Olfactory Measures as Predictors of Conversion to Mild Cognitive Impairment and Alzheimer’s Disease

Abstract

Background: Early biomarkers of prodromal Alzheimer’s disease (AD) are critical both to initiate interventions and to choose participants for clinical trials. Odor threshold, odor identification and odor familiarity are impaired in AD. Methods: We investigated the relative abilities of standard screening (MMSE) and olfactory measures to predict transitions from cognitively normal (CN) to mild cognitive impairment (MCI), from CN to AD, and MCI to AD. The archival sample of 497, from the UCSD ADRC, included participants who were CN, MCI, AD and converters to MCI or AD. Apoe ε4 status, a genetic risk factor, was available for 256 participants, 132 were ε4 carriers. A receiver operating characteristic curve (ROC) curve plots the trade-off between sensitivity and specificity. Area under the ROC curve (AUC) was used to determine diagnostic accuracy. Results: Different measures were better predictors at specific stages of disease risk; e.g., odor familiarity, odor identification and the combination showed higher predictive value for converting from MCI to AD in ε4 carriers than the MMSE. Combining odor familiarity and odor identification produced an AUC of 1.0 in ε4 carriers, MMSE alone was 0.58. Conclusions: Olfactory biomarkers show real promise as non-invasive indicators of prodromal AD. The results support the value of combining olfactory measures in assessment of risk for conversion to MCI and to AD.

Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer’s Disease

“…Our studies find that even in patients predisposed to AD due to a genetic mutation of PS1 there is evidence of viral infection in the OB suggesting that viral infection and inflammatory response in the OT are part of the etiology of the disease. Taken together with a parallel body of literature indicating that early AD is characterized by smell loss 1-3 , amyloid deposition in the olfactory epithelium (OE), and olfactory sensory neuron (OSN) dysfunction 4, 5 , our study raises the possibility that viral infection of the OB/OT accelerates AD. Because sniff-induced beta and theta-coupled gamma oscillations generated in the OB are directionally coupled to the hippocampus 25-28 , smell loss would result in decreased hippocampal gamma oscillations that have been postulated to lead to neurodegeneration and cognitive decline 29-31 .…”

“…Thus, it is essential to identify contributory pathological processes in early disease to prevent progression to dementia, disability, and death. An early process in AD, prior to clinical dementia, is a deficit in the sense of smell 1-3 accompanied by amyloid-beta (Aβ) deposition in the olfactory bulb (OB) 4, 5 . The OB receives olfactory input from olfactory sensory neurons in the olfactory epithelium (OE) 3, 6 then transmits olfactory information via the olfactory tract (OT) to the entorhinal cortex and hippocampus, brain regions essential for learning and memory that are affected in AD.…”

Sensory Loss and Dementia

“…This finding was replicated in a larger sample of 728 older community-dwelling individuals showing that subjects with intact cognition and normal olfactory identification did not transition to dementia after 4 years (Devanand and others 2020). Prediction of the conversion from MCI to AD dementia can also be improved by combining information about a person's ApoE genotype, those with 𝜺4 more likely to convert (Wheeler and Murphy 2021). Poor performance on odour identification tasks has also been more broadly linked to a faster rate of cognitive decline in people without dementia (Dintica and others 2019).…”

“…Epidemiological studies have linked individual sensory systems to cognitive decline and dementia (Livingston and others 2020;Tran and others 2020;Wheeler and Murphy 2021). In this section, we present evidence for the link between each type of sensory loss and neurobiology of dementia.…”

“…In other modalities the definition of sensory varies substantially. In vision, the tests used range from visual acuity to contrast sensitivity and in olfaction, the type of odour identification task used varies (Ikram and others 2012;Quarmley and others 2017;Dintica and others 2019;Swenor and others 2019;Livingston and others 2020;Wheeler and Murphy 2021).…”