Objective: To evaluate (1) the association between neurofibrillary tangle staging and cognition for participants with diffuse Lewy Body (LB) pathology, (2) whether this association differs by sex.

Background: Sex differences in dementia are well known; women are more likely to have Alzheimer’s disease (AD) pathology whereas men are more likely to have pure LB pathology [1]. Comparison of AD pathologies in women and men, adjusting for age, education and other co-pathologies, showed that women have a higher tau tangle density [2]. Additionally, AD pathology is more likely to lead to a clinical dementia profile in women compared to men, primarily in association with neurofibrillary tangles [3]. In terms of LBD, AD co-pathology is common and is associated with a worse prognosis [4,5]. However, sex is included as a covariate in these few studies, and sex differences in terms of neurofibrillary tangle effects on cognition in participants with diffuse LB pathology are unclear.

Method: The analysis included data from Uniform Data Set (UDS) [6] and Neuropathology Data Set [7] from the National Alzheimer’s Coordinating Center including 39 past and present Alzheimer’s Disease Research Centers. The data included UDS visits conducted between September 2005 and August 2019. 128 women and 128 men with diffuse Lewy bodies, matched for age, education, and AD pathology staging were included.

[table1]

Braak stage was used for neurofibrillary tangle involvement. Moderation analysis was conducted with sex as the moderator, Braak staging as the predictor, CDR® Dementia Staging Instrument-Sum of Boxes score (CDR®-SOB) as the outcome, adjusting for age, education, Thal phase and neuritic plaque density.

[figure1]

Results: CDR® scores were similar across men and women. In the overall sample, increase in Braak staging was significantly associated with increase in CDR®-SOB (B=0.97, p<.001). Moderation analysis showed a significant interaction between sex and Braak staging (p=.033, Figure 2), with a significant association between Braak staging and CDR®-SOB only for women (B=1.47, p<.001; B=0.44, p=.34 for men).

[figure2]

Conclusion: Increased neurofibrillary tangle deposition is associated with worse cognitive decline in participants with diffuse LB pathology, and this association is moderated by sex in a sample of men and women with similar age, education and AD pathology staging.

References: [1] Barnes LL, Lamar M, Schneider JA. Sex differences in mixed neuropathologies in community-dwelling older adults. Vol. 1719, Brain Research. Elsevier B.V.; 2019. p. 11–6. [2] Oveisgharan S, Arvanitakis Z, Yu L, Farfel J, Schneider JA, Bennett DA. Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol. Springer Verlag; 2018 Dec 1;136(6):887–900. [3] Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005 Jun;62(6):685–91. [4] Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol. Lancet Publishing Group; 2017 Jan 1;16(1):55. [5] Lemstra AW, De Beer MH, Teunissen CE, Schreuder C, Scheltens P, Van Der Flier WM, et al. Concomitant AD pathology affects clinical manifestation and survival in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. BMJ Publishing Group; 2017 Feb 1;88(2):113–8. [6] Besser L, Kukull W, Knopman DS, Chui H, Galasko D, Weintraub S, et al. Version 3 of the National Alzheimer’s Coordinating Center’s Uniform Data Set. Alzheimer Dis Assoc Disord. 2018 Oct;32(4):1. [7] Besser LM, Kukull WA, Teylan MA, Bigio EH, Cairns NJ, Kofler JK, et al. The Revised National Alzheimer’s Coordinating Center’s Neuropathology Form—Available Data and New Analyses. J Neuropathol Exp Neurol. 2018 Aug 1;77(8):717–26.

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