Abstracts

Rationale: Epilepsy is highly comorbid with Alzheimer’s Disease (AD) with up to 22% of AD patients with clinically identifiable seizures. Once largely considered a side effect of ß-amyloid (Aß) and tau induced neuronal hyperexcitability, recent data point to epilepsy as having a key role in the progression of AD and a bidirectional relationship with epilepsy inducing pathological features consistent with those seen in AD and vice versa. Both epilepsy and AD promote neuroinflammation and microglial dysfunction which contributes to the accumulation of Aß plaques. In addition, apolipoprotein E4 (APOE4) is the most prevalent risk factor for AD and has been linked to seizures independent of AD as well as microglial dysfunction. Thus, we hypothesized that seizures exacerbate AD neuropathology and that APOE4 and microglial phagocytic and immune dysregulation may underlie this relationship.

Methods: To test our hypothesis, we examined human temporal cortex from AD cases with (AD+Sz) and without (AD-Sz) known seizure history, and controls for Aß coverage and levels of APOE4, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and C-C Motif Chemokine Ligand 5 (CCL5), given their roles in microglial homeostasis, phagocytosis, and chemotaxis, respectively. Aß coverage was analyzed by quantitative immunohistochemistry (IHC), and APOE4, TREM2, and CCL5 concentrations were measured by Luminex Multiplex assays of cortical lysate. Controls to AD and AD+Sz to AD-Sz were compared via unpaired t-tests. Potential correlations between the multiplex analytes and Aß_1-42 were examined via simple linear regressions.

Results: As expected, quantitative immunohistochemistry revealed that when grouped together, all AD cases had significantly elevated Aß compared to controls in both the grey matter (GM) (n=17-22, p < 0.0001) and white matter (WM) (p < 0.01) of temporal cortical tissue. In addition, we found that AD+Sz have higher Aß coverage in cortical WM than AD-Sz (n=6-16, p< 0.05), with no significant differences found in the GM (p=0.3028). Luminex multiplex assay revealed a significant increase in APOE4 concentrations in all AD compared to control (n=5-20, p< 0.01) with a trend towards an increase in AD+Sz compared to AD-Sz (n=10, p=0.06). Further, TREM2 concentrations were reduced all AD cases compared to control (n=5-20, p< 0.05) and in AD+Sz compared to AD-Sz (n=10, p< 0.05). CCL5 was significantly increased in all AD compared to controls (n=5-20, p< 0.05) with no significant difference between AD+Sz and AD-Sz (n=10). However, CCL5 was positively correlated with Aß across all groups (p < 0.05, R²=0.189).

Conclusions: Overall, our data highlight a novel role of seizures to elevate Ab pathology in the WM of AD temporal cortex and that APOE4 and microglial dysregulation may underlie the worsened pathology, suggesting that therapies targeting microglia may attenuate disease progression in AD patients with epilepsy.

Funding: Please list any funding that was received in support of this abstract.: National Institute on Aging: Institutional National Research Service Award T32AG000255-23 (AB), National Institute of Neurological Disorders and Stroke R21NS105437 (FEJ), R37NS115439 (FEJ) and R01NS101156 (DMT).