Involvement of ApoE4 in dementia with Lewy bodies in the prodromal and demented stages: evaluation of the Strasbourg cohort

Abstract

Background: ApoE4 as a risk factor for AD is no longer a matter of debate. However, it is still an issue for dementia with Lewy bodies (DLB). We wanted to determine the involvement of ApoE4 according to different clinical parameters in our cohort of patients from Strasbourg. Methods: ApoE genotyping was performed on the AlphaLewyMA cohort. In this cohort, 197 patients were genotyped. Among them 105 DLB patients, 37 Alzheimer's disease (AD), 29 comorbidity AD/DLB and 26 control subjects (CS). These groups are also classi ed according to the stage of evolution of the disease: prodromal or demented. We analyzed other parameters in relation to ApoE4, such as socio-educational levels (SEL) and Alzheimer CSF biomarkers (t-Tau, P-Tau, Aβ-42 and Aβ40).Results: There were signi cantly more ApoE4 carriers in the AD (51.4%) and AD/DLB (72.4%) groups compared to the DLB (25.7%) and CS (11.5%) groups (P<0.0001). No signi cant difference was found between the percentage of ApoE4 in the DLB and CS groups, idem between AD and AD/DLB groups. For AD group, we nd a correlation between the age of onset of the disease and the SEL. For DLB group, the correlation does not reach signi cance despite a strong trend (p = 0.056). Interestingly, in this latter group, taking the median of SEL (Education=11 years, i.e. one year before bachelor), the group of patients with high SEL (≥ 11) has signi cantly more patients with ApoE4 than the group of patients with low SEL (<11). Finally, the AD biomarkers do not seem to be impacted by the presence of ApoE4, except for Aβ42. DLB ApoE4 demented patients show a more marked decrease of CSF Aβ42.Conclusions: ApoE4 does not appear to be a risk factor for "pure" DLB patients with the possible exception of patients with high SEL. In the DLB group, ApoE4 would be responsible for the Aβ42 decrease between the prodromal and demented group, suggesting a strong link between ApoE4 and amyloidopathy thus con rming its strong link with AD.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identi er: NCT01876459) Regarding genetic risk factors, however, AD and DLB are relatively different. AD and DLB are the subject of numerous GWAS studies, revealing many risk factors in AD such as TREM2, PICALM, BIN1, CLU, CR1, SORL1, CD33 and others (5, 6) some of which are even correlated with Alzheimer biomarkers (7), but different risk factor for DLB: SNCA, GRN, LRP10, SNCB, LRRK2, .Of all these genetic risk factors that have been identi ed for AD, apolipoprotein E4 (ApoE4) appears to be the most important (12, 13). For DLB, there is a substantial literature suggesting that ApoE4 may also be a risk factor including autopsy studies (14-16) and GWAS (9-11, 17). However, recent neuropathologic studies question this and state that this risk factor is only associated with DLB when there is a huge AD comorbidity (18-22), calling into question the direct impact of ApoE4 on synucleinopathy (studies agreeing that ApoE4 is not a risk factor for PD, e.g. ( 14)). In the past, some clinical studies have also questioned ApoE4 as a risk...