Background: Both Lewy body (LB) and Alzheimer’s disease (AD) pathology staging impacts the likelihood of having LB dementia (LBD) and AD phenotype. Compared to males with limbic/neocortical LB pathology, females are less likely to have an LBD phenotype. Compared to females with similar LB and AD pathology staging, AD co-pathology reduces the LBD phenotype likelihood more for males. We aimed to expand this sex comparison to the full range of LB/AD pathology level (low, intermediate, high likelihood of LBD phenotype) from McKeith 2017 criteria, based on both LB (olfactory, amygdala, brainstem, limbic, neocortical) and AD pathology staging (none, low, intermediate, high).

Methods: Data were from National Alzheimer’s Coordinating Center for 206 females and 324 males with low/intermediate/high LB/AD pathology level (128/50/28 females, 158/79/87 males), excluding people with other neurodegenerative diagnoses contributing to cognitive decline. Interaction between sex and LB/AD pathology level for clinical outcomes were assessed with generalized linear models adjusting for age at last visit.

Results: Majority identified as Non-Hispanic (96%) and White (92%). Females died older and had fewer years of education (p=.027, p<.001). Most had dementia at last visit (91% of females, 89% of males, p=.42). Females had higher levels of AD co-pathology and lower levels of LB pathology staging (p<.001, p=.017). Higher LB/AD pathology level was associated with higher likelihood of LBD clinical diagnosis (B=1.39 females; B=1.73 males) and lower likelihood of AD clinical diagnosis (B=-1.30 females, B=-1.43 males); more so for males (p<.001 for both). Higher LB/AD pathology level was associated with higher likelihood of cognitive fluctuations (B=0.93 females, B=1.00 males), visual hallucinations (B=0.76 females, B=0.86 males), rapid eye movement sleep behavior disorder (B=0.76 females, B=1.39 males), and parkinsonism (B=0.98 females, B=1.44 males); more so for males (p<.001 for all).

Conclusions: Females with LB pathology have higher levels of AD co-pathology and lower likelihood of LBD phenotype. However, even if females have similar LB/AD pathology level as males, females are less likely to have an LBD phenotype, including a lower likelihood for all LBD core clinical features. Clinical features may fall short in identifying particularly females with LB pathology during life.

Acknowledgments: The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI David Holtzman, MD), P30 AG066518 (PI Lisa Silbert, MD, MCR), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI Julie A. Schneider, MD, MS), P30 AG072978 (PI Ann McKee, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Jessica Langbaum, PhD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Glenn Smith, PhD, ABPP), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P30 AG086401 (PI Erik Roberson, MD, PhD), P30 AG086404 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). EB receives research funding from NIA (R00AG073453).