Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence

Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer's disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients.