Alvarenga, M. O. P., Frazão, D. R., Matos, I. G. D., Bittencourt, L. O., Fagundes, N. C. F., Rösing, C. K., Maia, L. C., & Lima, R. R. (2021). Is There Any Association Between Neurodegenerative Diseases and Periodontitis? A Systematic Review. Frontiers in Aging Neuroscience, 13. https://doi.org/10.3389/fnagi.2021.651437
Alvarenga et al. systematically reviewed 534 studies (12 included) to evaluate whether periodontitis is linked to neurodegenerative disease. They report consistent associations but insufficient evidence for causality, emphasizing two proposed pathways: systemic inflammation (cytokine-mediated neurotoxicity) and bacteremia (direct microbial or endotoxin effects). This review establishes the central mechanistic debate explored across this bibliography. While it presents both pathways as plausible, later experimental studies diverge in how these mechanisms operate. For example, Lei et al. (2023) support bacteremia through BBB disruption, whereas Eid et al. (2025) demonstrate neurodegeneration without BBB permeability changes. This inconsistency highlights a key gap identified by Alvarenga et al.: mechanistic evidence is fragmented and difficult to translate into human disease models. A major limitation is the heterogeneity of included studies and lack of longitudinal human data, which prevents resolution of causality and limits comparison across mechanisms.
Chacón, T., & Hernández-Hincapié, H. (2026). Relationship periodontitis and Alzheimer's disease: Relevant aspects from an epigenetic view. Journal of Alzheimer’s Disease, 109(2), 499–525. https://doi.org/10.1177/13872877251397406
Chacón and Hernández-Hincapié review epigenetic mechanisms linking periodontitis and AD, focusing on how chronic inflammation alters gene expression through DNA methylation and histone modification. They identify shared inflammatory and regulatory pathways and propose epigenetic biomarkers as potential therapeutic targets. This review strengthens the inflammatory pathway by showing how systemic inflammation may produce long-term, heritable changes in gene regulation relevant to neurodegeneration. Unlike Lei et al. (2023), which emphasizes physical BBB disruption, this article suggests that sustained inflammatory signaling alone could drive AD pathology through epigenetic modification. However, its conclusions contrast with Eid et al. (2025), which attributes pathology to bacterial components rather than systemic inflammation. This divergence underscores a broader tension: whether inflammation is a primary driver or a secondary consequence of bacterial exposure. A key limitation is reliance on emerging epigenetic data, much of which lacks validation in human clinical populations.
Aragón, F., Zea-Sevilla, M. A., Montero, J., Sancho, P., Corral, R., Tejedor, C., Frades-Payo, B., Paredes-Gallardo, V., & Albaladejo, A. (2018). Oral health in Alzheimer’s disease: a multicenter case-control study. Clinical Oral Investigations, 22(9), 3061–3070. https://doi.org/10.1007/s00784-018-2396-z
Aragón et al. conducted a multicenter case-control study comparing oral health in AD patients and matched controls. They found significantly poorer oral health in AD patients across multiple measures, though disease severity did not correlate with further decline. This study complicates the directionality of the periodontitis–AD relationship by suggesting that neurodegeneration may precede or exacerbate oral health decline. In contrast to mechanistic studies (Lei et al., Eid et al.), which assume periodontitis contributes to AD, Aragón et al. introduce the possibility of reverse causation or shared risk factors. When considered alongside Alvarenga et al. (2021), this reinforces the need to distinguish correlation from causation before evaluating mechanisms. A limitation is its observational design, which cannot resolve temporal sequence or isolate biological pathways, making it difficult to determine whether inflammation or bacteremia is primary.
Eid, F., Boushehri, M., Boucher, C., Rajkanth, N., Sa, A. F., Alhoutan, T., Vavetsi, K., Dibart, S., & Ma, Y. (2025). Chronic Lipopolysaccharide Exposure Causes AD-Like Pathology in Male Mice With Intact Blood–Brain Barrier. The FASEB Journal, 39(9), e70601. https://doi.org/https://doi.org/10.1096/fj.202403117RR
Eid et al. investigated chronic exposure to Porphyromonas gingivalis lipopolysaccharide (LPS) in male mice and found that it induced cognitive decline and AD-like pathology without increasing BBB permeability or systemic inflammation. Instead, LPS triggered localized neuroinflammation. This study provides strong evidence for a bacteremia-driven mechanism that operates independently of BBB disruption, directly challenging the pathway proposed by Lei et al. (2023). It suggests that bacterial components alone may be sufficient to induce neurodegeneration, shifting the focus from systemic inflammation to localized immune activation. When compared with Chacón and Hernández-Hincapié (2026), it raises the question of whether inflammation is a downstream effect rather than a primary cause. A major limitation is its reliance on a male mouse model, which may not translate to human AD pathology or capture sex-specific disease variation.
Lei, S., Li, J., Yu, J., Li, F., Pan, Y., Chen, X., Ma, C., Zhao, W., & Tang, X. (2023). Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway. International Journal of Oral Science, 15(1). https://doi.org/10.1038/s41368-022-00215-y
Lei et al. examined how P. gingivalis bacteremia affects BBB integrity and found that it increases permeability via downregulation of Mfsd2a and upregulation of Caveolin-1, enhancing transcytosis. This study supports a bacteremia-mediated mechanism in which BBB disruption enables entry of pathogens or inflammatory mediators into the brain. However, its findings directly conflict with Eid et al. (2025), which observed AD-like pathology without BBB permeability changes. Together, these studies highlight a critical unresolved question: whether BBB disruption is necessary for neurodegeneration or simply one of multiple possible pathways. Compared to inflammation-centered models (Alvarenga et al., 2021; Chacón & Hernández-Hincapié, 2026), this study emphasizes structural changes in the BBB rather than systemic signaling. A limitation is its reliance on experimental models, which may oversimplify the complexity of human neurovascular systems.