessment (MoCA) at baseline and a 5-year follow up for respondents with available APOE genotype information.

The researchers retrieved cognitive ability data from a total of 864 respondents and odor sensitivity and identification data from 865 and 1156 respondents, respectively. Compared with noncarriers, respondents carrying the APOE ε4 allele had worse odor sensitivity ([odds ratio] OR, 0.63; 95% CI, 0.49-0.81). Although APOE ε4 carriers had worse sensitivity at baseline (OR, 0.59; 95% CI, 0.39-0.90), they did not decline further at the 5-year follow-up (OR, 0.90; 95% CI, 0.58-1.40).

After adjusting for cognition, the researchers noted unchanged aging trajectories for carriers and noncarriers, indicating a direct association between APOE ε4 and odor sensitivity.

The researchers detected no association between odor identification and APOE ε4 carrier status at baseline (OR, 1.57; 95% CI, 0.89-2.77). However, odor identification deficits declined more rapidly in APOE ε4 carriers over a period of 10 years (OR, 0.26; 95% CI, 0.13-0.52; P <0.001). Similarly, the researchers found no differences in cognition between carriers and noncarriers at baseline (OR, 1.08; 95% CI, 0.62–1.91). However, cognition declined more rapidly in carriers over the next 5 years (OR, 0.55; 95% CI, 0.34-0.89; P =.015).

Study limitations include the statistical models’ lack of correction for participant dropout and the likely lack of inclusion of confounding variables.

“In summary, we present evidence that APOE ε4 carriers among diverse US older adults living at home lose their odor sensitivity well before rapid declines in odor identification and cognition,” the researchers concluded. “In APOE ε4 carriers, odor sensitivity in particular may be a useful early indicator of further olfactory dysfunction, cognitive decline, and ultimately neurodegenerative disease, especially in studies aiming to identify at-risk patients early in the disease course.”


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. Published online July 26, 2023. doi:10.1212/WNL.0000000000207659

This article originally appeared on Neurology Advisor