Neuroimaging biomarkers and impaired olfaction in cognitively normal individuals

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The prevalence and severity of impaired olfaction increases with age.1 It affects more than half of the population aged 65 to 80 years, and 62 to 80% of persons older than 80 years.1 Impaired olfaction negatively affects quality of life, enjoyment of food, physical and mental well‐being and safety, and mortality.2 The association with increased mortality in older individuals may be mediated by cognitive impairment.2
Factors that may contribute to olfactory loss in aging include damage to olfactory epithelium, nasal engorgement, sensory loss of receptor cells to odorants, decrease in mucosal metabolizing enzymes, and neurochemical changes in the brain.1 However, olfactory impairment in aging or neurodegenerative disease may result from the expression of aberrant proteins in the olfactory system that cause structural or functional abnormalities in the olfactory system (eg, olfactory epithelium, olfactory bulb, central olfactory cortex, or olfactory circuitry).1
Olfactory impairment has been associated with cognitive decline,5 mild cognitive impairment (MCI),6 Alzheimer disease (AD) dementia,7 vascular dementia,12 Parkinson disease (PD),13 dementia with Lewy bodies,14 and the progression from MCI to AD dementia.6 In cognitively normal (CN) elderly individuals, worse odor identification (OI) has also been associated with markers of brain pathology, such as increased cortical amyloid and thinner entorhinal cortex,15 and with neurofibrillary pathology in the entorhinal cortex and hippocampus in autopsy studies.16 Thus, changes in olfactory function in CN persons could represent preclinical neurodegenerative disease.3
There is a need for inexpensive noninvasive tests to identify older healthy persons potentially at risk for AD for enrollment in AD prevention trials. One of the earliest brain regions affected by AD is the olfactory system,17 suggesting that olfactory impairment may be an early sign of AD brain pathology, an intermediate marker in the causal pathway from brain biomarker pathology to cognitive impairment. Amyloid‐β (Aβ) accumulation has been described in areas of the olfactory network in AD and amnestic MCI participants but also in elderly persons with normal neuropsychological test scores.19 A recent meta‐analysis suggested that odor identification and recognition could be the most interesting candidate for inclusion in a group of biomarkers to detect subclinical AD,20 especially when combined with clinical/neuropsychological21 assessment and imaging biomarkers.22
We hypothesized that in vivo neuroimaging biomarkers of AD pathology are associated with olfactory impairment among older CN individuals. The objective of the present study, therefore, was to examine the cross‐sectional associations between neuroimaging measures of amyloid accumulation and neurodegeneration and a simple measure of OI in a large population‐based cohort of CN older persons.

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