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

Abstract

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.

Keywords: Alzheimer’s disease; anticoagulant; atrial fibrillation; catheter ablation; dementia; hypoperfusion; rhythm control.

Fig.1

Plausible mechanisms by which atrial fibrillation (AF) induces vascular dementia and Alzheimer’s disease (AD). AF causes cerebral infarction due to the embolic mechanism through thrombus formation within the heart chamber and can be a risk of vascular dementia (left cascade). Meanwhile, persistent AF may accelerate the three major pathological hallmarks of AD, namely senile plaques, amyloid angiopathy, and neurofibrillary tangles, through AF-associated cerebral hypoperfusion (right cascade). In addition, cerebral hypoperfusion can cause hypoperfusive vascular dementia. Although further research should be conducted to reach definitive conclusions, anticoagulation therapy may prevent vascular dementia, while rhythm/rate control may prevent AD. Since AD frequently coexists with cerebrovascular diseases (AD with CVD) in the elderly, and both dementing disorders may be induced by AF, optimal management of AF should be considered for prevention of the two major subtypes of dementia. Possible confounding pathologies that contribute to dementia in AF patients are not included in the figure for simplification (see text for details).

Fig.2

Vascular changes may influence Alzheimer’s disease lesion burden. A) Scheme and arrows indicate how cerebrovascular factors affect amyloid-β (Aβ) processing and clearance. (1) Hypoperfusion, as a result of arteriolosclerosis or blood–brain barrier disruption, elevates BACE1 levels and activity, leading to Aβ overproduction. (2) Aβ overproduction leads to amyloid plaque formation and cerebral amyloid angiopathy (CAA); CAA impairs Aβ clearance efficiency, thus forming a cycle of Aβ clearance failure. (3) CAA further potentiates deficiencies of blood flow by aggravating preexisting arteriosclerosis and BBB disruption, thus forming a cycle of Aβ overproduction. AF can modify and drive such vicious cycles through concomitant hypoperfusion. B) AF may accelerate Alzheimer’s disease indirectly through cerebrovascular disease such as cardioembolic stroke and white matter changes. Note that arteriolosclerosis is known to be associated with ischemic stroke while CAA with white matter changes, which may further drive the vicious cycle of dementia.