Objective: To assess whether the association between Lewy body (LB) pathology stages and cognition differs for women and men

Background: Progression of LB pathology is associated with cognitive decline [1,2]. For individuals with pure LB pathology, brainstem-predominant LB pathology was not associated with a change in cognitive performance, whereas limbic and neocortical LB pathology was associated with lower cognitive performance compared to healthy controls [2]. However, in those with pure limbic or neocortical LB pathology, cognitive decline differs for men and women [3] and sex can play a role in the association of different LB pathology stages with cognition.

Method: Data was obtained from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS) [4] and Neuropathology Data Set [5] for UDS visits conducted between September 2005 and August 2019 at 33 AD Research Centers. Analysis included individuals with available data on LB pathology staging (1=brainstem-predominant, 2=limbic or amygdala-predominant, 3=neocortical) excluding those with other neuropathologic diagnoses (e.g., high level Alzheimer’s disease neuropathologic change, hippocampal sclerosis, frontotemporal lobar degeneration) (141 women, 307 men). Interaction between sex and LB pathology for cognition at last visit (CDR® Dementia Staging Instrument-Sum of Boxes [CDR-SOB]) was assessed with linear models controlling for education and age at last visit.

Results: Compared to men, women were older at last visit and death, had less years of education and had cognitive decline onset at an older age (p<.002 for all) [table1]. Brainstem-predominant was associated with lowest (B=-4.01), limbic or amygdala-predominant (B=-2.61) was associated with lower CDR-SOB than neocortical LB (p<.001). LB pathology stage association with CDR-SOB differed for women and men (p<.001) [table2]. Scores across LB pathology stages differed more for women than men. In a subanalysis where amygdala- and limbic-predominant LB were coded separately, sex differences for LB pathology association with CDR-SOB continued to be significant (p<.001).

Conclusion: Neocortical LB is associated with worse cognitive decline whereas brainstem-predominant LB pathology group has the least cognitive decline. Cognitive changes across the LB pathology stages were more pronounced for women, supporting LB clinicopathological correlations differ by sex.

References: 1. Beach TG, Adler CH, Lue LF, Sue LI, Bachalakuri J, Henry-Watson J, et al. Unified Staging System for Lewy Body Disorders: Correlation with Nigrostriatal Degeneration, Cognitive Impairment and Motor Dysfunction. Acta Neuropathol. 2009;117(6):613.
2. Ryman SG, Yutsis M, Tian L, Henderson VW, Montine TJ, Salmon DP, et al. Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer’s Disease Pathology. J Alzheimer’s Dis. 2021 Jan 1;80(3):1243–56.
3. Bayram E, Coughlin DG, Banks SJ, Litvan I. Sex differences for phenotype in pathologically defined dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2021 Jul 9;92(7):745–50.
4. 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.
5. 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.

Acknowledgments: The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADCs: P50 AG005131 (PI James Brewer, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG005138 (PI Mary Sano, PhD), P50 AG005142 (PI Helena Chui, MD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005681 (PI John Morris, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG008051 (PI Thomas Wisniewski, MD), P50 AG008702 (PI Scott Small, MD), P30 AG010124 (PI John Trojanowski, MD, PhD), P30 AG010129 (PI Charles DeCarli, MD), P30 AG010133 (PI Andrew Saykin, PsyD), P30 AG010161 (PI David Bennett, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG013854 (PI Robert Vassar, PhD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P30 AG019610 (PI Eric Reiman, MD), P50 AG023501 (PI Bruce Miller, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG028383 (PI Linda Van Eldik, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P30 AG035982 (PI Russell Swerdlow, MD), P50 AG047266 (PI Todd Golde, MD, PhD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG049638 (PI Suzanne Craft, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Marwan Sabbagh, MD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-modulates-cognitive-association-of-lewy-body-pathology/