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Smell identification, cognition and hormone therapy

14 November, 2016

Failure to identify odors may be an early sign of cognitive impairment. A recent study included persons aged 65 years or older without dementia (males and females, n = 1037) [1]. They were asked to identify 40 different odors, and their success rate was scored. Also, a brain MRI and a battery of cognitive tests were performed. Follow-up at 2 and 4 years in 757 participants showed that low baseline scores correlated with cognitive decline and the appearance of Alzheimer's disease. MRI hippocampal volume did not show predictive utility in this cohort. The investigators suggested that the inexpensive smell test could be useful as a predictor of future cognitive impairment.


The above study by Devanand and colleagues is one of several similar ones showing that low performance in smell testing correlated with a higher risk of cognitive impairment [1]. In a recent study among 1430 cognitively normal participants (mean age 79.5 ± 5.3 years, 49.4% men, mean 3.5 years of follow-up), there were 250 incident cases of minimal cognitive impairment (MCI). An association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in Brief Smell Identification Test score, and an increased risk of MCI was established [2]. The same was demonstrated in patients with Parkinson's disease: worse baseline olfaction was associated with long-term cognitive decline [3]. Interestingly, even a simple test, using a container of 14 g of peanut butter, which was opened and moved up 1 cm at a time during the participant's exhale-until-odor detection, while measuring the distance between the subject's nostril and container, appeared to be a sensitive and specific test for probable Alzheimer's disease [4]. A nice overview on the influence of age on the olfactory system and pathways mentioned that the magnitude of olfactory deficits, which occur in neurodegenerative and neurodevelopmental diseases, appears to be associated with the relative damage to the basal cholinergic system [5]. Perhaps the link between cognition and olfactory function involves the apolipoprotein E É›4 allele (ApoE) that has been associated with increased cognitive and olfactory deficits [6].

The question arises whether there might be an association between postmenopausal hormone therapy (HT) and smell deficits. There is a lack of data on this issue, and the clinical information is controversial. Some studies found no association; as an example, Hughes and colleagues did a cross-sectional study of 62 postmenopausal women and could not demonstrate any influences of opposed or unopposed estrogen HT on a range of olfactory tests [7]. Contrarily, in another study, a total of three olfactory and 12 neurocognitive tests were administered to 432 healthy postmenopausal women with varied HT histories. National Adult Reading Test and Odor Memory/Discrimination Test scores were positively influenced by HT [8]. In view of the above mentioned potential link between ApoE allele and olfactory function, and studies on the neuroprotective effects of estrogen, the following results of a trial investigating olfactory threshold sensitivity in non-demented, postmenopausal women (mean age 73 years) seems intriguing [9]. ApoE-positive females who had received HT performed significantly better than those without HT, but at levels similar to those of ApoE-negative females. Based on these data, the authors suggested that HT may offer protection against loss of olfactory function in ApoE-positive individuals in preclinical stages of Alzheimer's disease.

Smelling is a complicated and multifactorial process, which involves many nasal factors, neuronal pathways and brain centers. It is therefore difficult to isolate the effect of a single derangement or therapy on the integrity and function of the odor-detecting system. Unlike in animals, when better smell ability may determine survival, in humans the importance of smelling is not considered high. Nevertheless, it becomes clear that a decline in the performance of this sense should raise a suspicion for an early neurodegenerative process.

Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel


  1. Devanand DP, Lee S, Manly J, et al. Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community. Neurology 2015;84:182-9
  2. Roberts RO, Christianson TJ, Kremers WK, et al. Association between olfactory dysfunction and amnestic mild cognitive impairment and Alzheimer disease dementia. JAMA Neurol 2016;73:93-101
  3.  Fullard ME, Tran B, Xie SX, et al. Olfactory impairment predicts cognitive decline in early Parkinson's disease. Parkinsonism Relat Disord 2016;25:45-51
  4. Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer's disease. J Neurol Sci 2013;333:19-24
  5. Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol 2014;5:20
  6. Oleson S, Murphy C. Olfactory dysfunction in ApoE ɛ4/4 homozygotes with Alzheimer's disease. J Alzheimers Dis 2015;46:791-803
  7. Hughes LF, McAsey ME, Donathan CL, Smith T, Coney P, Struble RG. Effects of hormone replacement therapy on olfactory sensitivity: cross-sectional and longitudinal studies. Climacteric 2002;5:140-50
  8. Doty RL, Tourbier I, Ng V, et al. Influences of hormone replacement therapy on olfactory and cognitive function in postmenopausal women. Neurobiol Aging 2015;36:2053-9
  9. Sundermann EE, Gilbert PE, Murphy C. The effect of hormone therapy on olfactory sensitivity is dependent on apolipoprotein E genotype. Horm Behav 2008;54:528-33

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