Clinical effects of Lewy body pathology in cognitively impaired individuals

Abstract

There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer's disease (AD) pathology (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson's disease or dementia with Lewy bodies at baseline. Among these LB-positive patients, 48% had AD pathology. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). When examining independent cross-sectional effects, LB pathology but not amyloid-β or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-β, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson's disease. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials.

Fig. 1. Prevalence of Aβ, tau and LB pathology.

a, Prevalence of Aβ (A), tau (T) and LB positivity. b, Prevalence of A/T/LB groups (number of participants is shown in Extended Data Table 1). c, Prevalence of AD/LB groups. d–f, Proportions of these groups with increasing age. Percent is calculated based on the study population of 883 patients. Percentages in a add up to more than 100 because one can be positive in more than one biomarker. Note that AD positivity refers to being both Aβ and tau positive, whereas LB positivity refers to being α-syn SAA-positive. In d, using age as independent variable and pathology as dependent in logistic regression models, age had an odds ratio (OR) of 1.023 (95% confidence interval (CI) 1.001–1.047) for LB, 1.048 (95% CI 1.027–1.069) for Aβ and 1.035 (95% CI 1.016–1.055) for tau.

Fig. 2. Comparisons between AD/LB groups and the independent effects of LB, Aβ and tau pathologies on clinical outcomes.

a–l, Analyses were performed using linear regression models with AD/LB groups (a–c,g–i) or all three binarized pathologies (d–f,j–l) as independent variables in the same model, adjusted for age, sex, education (for cognitive outcomes) and cognitive stage (MCI/dementia). In g,h,j,k, logistic regression models with the same covariates were used because the outcomes were binary. Outcomes were z scored (according to the distribution in Aβ-negative controls) cognitive tests (a–f) and motor questionnaires (i,l) or binary assessment of correct visuospatial task (g,j) or presence of hallucinations (h,k). Boxes (a–c,g–i) show interquartile range, the horizontal lines are medians and the whiskers were plotted using the Tukey method. In d–f,l, the dot/center shows the estimate of the pathology and the error bars show the 95% CI, where negative values equal worse performance. In j,k, the dot/center represents ORs, where values <1 equal a decrease, and error bars show the 95% CI of the ORs. Worse performance is marked in red. AD positivity was defined as the presence of both Aβ and T. LB positivity was defined as the presence of an abnormal α-syn SAA result. The effect of LB pathology on clinical outcome with/without adjusting for Aβ and T is shown in Extended Data Table 2. Overall, 302 participants were AD−/LB−, 106 were AD−/LB+, 377 were AD+/LB− and 98 were AD+/LB+ and 204 were LB+, 607 were Aβ+ and 489 were tau+. The statistical analyses with corrections for multiple comparisons are shown in Supplementary Fig. 1. Missing data are shown in Supplementary Table 1. *P < 0.05; **P < 0.01; ***P < 0.001 (two-sided).

Fig. 3. Comparisons between AD/LB groups and the independent effects of LB, Aβ and tau pathologies on longitudinal cognitive function.

a–h, Significant effects (two-sided) were examined using linear mixed-effects (LME) models. The AD/LB group × time interaction was examined, adjusted for age, sex, education and cognitive stage (MCI/dementia) (a–d). The interaction time × all three pathologies (binarized) were examined in the same LME model adjusted for age, sex and education, to examine the independent effect of pathology and cognitive progression (e–h). Outcomes were z scored cognitive tests according to the distribution in Aβ-negative controls. The effect of LB pathology on clinical outcome with/without adjusting for Aβ and tau is shown in Extended Data Table 3. Estimated marginal means and 95% CI of the means obtained from LME models by AD/LB group (a–d). The dot/center shows the interaction estimates of time × pathology and error bars represent the 95% CI (e–h). Binomial mixed-effects models were used as the outcome was binary (c,g). Overall, 302 participants were AD−/LB−, 106 were AD−/LB+, 377 were AD+/LB− and 98 were AD+/LB+ and 204 were LB+, 607 were Aβ+ and 489 were tau+. The statistical analyses with corrections for multiple comparisons are shown in Supplementary Fig. 2. Missing data are shown in Supplementary Table 2. *P < 0.05; **P < 0.01; ***P < 0.001 (two-sided).