Alzheimer’s disease begins in the olfactory bulb, with evidence suggesting that this is related to failing drainage of cerebrospinal fluid from that part of the brain. It has been noted that a faltering of the sense of smell takes place with aging. This may be a useful way to assess the overall state of the brain on the path towards neurodegenerative conditions, but, considered as a whole, comparatively little work has taken place on this aspect of sensory decline with age.

Olfaction, from an evolutionary aspect, is the oldest of our senses. Across different species, it modulates the interactions between an organism and the surrounding environment even before birth. Nevertheless, the majority of the studies on chemo-sensation have been developed in rodents, with a less rich literature in humans. The incomplete understanding of human olfaction may relate to the complexity of studying the multiple olfactory centers distributed in several brain regions comprising the cortical and the subcortical pathways, e.g., olfactory bulb, piriform and entorhinal cortex, amygdala, orbitofrontal cortex, and hypothalamus. This anatomical heterogeneity implies an extensive connection among the olfactory sensory areas which constitute a complex network essential to associate the olfactory stimulus with other cerebral regions, such as those involved in the processing of memories and emotions and multisensory integration with other senses.

Another challenge facing smell research in humans relates to its minor clinical implication as compared to impairment of vision and hearing: the occurrence of blindness or deafness produces a massive personal and social deficit which severely disrupts someone’s life. In line with these observations, the different attention paid to these three senses has been also described, in that older adults in the US received assistance for vision and hearing deficits, whereas no testing for olfactory dysfunction was performed. While vision and hearing have been treated as primary senses for general health, olfaction is gaining increasing importance in clinical settings since its impairment represents an overarching non-invasive biomarker in predicting dementia during aging. With the frequent decline in smell acuity, mostly attributed to the reduced turnover of the olfactory neuroepithelium with aging, the early and pronounced olfactory deficit described in different neurodegenerative diseases, ranging from Alzheimer’s to Parkinson’s and Huntington’s diseases remains yet poorly understood.

In an attempt to put olfaction forward as an early biomarker for pathological brain aging, we draw a comparison with vision and hearing, regarded as more relevant for general health. This perspective article wants to encourage further studies aimed at understanding the mechanisms responsible for the early smell dysfunction in individuals a decade or more before the onset of cognitive symptoms.