Dysautonomia and Neuroinflammation as Early Drivers of Alzheimer's Disease Pathogenesis: A Systematic Review
Poster #: 189
Session/Time: B
Author:
Moira Christine Offord, BS, MS
Mentor:
Alberto E. Musto, MD, PhD
Research Type: Review Article
Abstract
INTRODUCTION:
Alzheimer's disease (AD) has been noted as progressive neurodegeneration followed by cognitive decline. However, potential neuroinflammatory biomarkers could hold the key to uncovering its pathogenesis.
MAIN BODY:
Through a systematic review conducted in accordance with PRISMA guidelines, PubMed and OVID Medline were searched for articles published between 2015 and 2026. Studies that were included reported original data with keywords associated with dysautonomia, neurofibrillary tangles, glymphatic clearance, and vagal nerve stimulation. Two independent reviewers screened abstracts and full texts for consensus of the studies that encompassed genome-wide association studies, biomarker analyses, neuroimaging, and experimental models.
RESULTS:
concluded that the major distribution of affected regions from AD was brainstem degeneration, followed by major degeneration of the hippocampus. This included increased cerebrospinal fluid CSF involvement with the main cells affected, which were notably glial cells, followed by neurons. Inflammatory markers such as YKL-40 and cytokines TNF-α, TGF-β, and IL-6 were noted to impact signaling proteins FAF1 and caspase family proteins to increase neurodegeneration and the occurrence of amyloid-beta 42 (Aβ42) plaque deposition and neurofibrillary tangle (NFT) formation. Finally, the biological mechanism that primarily resulted was a neuroinflammation leading to microgliosis and astrocytosis, causing an increased occurrence of hyperphosphorylated tau preceding NFT formation and Aβ42 plaque deposition in the brain, as well as poor clearance of neurotoxic plaques from the brain through the CSF due to cellular stress. Further neurovascular damage from chronic hypertension from dysautonomia yielded a breakdown in the blood-brain barrier (BBB), leading to albumin leakage and further microgliosis, resulting in further Aβ42 accumulation, contributing to the patient's cognitive decline. Key genetic contributors include APOE v4, CNTNAP2, and HLA-DR/DQ polymorphisms, a family of neuroinflammatory markers that exhibit population-specific risk profiles and suggest ancestral biomarkers. Proposed treatments that were observed were glymphotherapeutics, transcutaneous vagus nerve stimulation (tVNS), natural compounds like Tanshinone IIA and Lycium barbarum extract, and lifestyle changes that contribute to sleep, diet, and hormonal fluctuations.
CONCLUSION:
Conclusively, these studies show that potential dysautonomia observed in hypertensive states of AD patients are followed by neuroinflammation, an early occurrence of a cascade of symptoms observed in Alzheimer's disease, resulting in neurovascular damage, microgliosis and astrocytosis, therefore increased NFT and Aβ42 buildup in the brain, ensuing brainstem atrophy in the upper posterior region localized around the vagus nerve and hippocampal atrophy, with the result of cognitive decline and loss of episodic memory. Collectively, these studies underscore the need for integrative, personalized approaches to AD diagnosis and treatment, emphasizing early intervention through identification of potential ancestral markers linked to dysautonomia that could hold the key to the pathogenesis of Alzheimer's disease, and further treatment through direct vagal nerve stimulation as a result.
Alzheimer's disease (AD) has been noted as progressive neurodegeneration followed by cognitive decline. However, potential neuroinflammatory biomarkers could hold the key to uncovering its pathogenesis.
MAIN BODY:
Through a systematic review conducted in accordance with PRISMA guidelines, PubMed and OVID Medline were searched for articles published between 2015 and 2026. Studies that were included reported original data with keywords associated with dysautonomia, neurofibrillary tangles, glymphatic clearance, and vagal nerve stimulation. Two independent reviewers screened abstracts and full texts for consensus of the studies that encompassed genome-wide association studies, biomarker analyses, neuroimaging, and experimental models.
RESULTS:
concluded that the major distribution of affected regions from AD was brainstem degeneration, followed by major degeneration of the hippocampus. This included increased cerebrospinal fluid CSF involvement with the main cells affected, which were notably glial cells, followed by neurons. Inflammatory markers such as YKL-40 and cytokines TNF-α, TGF-β, and IL-6 were noted to impact signaling proteins FAF1 and caspase family proteins to increase neurodegeneration and the occurrence of amyloid-beta 42 (Aβ42) plaque deposition and neurofibrillary tangle (NFT) formation. Finally, the biological mechanism that primarily resulted was a neuroinflammation leading to microgliosis and astrocytosis, causing an increased occurrence of hyperphosphorylated tau preceding NFT formation and Aβ42 plaque deposition in the brain, as well as poor clearance of neurotoxic plaques from the brain through the CSF due to cellular stress. Further neurovascular damage from chronic hypertension from dysautonomia yielded a breakdown in the blood-brain barrier (BBB), leading to albumin leakage and further microgliosis, resulting in further Aβ42 accumulation, contributing to the patient's cognitive decline. Key genetic contributors include APOE v4, CNTNAP2, and HLA-DR/DQ polymorphisms, a family of neuroinflammatory markers that exhibit population-specific risk profiles and suggest ancestral biomarkers. Proposed treatments that were observed were glymphotherapeutics, transcutaneous vagus nerve stimulation (tVNS), natural compounds like Tanshinone IIA and Lycium barbarum extract, and lifestyle changes that contribute to sleep, diet, and hormonal fluctuations.
CONCLUSION:
Conclusively, these studies show that potential dysautonomia observed in hypertensive states of AD patients are followed by neuroinflammation, an early occurrence of a cascade of symptoms observed in Alzheimer's disease, resulting in neurovascular damage, microgliosis and astrocytosis, therefore increased NFT and Aβ42 buildup in the brain, ensuing brainstem atrophy in the upper posterior region localized around the vagus nerve and hippocampal atrophy, with the result of cognitive decline and loss of episodic memory. Collectively, these studies underscore the need for integrative, personalized approaches to AD diagnosis and treatment, emphasizing early intervention through identification of potential ancestral markers linked to dysautonomia that could hold the key to the pathogenesis of Alzheimer's disease, and further treatment through direct vagal nerve stimulation as a result.