Biomarkers.

Background: Identification of concomitant Lewy Body (LB) pathology might be important for the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice and trials. Here, we aimed to determine whether the presence of LB pathology exacerbates AD-related disease progression.

Methods: Cognitively impaired (Mild Cognitive Impairment [MCI] and dementia, n=795) individuals from the ADNI cohort with available CSF α-synuclein amplification assay (SAA) and CSF p-tau/Aβ measures were included. Linear mixed models (LMMs) with random slope and intercept were run to assess group effects on longitudinal cognition and cortical metabolism using FDG-PET, corrected for age, sex, and baseline cognitive state, and education in case of cognition models. To investigate potential non-linear changes in cognitive functioning, LMMs additionally included an interaction between AD/LB group and time squared (time). Differences between AD/LB groups (n=61) in pathological scores were assessed using ordinal logistic regression models, corrected for sex, age at death, measurement interval and post-mortem interval.

Results: Participants were on average 75 years of age (SD=7.89), 40.8% were female, and 184 (23.1%) had no biomarker evidence of AD/LB pathology, 39 (4.9%) had isolated LB pathology (AD-LB+), 395 (49.7%) had only AD pathology (AD+LB-), and 177 (22.3%) had both pathologies (AD+LB+, Table 1/Figure 1). At baseline, the AD+LB+ group showed worst performance for most cognitive outcomes compared to the other groups, including the AD+LB- group (MMSE: p=0.008; PACC: p<0.0001). Over time, both the AD+LB- and AD+LB+ groups deteriorated faster in global cognitive function compared to the AD- groups. Importantly, this decline was more pronounced for the AD+LB+ group when compared to the AD+LB- group (MMSE: β =-0.15, p=0.005, PACC: β =-0.026, p=0.0015, Table 2/Figure 2). Furthermore, the AD+LB+ group showed more cortical hypometabolism at baseline and over time compared to the AD+LB- group, particularly in posterior brain regions (Figure 3). Neuropathological examination showed that the α-syn SAA had 96.3% (26/27) sensitivity and 96.4% (27/28) specificity (Figure 1).

Conclusion: In a cognitively impaired AD population, co-existing LB-positivity exacerbates cognitive decline and cortical brain hypometabolism. In vivo detection of LB pathology could improve the prognostic work-up of AD in clinical practice and might have implications for the design of clinical AD trials.