The effect of Lewy body (co-)pathology on the clinical and imaging phenotype of amnestic patients
Authors: Silva-Rodríguez Jesús , Labrador-Espinosa Miguel A , Zhang Linda , Castro-Labrador Sandra , López-González Francisco Javier , Moscoso Alexis , Sánchez-Juan Pascual , Schöll Michael , Grothe Michel J 
Published: January 2025

Abstract
Lewy body (LB) pathology is present as a co-pathology in approximately 50% of Alzheimer’s disease (AD) dementia patients and may even represent the main neuropathologic substrate in a subset of patients with amnestic impairments. However, the degree to which LB pathology affects the neurodegenerative course and clinical phenotype in amnestic patients is not well understood. Recently developed α-synuclein seed amplification assays (αSyn-SAAs) provide a unique opportunity for further investigating the complex interplay between AD and LB pathology in shaping heterogeneous regional neurodegeneration patterns and clinical trajectories among amnestic patients.
We studied 865 patients from the ADNI cohort with clinical diagnoses of aMCI (N=661) or AD dementia (N=211), who had CSF and FDG-PET data available. CSF samples were analyzed for peptide levels of Aβ1-42 and p-tau181, and αSyn positivity was evaluated using a novel αSyn-SAA. Based on positive/negative results on the different biomarkers, subjects were classified as “AD-LB-” (N=304), “AD+LB-” (N=335), “AD+LB+” (N=158) and “AD-LB+” (N=68). We analyzed group differences in regional FDG-PET patterns, demographics, APOE4 genotype, baseline and longitudinal domain-specific cognitive profiles (memory vs executive function/visuospatial performance), as well as risk for developing hallucinations.
AD+LB+ showed worse global cognition (MMSE: p=0.005) and declined faster (p&lt;0.001) than AD+LB-, but both groups exhibited similar memory-predominant cognitive profiles. In FDG-PET, AD+LB+ showed more severe hypometabolism compared to AD+LB-, but both groups were characterized by largely identical patterns of temporo-parietal hypometabolism. By contrast, AD-LB+ were less globally impaired (p&lt;0.001) but characterized by a markedly more dysexecutive and visuospatial profile (p&lt;0.003) and a strikingly different posterior-occipital pattern of hypometabolism. APOE4 positivity was similar between AD+LB+ and AD+LB- (72% vs. 75%, p=0.28) but lower in AD-LB+ (28%, p&lt;0.001). On a group level, AD+LB+, AD+LB-, and AD-LB+ showed similar risks of developing hallucinations, but patients with a LB-like posterior-occipital hypometabolism pattern had a significantly higher risk compared to those showing an AD-typical temporo-parietal pattern (HR=2.58, p=0.004).
In conclusion, LB co-pathology in AD was associated with more severe hypometabolism and faster cognitive decline, but did not affect the regional hypometabolic pattern or cognitive profile. By contrast, patients with relatively pure LB pathology showed a more executive/visuospatial-predominant cognitive profile and a distinct posterior-occipital hypometabolism pattern characteristic for LB disease. These findings indicate that the presence of LB pathology may have different consequences for the clinical phenotype depending on AD co-morbidity, which may have critical implications for accurate diagnosis and prognosis of patients presenting with amnestic syndromes.