Relationships between lewy and tau pathologies in 375 consecutive non‐Alzheimer's olfactory bulbs

The olfactory bulb is highly susceptible to Lewy-related pathology (ie, Lewy bodies and Lewy neurites). Here we report the frequency of Lewy-related pathology in a range of non-Alzheimer’s disorders and the factors that might contribute to risk for Lewy-related pathology, using multiple logistic regression methods. Excluding Alzheimer’s disease (AD) and overt Lewy body disease, olfactory bulbs from 375 consecutive elderly brains were studied with a-synuclein immunohistochemistry. We scored (1) the density and distribution of olfactory Lewyrelated pathology, (2) Lewy-related pathology in additional brain regions vulnerable for Lewy-related pathology, and (3) phospho-tau immunoreactivity. Genotyping for APOE and MAPT was performed in progressive supranuclear palsy (PSP) and corticobasal degeneration cases. Olfactory Lewy-related pathology was detected in 43 cases (11%); see Table 1. The distribution and morphology of Lewy-related pathology were similar to previous reports (Supplemental Figure). Twenty-one of 43 cases (49%) were discovered to have Lewy-related pathology in the olfactory bulb, and in 6 cases (14%) it was restricted to the olfactory bulb (Supplemental Table), further supporting the value of the olfactory bulb for screening for Lewy-related pathology. Subjects with Lewy-related pathology were older and had greater Braak neurofibrillary tangle (NFT) stage for both the overall cohort and the PSP subgroup. Logistic regression modeling revealed Braak NFT stage (odds ratio, 4.4, P 5 0.003) as an independent variable for Lewy-related pathology in PSP, and both Braak NFT stage (odds ratio, 1.8; P 5 0.01) and age (odds ratio, 1.1; P 5 0.04) were significant for the overall cohort. Within the olfactory bulb, no correlation was found between tau burden and Lewy-related pathology (r 5 0.08, P 5 0.60). Neither the APOE nor the MAPT genotype was associated olfactory bulb Lewy-related pathology. Regarding Lewy-related pathology among other neurodegenerative disorders, we confirmed that Lewy-related pathology appears to be associated with aging, which is in line with a previous report in a multicenter elderly cohort; however, the underlying mechanism of Lewy-related pathology in aging remains to be determined. In contrast, it has been reported that subjects with Lewy bodies in the setting of advanced AD had both younger age at death and age of dementia onset compared with those without Lewy-related pathology. In a hospitalbased cohort, Jellinger reported an association between concurrent Lewy-related pathology and Alzheimer’s pathology, regardless of age at death in the 7th to 10th decades. These findings suggest that disease-specific factors accelerate Lewy-related pathology in the olfactory bulb in AD. The current study is the largest series of pathologically confirmed PSP to undergo screening for olfactory bulb Lewy-related pathology. It is noteworthy that Alzheimer’s-type tau pathology quadruples the risk for Lewy-related pathology in PSP, even though cases with advanced Alzheimer’s pathology were specifically excluded. In this study, we confirmed that olfactory bulb screening identifies Lewy-related pathology in a range of non-AD neurological conditions in which this pathology was not previously suspected; moreover, in some cases this is the only brain region affected. The pathogenesis of olfactory bulb Lewyrelated pathology might be different from that found in AD.