Objective: Assess olfactory dysfunction in carriers of the p.N279K and p.P301L MAPT mutations, which cause FTDP-17, to understand how genotypic differences contribute to the severity and character of olfactory dysfunction associated with neurodegenerative disease.

Background: Olfactory dysfunction is a common non-motor manifestation often preceding motor or cognitive symptoms in Parkinson’s disease, Alzheimer’s disease, spinocerebellar ataxia, corticobasal degeneration, and other neurodegenerative diseases. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Since the p.N279K and p.P301L MAPT mutations have different molecular, neuropathological and phenotypic consequences, evaluating differences in olfactory dysfunction in carriers of these two mutations is able to provide unique insight into how differences in genotype contribute to the severity and the character of olfactory dysfunction associated with neurodegenerative disease.

Methods: Olfactory dysfunction was evaluated in members the PPND (p.N279K) and Gdansk (p.P301L) kindreds using the University of Pennsylvania Smell Identification Test. In the PPND kindred, 20 mutation carriers and 11 family-member controls were evaluated; nine of these had two to four replicate tests to longitudinally characterize changes in olfactory dysfunction. In the Gdansk kindred, single tests were administered to eight mutation carriers and eight age- and education-matched controls.

Results: Olfactory dysfunction in carriers of both MAPT mutation carriers is strongly age-dependent, precedes symptomatic onset, and is allele specific, with p.N279K carriers showing more severe deficit than p.P301L carriers. Principal component analysis using individual odor responses revealed that olfactory dysfunction is not odor-class specific, even though kindred members cluster according to genetic and disease status.

Conclusions: Olfactory function is impaired in affected and at-risk carriers of MAPT mutations in an age-dependent and allele-specific, but not odor-class specific, manner. This clearly implicates MAPT in normal olfactory function and indicates that mutations having distinct effects on MAPT function differentially affect olfactory dysfunction. This MAPT allele-specific effect on olfactory dysfunction suggests that genetic variability impacts olfactory function in neurodegenerative diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/allele-specificity-in-neurodegenerative-olfactory-dysfunction/