Objective: To investigate the association of apolipoprotein E ɛ4-allele (APOE-ε4) with amygdala volumes longitudinally in Parkinson’s disease (PD).

Background: APOE-ε4 is a genetic risk factor for Alzheimer’s disease and Lewy body dementias [1, 2], highlighting that APOE-ε4 plays an important role in modulating not only the pathogenesis of amyloid-β (Aβ) and tau but also α-synuclein. In PD, α-synuclein aggregates (Lewy bodies and Lewy neurites) are often observed in the amygdala [3]. Given that amygdala is one of the earliest structures to be affected by α-synuclein pathology in PD, we investigated whether APOE-ε4 carriers show greater amygdalar atrophy.

Method: We used 3T structural MRIs (T1, T2/proton-density weighted, or FLAIR) from PD patients who underwent at least one follow-up scan from the ONDRI cohort. The volume of amygdala as a specific region-of-interest was obtained using the FreeSurfer longitudinal processing stream, supplemented by improved skull stripping and lesion masks to minimize segmentation errors. The average of the left and right amygdala was analyzed. Linear mixed models were used to investigate the influence of APOE-ε4 on amygdala volumes, adjusting for head size, age at scans and sex. Linear regressions were used to assess the association of amygdala volumes with blood biomarkers (Aβ-42/40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau 181) at baseline.

Results: A total of 140 PD patients were studied: 107 APOE-ε4 non-carriers (age = 67.9 ± 6.7) and 33 APOE-ε4 carriers (age = 67.6 ± 5.2). Amygdala volumes were smaller in APOE-ε4 carriers versus non-carriers at baseline (β=-130.98, p=0.050). APOE-ε4 was associated with progressively smaller amygdala volumes on average over time (β=-143.62, p=0.038). The rate of change of amygdala volume over time did not differ based on APOE-ε4 status (time x APOE-ε4, β=-3.72, p=0.492). The Aβ-42/40 ratio was also associated with amygdala volume (β=-5857.7, p=0.015) independently of APOE-ε4 (β=-159.21, p=0.017), whereas GFAP, NfL, and phosphorylated tau 181 were not associated with amygdala volume.

Conclusion: These preliminary findings suggest that APOE-ε4 may contribute to amygdalar atrophy in PD, possibly by influencing α-synuclein pathology independently of Aβ pathology. A more comprehensive cognitive and whole-brain analysis with a larger longitudinal sample is warranted.

References: [1]. Guerreiro R, Ross OA, Kun-Rodrigues C, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018 Jan;17(1):64-74.

[2]. Kunkle BW, Grenier-Boley B, Sims R, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019 Sep;51(9):1423-1424.

[3]. Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/apolipoprotein-e-%c9%9b4-allele-and-amygdala-atrophy-in-parkinsons-disease-a-preliminary-longitudinal-analysis-from-the-ondri-cohort/