Marked olfactory decline may signal subsequent dementia in diabetic seniors

Among older adults with type 2 diabetes (T2D), a poor sense of smell precedes the development of probable dementia, as reported in a recent study.

“To the best of our knowledge, this is the first longitudinal study to demonstrate that lower Open Essence (OE) test score in addition to higher age, lower Mini-Mental State Examination (MMSE) score, higher total protein concentration, and more frequent use of a sulfonylurea are significantly associated with the development of probable dementia in [our patient population],” according to a team of researchers from Juntendo University in Tokyo, Japan.

The OE test has been validated and used in recent studies to assess olfactory sensation. It includes a self-completed olfaction test kit, with which an individual identifies various types of odours from paper cards. The odorants included Indian ink, wood, perfume, menthol, orange, curry, cooking gas, rose, Japanese cypress wood, plus three additional, as follows: socks that smell of sweat, condensed milk, and roasted garlic. Olfactory dysfunction was defined as having score of ≤7 out of a total of 12. [Chem Senses 2014;39:39-46; Ann Otol Rhinol Laryngol 2012;121:413-418]

“Despite the clinical relevance and accessibility of olfactory function testing, [the sense of smell] is often overlooked as an early marker of future dementia in clinical practice,” the researchers noted. “Olfactory function testing could provide an opportunity for early intervention to slow down or halt cognitive decline in older patients with T2D who do not have clinically apparent symptoms of cognitive decline.”

In the study, the researchers followed 151 older Japanese T2D outpatients (median age 71 years, 50.3 percent men, median duration of diabetes at baseline 13 years) for 3 years. At baseline, 112 patients had normal cognitive function (MMSE score 27) and 39 had possible cognitive impairment (MMSE score ≥24 to ≤26). The mean OE score was 7.

Fourteen patients (9.3 percent) developed probable dementia after 3 years. They were older (median, 74.5 vs 70 years), had lower education levels, lower baseline scores on MMSE (median, 25 vs 28) and OE (median, 3.5 vs 7) tests, higher total protein (median, 7.5 vs 7.3 g/dL) and leptin (median, 30 vs 28 ng/mL) concentrations, and higher urinary albumin excretion (median, 52.1 vs 23.6 mg/g creatinine) compared with the patients who did not develop the neurocognitive disorder. [Diabetes Res Clin Pract 2021;174:108740]

“Notably, 14.2 percent of patients with olfactory dysfunction at baseline developed probable dementia. In contrast, none of the patients with normal olfactory function in the possible cognitive impairment group [did] over 3 years of follow-up,” the researchers pointed out.

On stepwise multivariate regression analysis, a decline in OE test score over 3 years strongly correlated with that in MMSE score (p=0.001). This result, according to the researchers, established the possibility of olfactory impairment being involved in the pathogenesis of cognitive decline. [J Am Geriatr Soc 2018;66:140-144]

While unclear, there are several mechanisms underlying the link between the decline in the sense of smell and cognitive abilities in T2D. For the most part, insulin in the brain may regulate both cognition and olfaction, given that insulin receptors are abundantly expressed throughout the brain, especially in olfactory-related regions such as the olfactory epithelium, olfactory bulb, and hippocampus. [Trends Endocrinol Metabolism 2005;16:59-65; Eur J Pharmacol 2013;719:170-179; Chem Senses 2012;37:769-797]

Two previous studies demonstrated that intranasal insulin administration could improve cognitive function in patients with T2D, as well as olfactory function in healthy volunteers. These support the hypothesis that insulin action in the brain acts as a mediator of olfaction and cognition, the researchers pointed out. [Diabet Care 2014;37:751-759; Sci Rep 2019;9:7222]

At the end of the day, diabetes-related cognitive decline adversely affects self-management and medical adherence in T2D, especially among older patients. “Thus … early detection of cognitive impairment by identifying makers for early diagnosis and predicting cognitive decline in patients with T2D is needed. Our data suggest that the OE test is useful for this purpose,” they said.