Epilepsy in Alzheimer's Disease: Seizing the Asymmetry in Amyloid,Tau,and Neurodegenerative Pathology

Abstract

Association of Seizure Foci and Location of Tau and Amyloid Deposition and Brain Atrophy in Patients With Alzheimer Disease and Seizures

Lam AD, Thibault EG, Mayblyum DV, Hsieh S, Pellerin KR, Sternberg EJ, Viswanathan A, Buss S, Sarkis RA, Jacobs HIL, Johnson KA, Sperling RA. Neurology. 2024 Nov 12;103(9):e209920. doi: 10.1212/WNL.0000000000209920. Epub 2024 Sep 27. PMID: 39331846; PMCID: PMC11441794.

Background and objectives: Alzheimer disease (AD) is associated with a 2 to 3-fold increased risk of developing late-onset focal epilepsy, yet it remains unclear how development of focal epilepsy in AD is related to AD pathology. The objective of this study was to examine spatial relationships between the epileptogenic zone and tau deposition, amyloid deposition, and brain atrophy in individuals with AD who developed late-onset, otherwise unexplained focal epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then there would be increased tau and amyloid deposition within the epileptogenic hemisphere.

Methods: In this cross-sectional study, we performed tau and amyloid PET imaging, brain MRI, and overnight scalp EEG in individuals with early clinical stages of AD who developed late-onset, otherwise unexplained focal epilepsy (AD-Ep). Participants were referred from epilepsy and memory disorders clinics at our institutions. We determined epilepsy localization based on EEG findings and seizure semiology. We quantified tau deposition, amyloid deposition, and atrophy across brain regions and calculated asymmetry indices for these measures. We compared findings in AD-Ep with those in a control AD group without epilepsy (AD-NoEp).

Results: The AD-Ep group included 8 individuals with a mean age of 69.5 ± 4.2 years at PET imaging. The AD-NoEp group included 14 individuals with a mean age of 71.7 ± 9.8 years at PET imaging. In AD-Ep, we found a highly asymmetric pattern of tau deposition, with significantly greater tau in the epileptogenic hemisphere. Amyloid deposition and cortical atrophy were also greater in the epileptogenic hemisphere, although the magnitudes of asymmetry were reduced compared with tau. Compared with AD-NoEp, the AD-Ep group had significantly greater tau asymmetry and trends toward greater asymmetry of amyloid and atrophy. AD-Ep also had significantly greater amyloid burden bilaterally and trends toward greater tau burden within the epileptogenic hemisphere, compared with AD-NoEp.

Discussion: Our results reveal a spatial association between the epileptogenic focus and tau deposition, amyloid deposition, and neurodegeneration in early clinical stages of AD. Within the limitations of a cross-sectional study with small sample sizes, these findings contribute to our understanding of the clinicopathologic heterogeneity of AD, demonstrating an association between focal epilepsy and lateralized pathology in AD.

Commentary

Alzheimer's disease(AD) and epilepsy, two seemingly distinct conditions, share an intricate connection that has fascinated researchers for decades. Historical accounts of seizures in dementia date back centuries, but only recently has this intersection garnered focused scientific attention. Epidemiological studies suggest that individuals with AD are at a markedly higher risk of developing epilepsy than the general population, ¹ with this co-occurrence linked to accelerated cognitive decline, diminished functionality, and earlier mortality.^1,2 Despite these dire implications, the mechanistic intersection between epilepsy-related neuronal hyperexcitability and AD pathology remains largely elusive. Against this backdrop, Lam et al's study ventures into this uncharted territory, delving into the spatial relationship between seizure foci and pathological hallmarks of AD. ³ By exploring amyloid, tau, and neurodegeneration (ATN) in the context of AD-associated epilepsy (AD-Ep), the authors unveil critical revelations into these intertwined conditions.

In this single-center, cross-sectional study, Lam et al compared MRI, amyloid, and tau PET imaging and overnight scalp EEG findings in AD-Ep participants with those in AD without epilepsy (AD-NoEp).

The study's most striking finding was the significantly greater tau burden in AD-Ep participants, with asymmetrically higher deposits in the epileptogenic hemisphere than in the non-epileptogenic hemisphere and AD-NoEp controls. These findings align with prior clinical and animal studies linking seizures, network hyperexcitability, and tau. For instance, a recent large postmortem study of ∼6000 autopsy specimens found significantly higher Braak stages of tau pathology in individuals with ongoing seizures. ⁴ Additional studies underscore a bidirectional relationship between seizures and tau, showing that seizures increase tau secretion, tau exacerbates seizure activity, and reducing tau levels mitigates seizure severity. ⁴ Tau is known to spread across neural networks trans-synaptically. ³ Additionally, ongoing seizures can interfere with normal protein clearance processes, accumulating tau.^3,5 This study's unique emphasis on lateralized tau pathology highlights a potential mechanistic link between hyperexcitability and AD progression, yet it leaves unanswered whether tau asymmetry drives seizures or if seizures exacerbate tau deposition. Longitudinal studies are essential to disentangle these temporal and causal relationships.

Another pivotal finding of the current was the subtle yet significant amyloid asymmetry in AD-Ep participants, with a higher burden observed in the epileptogenic hemisphere. AD-Ep participants also exhibited greater overall amyloid burden in both hemispheres than AD-NoEp controls. These findings support existing literature linking seizures to increased amyloid burden and hyperexcitability-induced amyloid aggregation. ⁴ Mechanistically, amyloid can amplify glutamate release and suppress GABAergic activity, fueling hyperexcitability and seizures. ⁶ Seizure-related enhanced neuronal activity may also impair the glymphatic system, reducing amyloid clearance and exacerbating its accumulation. ⁴ Amyloid's bilateral presence in AD-Ep participants hints at a broader network effect beyond localized pathology that warrants further scrutiny. Future prospective studies should examine the interaction between amyloid, tau, and hyperexcitability over time. These efforts could elucidate spatiotemporal dynamics and provide a foundation for therapeutic strategies to mitigate amyloid and tau accumulation and reduce seizure burden.

The study also explored cortical and subcortical atrophy, another critical facet of neurodegeneration in AD-Ep. Subtle asymmetry was identified in the epileptogenic hemispheres of AD-Ep, particularly in the frontal, lateral temporal, and lateral parietal lobes and hippocampus, amygdala, and nucleus accumbens. This asymmetry complements the pathological tau and amyloid asymmetries, underscoring the complex interplay within the epileptogenic hemisphere. Interestingly, cortical thickness was comparable between the epileptogenic and non-epileptogenic hemispheres in AD-Ep and AD-NoEp. This led the authors to propose that neurodegeneration may not directly drive epilepsy development in AD. These findings challenge previous studies that link epilepsy to neurodegeneration, significant cortical atrophy, and volume loss. ⁷ Longstanding epilepsy has been associated with pronounced cortical atrophy ⁷ while asymmetric atrophy has been previously documented in the epileptogenic hemisphere. ⁸ Additionally, cortical thinning associated with poorly-controlled seizures has been shown to improve following seizure control through epilepsy surgery. ⁹ The discrepancies in this study may reflect its limited statistical power, highlighting the need for larger and more diverse cohorts to better understand the causal relationship between neurodegeneration and epilepsy in AD. Future research should also examine whether effective seizure control in AD-Ep patients could mitigate atrophy and refine therapeutic approaches.

Although the study could not resolve whether lateralized pathology drives seizure activity or if hyperexcitability leads to pathology accumulation, it provided valuable insights into this conundrum. While amyloid burden was highest in the mesial temporal lobe (MTL), tau asymmetry was predominantly observed in the neocortex rather than the MTL. These findings support the hypothesis that high amyloid levels in the MTL may directly trigger local neuronal hyperexcitability and seizures. ³ However, tau asymmetry in the neocortex raises the possibility that tau pathology may have been more prominent in MTL earlier in the disease but led to more neocortical involvement as the disease progressed. This progression implies that localized tau pathology and network failures may act as initial triggers for broader dysfunction and tau deposition. ¹⁰ However, prospective imaging studies are crucial to elucidate the temporal dynamics of amyloid and tau interactions and their contributions to hyperexcitability, particularly in the MTL.

Interestingly, the authors found no association between epilepsy duration or scalp EEG abnormalities and amyloid or tau burden, whether global or regional. This lack of association suggests that the chronicity of seizures or detectable electrical abnormalities may not significantly influence the relationship between epilepsy and AD pathology. Subclinical or localized epileptiform activity, undetectable by EEG, may be more significant in driving ATN pathologies. Alternatively, other mediators, such as genetic predisposition or network-level disruptions, could underlie this complex interplay.

While Lam et al's study offers several novel insights, a critical lens reveals several notable shortcomings. With only eight AD-Ep participants, the study risks overgeneralization. A larger cohort would enhance the robustness of the findings and allow for the exploration of variability within the AD-Ep population. The cross-sectional design leaves unanswered questions about causality. Does pathological asymmetry drive seizures, or do seizures exacerbate focal pathology? Without longitudinal data, the plot remains speculative. Additionally, the cohort's homogeneity—comprising exclusively White, non-Hispanic, and highly educated participants—limits the applicability of the findings to more diverse populations. Future studies should recruit participants from varied ethnic, socioeconomic, and educational backgrounds to ensure broader relevance and applicability.

Within the constraints of its limitations, Lam et al's study lays a solid foundation for exploring the relationship between asymmetrical pathology and hyperexcitability in AD. Longitudinal studies could illuminate whether tau and amyloid asymmetry precede or result from epileptogenesis, shedding light on their temporal dynamics. Integrating high-resolution imaging with machine learning may uncover subtle patterns and interactions, offering new perspectives. Moreover, investigating whether tau- or amyloid-targeted therapies can reduce seizure activity or slow cognitive decline in AD-Ep could translate these findings into actionable treatments. Addressing these gaps and building on the study's results could pave the way for refined therapeutic strategies and improved outcomes for individuals facing the intertwined challenges of AD and epilepsy.