We studied the relation of the ability to identify familiar odors to the development of AD in nearly 500 older persons without evidence of cognitive impairment at enrollment. The analyses suggest that among older persons without the clinical manifestations of AD or its precursor, MCI, olfactory dysfunction is related to both the level of AD pathology in the bran and the risk of subsequently developing prodromal symptoms of AD in the form of MCI and declining episodic memory.
It has long been recognized that olfaction is impaired in persons with clinically diagnosed AD [22
]. Olfactory function is also impaired in MCI [26
], a precursor of AD, and in those with at least one copy of the apolipoprotein E ε4 allele [28
], a well established risk factor for AD. In previous research in this cohort, we showed that odor recognition performance predicted incidence of MCI and AD, rate of cognitive decline, and level of AD pathology on postmortem examination [4
]. The present analyses extend these findings by showing that the association of olfactory function with the clinical and pathologic manifestations of AD can be seen in otherwise asymptomatic individuals and that if persists even after accounting for the effects of other recognized behavioral and genetic markers of the disease. These data suggest that olfactory testing, when combined with other behavioral and biologic markers, may contribute to early detection of AD.
Prior research in this cohort suggests that the association between olfactory dysfunction and clinical AD is largely due to the accumulation of AD pathology, particularly neurofibrillary tangles, in central olfactory regions, especially entorhinal cortex and hippocampus [5
]. The involvement of these sites is important because they are thought to be among the first areas affecting by the pathologic changes of AD [36
]. Thus, olfactory symptoms might conceivably precede cognitive impairment in AD by a substantial period of time. In addition, decline occurs in other sensory systems with advancing age in association with cognitive decline [39
]. Because the entorhinal cortex processes input from multiple sensory modalities, it is possible that subtle changes in other sensory functions might be early signs of AD.
Confidence in these findings is strengthened by several factors. The diagnoses of MCI and AD were based on uniform structured clinical evaluations and widely accepted criteria. Rates of participation in follow-up clinical evaluations and brain autopsy were high. Odor identification was assessed with a standard scale. Episodic memory and AD pathology were assessed with previously established composite measures. An important limitation is that the cohort is selected so that the generalizability of the findings remains to be determined. In addition, securely establishing the value of olfactory testing in early diagnosis will likely require more extensive assessment of olfactory processing conducted proximate to death in a larger group of people.