Losing the ability to distinguish common smells could flag future mental decline among people at high genetic risk of Alzheimer’s disease, a study suggests.
Previous research has already found that individuals who carry the ε4 allele of the apolipoprotein (APO)E gene are at increased risk of Alzheimer’s disease.
The latest study, in Neurology, now indicates that older people with the ε4 allele who are still able to live at home lose their sensitivity to smell years before their ability to identify smells or their cognitive function are impaired.
Issues with sensitivity to smell were apparent among ε4 carriers a decade before problems in identifying smells occurred and they were already noticable at 65–69 years of age.
“Among patients carrying the APOE-ε4 allele, decreased ability to detect an odor may be one of the earliest signs that a patient is at risk of developing later cognitive decline,” researcher Matthew GoodSmith, MD, from the University of Chicago, told Inside Precision Medicine.
“As such, our work indicates a potential benefit of both genetic testing for the APOE-ε4 allele and olfactory testing in older individuals, and thus has implications for the field of precision medicine.”
The number of people with Alzheimer’s disease in the U.S. is set to more than double by 2060 and identifying early symptoms would enable interventions at a potentially modifiable stage in the disease.
GoodSmith and co-workers note that areas of the brain involved in processing smells are some of the earliest to be affected by the condition.
While sensitivity to and the identification of different smells may involve overlapping processes, the former may be considered a more peripheral sensory function while the latter requires additional central cognitive functioning.
To investigate further, the team studied information collected every 5 years between 2005 and 2015 as part of the National Social Life Health and Aging Project, a longitudinal survey in a nationally representative sample of home-dwelling older adults in the U.S.
Sensitivity to smell was measured from steadily increasing concentrations of n-butanol that were presented in felt-tip pens alongside blanks.
The ability to identify common odors with words or pictures was also measured. Both were then compared with cognitive function scores and APOE genotype.
The team found that older adults carrying an APOE ε4 allele had less sensitivity to smell than non-carriers, with an odds ratio (OR) of 0.63.
Specifically, people heterozygous for the allele had poorer sensitivity to smells than those with the ε3/ε3 reference genotype (ε3/ε4: OR=0.64, ε2/ε4: OR=0.31). This association was already obvious among APOE ε4 carriers aged 65-69 years old.
In contrast, there was no association between smell identification and APOE ε4 carrier status overall. Issues with identifying smells only became evident in APOE ε4 carriers at the age of 75–79 years, indicating that this developed later in life than insensitivity to smell.
Further analysis indicated that sensitivity to smells only weakly correlated with their identification.
The ability to identify different smells was similar in APOE ε4 carriers and non-carriers initially but declined more rapidly in the former over the course of a decade, with the interaction of carrier status and aging 10 years having an OR of 0.26.
Although APOE ε4 carriers tended towards losing the ability to identify smells more rapidly during the first 5 years of study, this sped up over the subsequent five years.
As with odor identification, cognition was not worse in APOE ε4 carriers initially, but declined more rapidly over the next 5 years. As expected, better cognition was associated with greater identification of smells, the researchers note.
Overall, they conclude: “These results suggest that earlier odor sensitivity testing may identify at risk patients, which could inform studies of the early stages of AD and identify patients for early intervention therapies.”
