In a group of community‐dwelling older people who died and underwent brain autopsy, ability to identify familiar odours proximate to death was inversely related to the level of Alzheimer's disease pathology. This association was primarily due to neurofibrillar pathology in the entorhinal cortex and hippocampus. The results suggest that impaired odour identification in old age is due in part to the accumulation of neurofibrillar pathology in central olfactory circuitry.
As noted above, two previous clinical–pathological studies did not observe an association between olfactory function and Alzheimer's disease pathology.1,2
However, these studies differ from the present study in important ways. Firstly, they assessed olfactory detection, whereas odour identification was assessed here. Thus, Alzheimer's disease pathology may affect higher order processes involved in identifying odours, but not lower order processes involved in their detection. Yet, tests of odour detection and odour identification are strongly correlated,27
perhaps because of the critical role of attention and anticipation in apparently simple acts of odour detection,28
and neurofibrillar pathology in Alzheimer's disease is characteristically present throughout the central olfactory system,6
including its first relay, the olfactory bulb,7,29
casting doubt on this explanation. A related issue is that olfactory detection can be difficult to reliably assess,30
and this might have affected previous results, especially as all participants in these studies had dementia when olfaction was assessed, and one study1
relied on a crude bedside test rather than a standard procedure. Secondly, the range of Alzheimer's disease pathology in the previous studies was restricted by limiting analyses to people meeting the pathological criteria for Alzheimer's disease and by reliance on categorical measures of Alzheimer's disease pathology. For example, nearly 90% of participants occupied the second of three points on a modified Braak scale in one study,2
and information on the Braak scale distribution was not provided in the other study.1
The lack of variability in Alzheimer's disease pathology in conjunction with binary measures of olfactory function may have limited the statistical power to detect an association between them.
Another factor differentiating this study from previous clinical–pathological research is that regional indices of neurofibrillar pathology were examined. Although prior research has shown that the level of neurofibrillar pathology in central olfactory regions is moderately correlated with levels of neurofibrillar pathology elsewhere in the brain,29,31,32
the correlations are far from perfect. We found that tangle density within components of the central olfactory system (ie, entorhinal cortex, CA1‐subiculum) was robustly related to odour identification performance, whereas tangle density in areas outside the system was not. This result supports the idea that neurofibrillar pathology is directly contributing to impairment in the ability to identify odours in old age. A previous clinical–pathological study of gait observed a similar regional dissociation in the effect of Alzheimer's disease pathology with gait impairment proximate to death associated with nigral but not cortical tangles.33
Thus, not only the level of neurofibrillar pathology, but also its regional distribution contributes to individual differences in a wide range of neurobehavioural functions in old age.
In neuroimaging studies of older people with Alzheimer's disease, olfactory functioning has been associated with metabolic and volumetric changes in medial temporal lobe.34,35,36
Our results show this association in people without dementia, consistent with studies showing reduced activation of central olfactory areas, including entorhinal cortex and hippocampus, during olfactory processing in older compared with younger people.37,38
Together, these data support the value of olfactory assessment for early detection of Alzheimer's disease.
In contrast with clinical–pathological studies of people with dementia,1,2
Lewy bodies were not related to olfactory impairment in this study of people with and without dementia proximate to death. The effect was in the direction observed in previous research, however, despite Lewy bodies being present in only one eighth of participants. These results are not inconsistent with a contribution of Lewy body pathology to age‐related olfactory dysfunction, therefore, although they imply that the effect may primarily occur after dementia is manifest or depend on brain regions not sampled in this study.
Confidence in these findings is strengthened by several factors. Odour identification was assessed with a standard test. Participants had a wide spectrum of odour identification ability and Alzheimer's disease pathology, enhancing our ability to observe an association between them. There was a high autopsy participation rate and a uniform postmortem examination with blinding to all clinical data, minimising important sources of error. The association of Alzheimer's disease pathology with odour identification persisted after controlling for presence of dementia or level of semantic memory. Alzheimer's disease pathology was assessed in a systematic fashion, and silver staining and immunohistochemistry produced comparable findings, suggesting that the observed association is robust.
This study also has important limitations. Findings are based on a selected cohort of older people, potentially reducing their generalisability. The advantage of studying olfaction in a defined population might be offset, however, by potential bias due to the likely low participation in brain autopsy in a clinical–pathological population‐based study. In addition, although the mean interval from smell assessment to death in this study was less than in previous research,1,2
it still exceeded 2 years, suggesting that these data may underestimate the strength of the association between Alzheimer's disease pathology and the ability to identify odours. Finally, we focused exclusively on odour identification; the association of Alzheimer's disease pathology with other olfactory functions remains to be established.