**4. Alzheimer's disease, dementia and olfactory deficits**

Olfactory deficiencies are evident in a number of neurodegenerative disorders such as AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), MCI, PD and Huntington disease [40, 51, 56–59]. In an extensive two year study with six-monthly follow up, all MCI patients with lower range of olfaction score but no subjective smelling loss detected by standard UPSIT (University of Pennsylvania Smell Identification Test) developed AD. In contrast, in a control group of higher olfaction score, AD occurrence was nil [60]. A similar association of lower olfaction score with development of AD pathology was evident in a multiethnic community cohort with UPSIT test [61]. In a comparative OI analysis of FTD and AD patients with normal age matched control individuals, OI score of FTD patients differed significantly with control group, however, there was a close resemblance in OI pattern of FTD patients with OI in AD patients [62]. An analysis using Pocket Small Test as indicator of OI performance in AD patients and healthy young and age matched control group of individuals detected reduced OI in an older control group

*Sino-Nasal and Olfactory System Disorders*

through the lateral olfactory tract [13].

**3. Aging effects in the olfactory system**

Not only does the olfactory bulb send axons to higher order olfactory centers (afferent fibers), an even larger number of centrifugal axons originating in higher olfactory centers innervate the olfactory bulb glomeruli (efferent fibers) [6, 13, 14]. These centrifugal neurons have been shown to provide modulatory feedback to neurons in the different layers of the main olfactory bulb which is important for experiencedependent modulation [13]. The origin of the centrifugal fibers is in the locus coeruleus (noradrenergic), the horizontal limb of the diagonal band of Broca (cholinergic), and the raphe nucleus (serotonergic) [15–18]. The centrifugal fibers travel mainly through the anterior olfactory nucleus and the anterior commissure, and very little

Age-associated impairment in the sense of olfaction has been well documented [19–23]. Akin to neurodegenerative pathology, a decline in olfactory acuity and olfactory dysfunction are common features of the normal aging process [24–27] detectable in over 50% individuals ranging in age from 65 to 80 years and almost in 75% of those above 80 years [24, 28–30]. This decline in olfactory function is detected using different kinds of tests such as psychophysical, psychophysiological and electrophysiological tests that determine odor detection, identification and discrimination, odor related physiological changes in cardiac and respiratory system as well as odor-event related potentials [29]. However, studies analyzing the mechanism of non-pathological, normal chronological age-related decline of olfactory acuity and impaired olfactory function are limited, despite the fact that deficits in the olfactory sense are considered as important symptom for early and differential diagnosis of neurodegenerative disorders [28]. At the anatomical level, the sense of olfaction is affected by age-associated ossification and closure of foramina of the cribriform plate [29, 31]. There is evidence of a quantitative reduction in the olfactory epithelium and its replacement by respiratory epithelium in normal subjects of the aging population which is evident in biopsies of the upper nasal septum [32]. It is now clearly evident that in the course of normal aging, suboptimal olfaction and olfactory dysfunction are associated with a number of anatomical and physiological features such as age-associated thinning of the olfactory neuroepithelium, altered cellular patterns and regional distribution of nuclei of olfactory sensory and sustentacular cells [29], reduction of mucosal metabolizing enzymes and sensory loss of olfactory sensory cells to various odorants along with a cumulative effect of environmental exposure to the olfactory epithelium [30]. An additional causative factor is the parallel loss of olfactory function in direct correlation with a clear age-associated decline in the volume of the olfactory bulb in adults of both genders [33–35]. Other than the olfactory bulb, a reduction in volume of AON, amygdala, hippocampus and piriform cortex in the limbic system contribute to a loss of olfaction due to their pivotal role in olfactory processing [36]. Testing the sensitivity and response of isolated sensory neurons to odorant mixtures indicates a loss of olfactory sensitivity and specificity in neurons derived from older subjects [37]. In older individuals, there is evidence of decreased beta-event related synchronization in response to certain pleasant odorants and, therefore, these individuals rated such odorants as less pleasant, thereby, denoting a decline in olfactory processing [38]. A change in olfactory perception represents subtle olfactory dysfunction that appears to precede a number neurodegenerative disorders and is presumed due to loss of synaptic function [39, 40]. Subsequent studies have shown that loss in olfactory sensitivity and perception is heterogeneous and appears to be more specific to heavier molecules [41]. Inherent allelic variations of brain

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than in a younger control group, and AD patients had even reduced OI compared to their age matched control group [27]. At the cellular level, a characteristic neuropathological feature of AD is the appearance of neurofibrillary tangles consisting of hyperphosphorylated tau protein [63]. In relation to olfactory dysfunction, the two key hallmarks of AD neuropathology are the detection of amyloid-beta (Aβ) and hyperphosphorylated tau protein in the olfactory system; both have been detected together with impaired olfaction much before a clinical presentation of the disease [57]. An analysis assessing OI as indicator of presymptomatic AD pathogenesis in cognitively normal aged individuals shows an association of reduced OI with lower cognitive score and older age as well as increased ratio of total tau protein to phosphorylated tau protein in cerebrospinal fluid [64]. Therefore, at the behavioral level, diminished OI has emerged as a practical and affordable biomarker of AD pathology [64] as well as prodromal symptom of AD [65].
