Olfactory Impairment in Presymptomatic Alzheimer's Disease

Abstract

Alzheimer's disease (AD) impairs olfaction, but it is uncertain how early this occurs in the disease process and whether the effect can be accounted for by other behavioral or genetic markers of the disease. We administered the Brief Smell Identification Test (BSIT) to 471 older people without dementia or cognitive impairment who then completed annual clinical evaluations and brain autopsy at death. BSIT score was associated with more rapid decline in episodic memory and with increased risk of developing incident mild cognitive impairment (MCI), even after controlling for baseline level of episodic memory and possession of an apolipoprotein E ε4 allele. In 34 people who died without evidence of cognitive impairment, lower BSIT score was associated with higher level of AD pathology, even after controlling for ε4 and for level of episodic memory function when olfaction was assessed. These analyses suggest that among older people without clinical manifestations of AD or MCI, olfactory dysfunction is related to both the level of AD pathology in the brain and the risk of subsequently developing prodromal symptoms of the disease and that these associations persist after accounting for the effects of other recognized behavioral and genetic markers of the disease.Alzheimer's disease (AD) is a leading cause of disability in old age, and the public health challenges posed by the disease are likely to increase in the coming decades with the aging of the United States population. Definitive classification of AD currently requires a brain autopsy, underscoring the need for biological or behavioral markers of the disease in the living. In particular, markers are needed to support early diagnosis because diseasemodifying therapeutic compounds for AD are under development, and it is generally assumed that such compounds will be most effective early in the disease course before pathology is widespread [1][2][3]. In addition to certain practical characteristic (i.e., reliable, non-invasive, simple to perform), the ideal biomarker should be related to AD neuropathology [1] in those with little or no clinical evidence of the disease. In view of the substantial clinical and neuropathologic heterogeneity of AD, accurate early diagnosis will most likely require the use of several markers in conjunction. In this context, therefore, markers that have little or no correlation with other markers will be most useful. In the present study, we focus on olfactory impairment as an early sign of AD. With clinical and neuropathologic data from the Rush Memory and Aging Project, we previously showed that difficulty identifying familiar odors predicted subsequent development of mild cognitive impairment, a precursor to dementia in AD [4], and was robustly correlated with level of AD pathology on postmortem examination [5]. Here, we conduct further analyses of individuals without dementia or MCI at study enrollment to test whether the association of olfactory dysfunction with AD is evident in this well functioning subgroup and whether it pe...

Odor identification and Alzheimer disease biomarkers in clinically normal elderly

“…In this group, lower Brief Smell Identification Test score was associated with a higher level of AD pathology on autopsy (measured by a composite measure of cortical amyloid plaques and NFTs), after controlling for age, sex, education, time from olfactory testing to death, APOE e4 carrier status, and episodic memory. 32 This finding supports the notion that odor identification ability is linked with the pathologic manifestations of AD, even in asymptomatic individuals; however, it is important to note the small sample size (n 5 34) and the advanced age of this sample (mean 85.2 years, SD 5 6.4 years).…”

The human brain representation of odor identification

“…In the clinic OI tests have been shown to have high sensitivity and specificity for predicting Alzheimer's disease (AD) at an early stage. This OI deficit is considered a central phenomenon as olfactory threshold, detection, and discrimination abilities are preserved (Arnold et al 1998;Morgan et al 1995;Serby et al 1991;Wilson et al 2007Wilson et al , 2009. Since AD pathology is first observed in entorhinal cortex and subsequently in the hippocampus (Braak and Braak 1992), OI impairments may arise from medial temporal lobe (MTL) pathology.…”

Olfactory assessment using the NIH Toolbox

“…4 Importantly, smell dysfunction is one of the hallmark "preclinical" signs of neurodegenerative diseases such as Alzheimer disease and Parkinson disease. [4][5][6][7] There are a variety of ways to assess olfactory capabilities and olfactory loss in humans, which were reviewed by Doty, 8 but most are not consistent with the requirements of the NIH Toolbox initiative to be an "off the shelf," brief and inexpensive test, suitable for use in ages 3 to 85 years. 9 Odor detection is evaluated by measuring the lowest concentration of an odorant at which an individual a) can just detect the odor's presence, or b) can discriminate it from a sample of odorless air.…”