Objective: The aim of our current report was to assess the impact of Apolipoprotein-E (ApoE) genotype on cognition in idiopathic Parkinson’s disease (PD) patients and in carriers of pathogenic mutations in the Alpha-synuclein (SNCA) and Glycocerebrosidase (GBA) genes.

Background: ApoE genotype is increasingly associated with the development of cognitive decline in PD. Data on the role of ApoE genotype in modifying the cognitive phenotype of genetic forms of PD are still scarce.

Method: Two independent PD cohorts were analyzed: Our first cohort (Athens) included 50 consecutive idiopathic PD patients, 35 carriers of the p.A53T SNCA mutation and 59 carriers of GBA mutations (13 mild /46 severe). Our second cohort (Tübingen) included 292 GBA variant carriers (170 risk/ 52 mild/ 70 severe). All patients underwent cognitive testing and were genotyped for ApoE.

Results: In the idiopathic PD subgroup of the Athens cohort, carriers of at least one ApoE-ε4 exhibited lower Montreal Cognitive Assessment test (MoCA) score as compared to non-carriers (22.2 vs 24.7/30) (p=0.044). Notably, in the p.A53T SNCA subgroup, ApoE-ε4 carriers also had lower MoCA scores compared to non-carriers (16.2 vs 24.4/30) (p=0.039). There were no ApoE-related differences in MoCA subscores. In the GBA subgroup from the Athens cohort, no difference in MoCA related to ApoE-ε4 could be evidenced (p=0.729). Accordingly, in the Tübingen GBA-carrier PD cohort there was no difference between ApoE-ε4 carriers and non-carriers when assessing the three subgroups of increasing GBA variant severity (p=0.585). Moreover, no associations between ApoE genotype and CSF total α-synuclein or amyloid-beta  could be verified.

Conclusion: Our results are in accordance with literature data regarding the impact of ApoE-ε4 on cognitive decline of idiopathic PD patients. This effect is also present in the p.A53T SNCA subgroup, which represents the archetypal pure synucleinopathy. These results support the emerging evidence indicating that APOE-ε4 directly exacerbates α-synuclein pathological deposition, beyond its established role in promoting Alzheimer’s disease co-pathology. Contrary, the lack of such an effect in two independent cohorts of GBA mutation carriers, who are considered to also suffer from predominant synucleinopathy-related cognitive decline, suggests differences in factors associated with cognitive decline between different genetic forms of synucleinopathies.

References: [1] Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, Van Ingelgom AJ, Davis MD, Kurti A, Knight JA, Linares C, Chen Y, Delenclos M, Liu CC, Fryer JD, Asmann YW, McLean PJ, Dickson DW, Ross OA, Bu G. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid.Sci Transl Med. 2020 Feb 5;12(529):eaay1809.
[2] Tipton PW, Bülbül N, Crook J, Quicksall Z, Ross OA, Uitti RJ, Wszolek ZK, Ertekin-Taner N. Effects of sex and APOE on Parkinson’s Disease-related cognitive decline.
Neurol Neurochir Pol. 2021;55(6):559-566.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-apoe-genotype-on-cognition-in-idiopathic-and-genetic-forms-of-parkinsons-disease/