Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease.

Olfactory dysfunction is an early and common sign in various neurodegenerative diseases. Microsmia or anosmia is present in approximately 90% of patients with Alzheimer’s disease (AD)1 and accumulating evidence suggests that this psychophysical biomarker predicts incident mild cognitive impairment (MCI),2 conversion of MCI to AD,3 more rapid cognitive decline in older adults initially free of dementia,4 and also correlates with severity of dementia and abundance of neurodegenerative disease pathology in the brain.5, 6 Olfactory deficits are found in other neurodegenerative disorders as well, especially Parkinson’s disease7, 8 and Huntington disease,9 and to varying degrees in frontotemporal dementias and corticobasal syndromes,10 pure autonomic failure,11 multiple system atrophy,12 Guamanian ALS-Parkinson’s-Dementia Complex,13 idiopathic ALS,14 progressive supranuclear palsy,15 and cerebellar degenerations.16, 17 The neuropathological basis of olfactory dysfunction in AD and PD is thought to be due mainly to accumulations of disease-related lesions, especially tau pathology in AD andα-synuclein pathology in PD, that occur in the olfactory bulb and primary olfactory sensory cortices of the cerebrum.18–23 The olfactory epithelium (OE) is a pseudostratified columnar epithelium lying deep within the recesses of the superior nasal cavity (for review, see24). It is composed of a mixture of mulitpotential and committed stem cells (basal cells), supporting cells, and chemosensory olfactory receptor neurons. Mature neurons give rise to fine, unmyelinated axons that form bundles (olfactory fila) that ascend through the cribriform plate to synapse in the olfactory bulb. Early research on the OE in AD described tau and neurofilament immunoreactive dystrophic neurites in the lamina propria adjacent to the epithelium layer in subjects with AD but not control subjects.25, 26 However, subsequent studies reported that dystrophic neurites, which also were found to express ubiquitin, α-, β-, and γ-synucleins, and amyloid-β, could be found in normal aging and other neurodegenerative diseases as well.27–30 In light of this presumed non-specificity, interest in the OE for diagnostic or mechanistic research into AD, PD, and other neurodegenerative diseases waned. Still, these previous studies are relatively few in number, had small sample sizes in each diagnostic group, and may have been otherwise confounded by the limited sensitivity and specificity of reagents available at the time and a variety of other technical challenges inherent in working with OE tissues. Thus, the frequency, extent, and disease specificity of these lesions and other forms of pathological protein expression have not been established, and the degree to which they may be associated with brain pathology or olfactory dysfunction is not known. Over the last twenty years, we have collected OE in many neurodegenerative disease and non-neurological control cases that have been autopsied in protocols of the University of Pennsylvania’s Center for Neurodegenerative Disease Research (CNDR). At the same time, there have been steady improvements in the sensitivity and specificity of immunochemical reagents to reveal pathological proteins in tissue, as well as the discovery of new proteins, such as TDP-43, that play important roles in neurodegenerative diseases.31 Here we present findings in a large sample of neuropathologically verified AD and control cases, as well as other neurodegenerative diseases representing a spectrum of tauopathies, synucleinopathies, and TDP-43 proteinopathies.