Olfactory deficits in normal aging, cognitive decline, and Alzheimer’s disease: What do they mean for research and practice?

Neurofibrillary tangles, a hallmark pathological feature of Alzheimer’s disease (AD), are found in the olfactory bulb early in the disease course of patients with AD, and odor identification deficits during life correlate with tangles in the olfactory bulb and its projection areas at autopsy (1,2). Therefore, after initial clinical studies established olfactory deficits in patients with AD compared to cognitively intact control subjects, (3,4) subsequent research has focused on the value of olfactory deficits in predicting the transition from mild cognitive impairment (MCI) to AD, and their association with cognitive decline in older adults without cognitive impairment (5,6) The most prominent deficit is in odor identification, which involves identifying a specific odor when presented to the nostrils, typically in the context of multiple choice testing. This type of testing is useful in humans because they possess markedly inferior olfactory abilities when compared to other mammalian species, e.g., canines and rodents, and therefore multiple choice items with very distinct odors are needed, e.g., an item presents the choices of paint thinner, cherry, coconut and cheddar cheese in the most widely used odor identification test, the scratch-and-sniff University of Pennsylvania Smell Identification test (UPSIT) (7). There are minor cross-cultural differences, and versions in different languages catering to specific countries/regions are available for the UPSIT. Deficits in odor discrimination, i.e., distinguishing between two odors, also occur in patients with MCI and AD, but are not as robust as odor identification in distinguishing patient groups (7). Odor sensitivity, which is the threshold above which an odor can be detected (tested by the same odor presented sequentially in different concentrations), can also be impaired but this decline usually occurs later in the disease process. This set of findings indicates that the olfactory deficit in MCI and AD is not primarily a peripheral deficit in nasal odor detection but rather a central deficit in odor identification in the olfactory bulb where neurofibrillary tangles are present, and the regions that receive inputs from the olfactory bulb: piriform cortex, hippocampal and entorhinal cortex, and orbitofrontal cortex. Odor memory and odor naming, which are likely to be controlled and modulated in these regions, play key roles in the process of odor identification.

Olfaction in Normal Aging
There is a general decline in odor identification with aging, which accelerates markedly above age 70 (13). An inverse correlation with age and olfactory test scores is corroborated in some studies of older adults without cognitive impairment (2,16). Practically, this means that absolute scores on olfaction tests cannot be used to define abnormality, and age-adjustment needs to be employed in a manner not dissimilar to that done for neuropsychological test scores. Gender is another factor to take into account; women score slightly better than men on odor identification tests but this difference is not as strong as the age effect and is minimal in disorders that involve severe olfactory pathology, e.g., AD.

Olfaction and Cognitive Decline in Older Adults
There is growing evidence that odor identification deficits are associated with cognitive decline and with the transition from normal cognition to MCI (2,6) In our study of a multiethnic community cohort of 1037 older adults in North Manhattan with an average age of 80 years, impairment in odor identification was superior to deficits in verbal episodic memory identified on the 12-item, 6-trial Selective Reminding Test in predicting cognitive decline in cognitively intact participants (6). This raises the interesting question of whether an odor identification test may be superior to memory testing in screening older adults at risk of cognitive decline, either for prognostic or therapeutic purposes in future research. There is other evidence from epidemiological studies supporting the notion that odor identification deficits are associated with future cognitive decline (14,15). Therefore, early olfactory impairment may signify early Alzheimer pathology and may be useful as part of a preclinical detection strategy, though the magnitude of the effect in cognitively intact individuals (odds ratios range from 1.5 to 2.0 in most studies) is not large and odor identification testing needs to be combined with other measures.

Olfaction, Mild Cognitive Impairment and Alzheimer’s disease
In both clinical and epidemiological samples, we have shown that there is a clear increase in odor identification deficits from normal to MCI to AD (4,6). In our longitudinal study of 148 outpatients with MCI, broadly defined, baseline odor identification deficits were associated with a 4-fold increased risk of conversion from MCI to AD, and contributed unique variance in the prediction of conversion from MCI to AD (5). In addition to UPSIT scores, measures of verbal episodic memory, informant report of functional decline, hippocampal and entorhinal cortex atrophy predicted the transition from MCI to AD. The correlations among these measures were not strong, reinforcing the view that multiple clinical markers and biomarkers like odor identification deficits may need to be assessed to improve diagnostic and predictive accuracy.

Limitations to olfactory testing
The UPSIT is highly reliable and is well-validated, and shorter versions of the test do not appear to be as robust in distinguishing patient groups and predicting longer term outcome (5). Other tests comparable to the UPSIT are available but they have not been tested as extensively. The practical limitation to the use of an odor identification test is that it can be affected by smoking and upper respiratory infections if they occur at the time of testing, and there are rare individuals who have congenital anosmia and therefore cannot perform on such tests. Further, these tests are not highly specific and can be abnormal in schizophrenia, Parkinson’s disease, Lewy body dementia, and possibly vascular dementia. Therefore, if an odor identification test is used for screening or to estimate prognosis, it is important to exclude these conditions.

Conclusions
In Alzheimer’s disease, the evidence indicates that olfactory dysfunction, typically assessed by an odor identification test, can occur early in the disease process, even at a preclinical stage where such a test may be superior to testing for verbal episodic memory. Olfactory testing may need to be combined with other measures for use as a screening tool to identify individuals at risk of cognitive decline in the general population. There is moderate predictive utility for cognitive decline in normal older adults and for the transition from normal to MCI, and strong predictive utility for the transition from MCI to AD. The unique variance contributed by olfactory deficits in prediction suggests that it may be particularly useful when combined with other tests for such purposes. The relative utility for these deficits compared to other biomarkers has not yet been tested rigorously in large samples. Age-related changes occur with olfaction, but they also occur with other markers of MCI and AD, including cognitive test performance, measures of MRI atrophy, FDG PET and amyloid PET abnormalities, and decreased amyloid β42 with increased tau and phospho tau in cerebrospinal fluid (9-12). In addition to the advantage of being easy to administer and cost-effective because of its relatively low price, an odor identification test may be a useful measure to select/stratify patients in treatment trials of cognitively impaired patients, or prevention trials in cognitively intact individuals, because olfactory deficits can predict cognitive decline in cognitively intact individuals and are an early biomarker of AD neuropathology. Odor identification tests remain primarily a research tool, but some clinical practitioners do use them. In this context, odor identification tests can be administered to provide potentially useful information only when combined with a thorough clinical, neuropsychological and, if necessary, imaging evaluation for patients who present with cognitive decline and an uncertain diagnosis, taking into account the conditions that need to be excluded before administering an odor identification test.

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D.P. Devanand, MD, Professor of Psychiatry and Neurology; Director, Division of Geriatric Psychiatry, Columbia University Medical Center, New York, United States

Excerpted article as reprint from IPA’s newsletter, the IPA Bulletin, Volume 32, Number 1