Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer's disease

J Neural Transm (Vienna). 2015 Oct;122(10):1475-97. doi: 10.1007/s00702-015-1404-6. Epub 2015 May 6.


We interact with the physical world through our senses, and these aid our behavioral performance and various activities of life. Sensory information is transmitted in neuronal networks, and the brain optimally interprets the external and internal milieu/environment. This paper delineates the framework in which the pathogenesis of memory and cognitive dysfunction is underpinned by sensory olfactory dysfunction. ERC is the gateway for olfactory input to the hippocampus, and there is seamless synchronization between sensory function and hippocampal activity. Transmission of olfactory information to the hippocampus is sequential-it is projected from the olfactory receptors to olfactory bulb to the primary olfactory cortex (comprised the anterior olfactory nucleus, the olfactory tubercle, and the piriform cortex) to the entorhinal cortex (ERC). Through perforant pathway ERC enables olfactory inputs to effectively excite hippocampal neurons. One of the earliest pathological changes in Alzheimer's disease (AD) include the olfactory dysfunction and the atrophy in ERC and hippocampus (rate in ERC is higher than in the hippocampus). Olfactory dysfunction negatively impacts the ERC and the deafferenting of the hippocampus from olfactory inputs upregulates memory decline. Olfactory dysfunction, therefore, is an important and early correlate of AD pathology. A number of factors described here may cause olfactory dysfunction; this may lead to hypoperfusion, hypometabolism, impaired synaptic transmission, and variable atrophy in olfaction-related regions. Improvement in olfactory function, therefore, is an important goal in order to attenuate cognitive neuropathology in aging and AD. This article seeks to provide a comprehensive and balanced overview of olfactory neuropathology in incipient AD, and suggests strategies to enhance olfactory function and ameliorate cognitive decline.

Keywords: Alzheimer’s disease; Entorhinal cortex; Hippocampus; Olfactory dysfunction; Perforant pathway; Soluble Aβ.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / physiopathology*
  • Animals
  • Brain / physiopathology
  • Disease Progression
  • Humans
  • Olfaction Disorders / physiopathology*
  • Olfactory Perception / physiology