The Role of Olfactory Challenge Tests in Incipient Dementia and Clinical Trial Design

Abstract

The brain changes associated with Alzheimer's disease (AD) develop slowly over many years before the onset of dementia. Biomarkers for AD that allow its detection during this clinically silent phase will be hugely important when disease-modifying treatments that halt or slow its progression become available. Early detection, leading to early treatment, may in some cases avert dementia. Biomarkers aid our understanding of the presymptomatic stages of the disease and enable the identification of individuals with early disease who, by participating in clinical trials of investigational treatments with disease-modifying potential, contribute unique and vital information necessary to evaluate novel therapies. Most currently available AD biomarkers are expensive and not widely available and there are major efforts underway to find cheaper, simpler options. The olfactory system is affected by AD and the results from simple and inexpensive tests of the sense of smell, especially when paired with other information, can help identify individuals early in the disease. We review recent literature relevant to the use of simple olfactory tests, including some novel approaches, as aids to the early detection of AD. We consider their possible role in the design and conduct of clinical trials and suggest how in the future, when more effective treatments become available, they might be integrated into screening programs for early AD detection.

Olfaction and risk of dementia in a biracial cohort of older adults

“…Evidence suggests that one of the earliest events in the AD-related degenerative process is involvement of the olfactory bulb and tract. 24 Olfactory bulb concentrations of tau, b-amyloid, and a-synuclein have been shown to significantly increase with the Braak stages, 3 and the degree of tau, b-amyloid, and a-synuclein pathology in the olfactory bulb has been shown to reflect the degree of respective pathologies in other brain regions, 25 suggesting a potential role for olfactory testing as a severity and progression marker in AD. 4 Deficits in OI precede impairment on olfactory threshold detection tasks 26 and remain after cognitive measures and odor detection deficits are controlled for, 5 suggesting a pathophysiologic process that originates near the central olfactory structures in the medial temporal lobe.…”

“…Olfactory testing may be a simple, inexpensive, and highly sensitive method of identifying older adults at risk for developing dementia, particularly when combined with other early markers. [1][2][3] While it is well established that olfactory deficits are present in symptomatic Alzheimer disease (AD), 4 recent studies have demonstrated that deficits in olfactory functioning occur very early in the disease process, often preceding the onset of other clinical symptoms. 5 In addition, several studies have reported that olfactory deficits in cognitively normal older adults are associated with increased risk for cognitive decline and dementia.…”

Efficacy of rivastigmine transdermal therapy on low food intake in patients with Alzheimer's disease: The Attitude Towards Food Consumption in Alzheimer's Disease Patients Revive with Rivastigmine Effects study

“…6,7 Further potential mechanisms for this improvement of appetite in patients with AD might be both the inflammatory effects of ChEI in cholinergic pathways, and their ability to improve smell and taste perception by increasing the acetylcholine concentration in olfactory mucosa and taste buds, respectively. 24,25 In addition to rivastigmine's inhibition of ChE, it might further contribute to improved swallowing by inhibiting BuChE. 9 All of these potential mechanisms serve as targets for illumination by future studies.…”

Acetylcholinesterase inhibitors are associated with weight loss in older people with dementia: a systematic review and meta-analysis

“…Conversely, it has been reported that AChEIs might improve nutritional aspects through anti-inflammatory effects over cholinergic pathways and their improving sensation of smell and taste 5 51. Moreover, improvement in swallowing function due to increased acetylcholine concentration by AChEIs may have an additional role in improving nutritional aspects 52…”

“…One is the occurrence of repeated actions and behavioural disorders due to episodic memory and impairment in attention resulting in increased energy loss in patients with dementia 3. Another potential explanation is alteration of the sensation of smell and taste in addition to impaired swallowing function due to cholinergic deficits 4 5. Cognitive deterioration affects daily functional status and instrumental activities which result in disability, dependence and decreased oral intake 6.…”