Cerebral Amyloid Angiopathy (CAA) is defined by the accumulation of amyloid protein in the walls of small and medium-sized blood vessels within the brain’s cortex and surrounding membranes (leptomeninges). This progressive deposition weakens the vessels, which can ultimately lead to bleeding and damage to brain tissue. CAA is primarily a disorder of aging, with risk and prevalence increasing significantly in the elderly population, especially over age 55. While often asymptomatic in its early stages, the condition is a major cause of serious neurological events, including strokes caused by hemorrhage and cognitive decline.
The Underlying Mechanism of CAA
The fundamental process in CAA involves the misfolding and buildup of the amyloid-beta (Aβ) peptide within the vessel walls. This Aβ peptide is the same substance that forms the plaques in the brain tissue of individuals with Alzheimer’s Disease (AD), but in CAA, the deposition is concentrated in the cerebral vasculature. The accumulation occurs in the media and adventitia layers of the arteries and arterioles, effectively replacing the vessel’s normal structural components, which causes the smooth muscle cells to degenerate.
This pathological accumulation is thought to result from a failure of the brain’s natural clearance mechanisms, which normally flush the Aβ peptide out along perivascular drainage pathways. As the Aβ protein builds up, it physically weakens the vessel wall, leading to a condition known as fibrinoid necrosis, which makes the vessels fragile and prone to rupture. The distinction between CAA and AD is that CAA involves deposition in the vessel walls, while AD involves plaques in the brain parenchyma, although the two conditions frequently coexist.
Advanced age is the most significant risk factor for sporadic CAA, with prevalence increasing sharply after age 60. Genetic factors also play a part, particularly the apolipoprotein E (APOE) gene. The APOE ε4 allele is associated with an increased risk of CAA and earlier onset of hemorrhage, while the APOE ε2 allele also confers a risk for CAA-related bleeding.
Clinical Manifestations in the Brain
The primary and most dramatic clinical presentation of CAA is spontaneous lobar intracerebral hemorrhage (ICH), which is bleeding into the superficial, or lobar, regions of the brain. This bleeding occurs because the amyloid deposition has rendered the small arteries fragile and susceptible to rupture. The symptoms of a major hemorrhage can resemble a stroke, including sudden headaches, confusion, localized weakness, or difficulty with speech, and the severity depends on the size and location of the bleed.
A person with CAA may also experience transient focal neurological episodes (TFNEs), sometimes informally referred to as “amyloid spells.” These episodes are typically brief, recurring events that can involve symptoms like temporary weakness, numbness, or visual disturbances. TFNEs are often related to small, temporary bleeds or localized swelling in the cortex, and they can sometimes be misdiagnosed as transient ischemic attacks (TIAs).
Progressive cognitive impairment and dementia are also major outcomes of CAA, resulting from the cumulative damage of chronic small bleeds and reduced blood flow. The condition causes numerous small, often silent, microbleeds and ischemic changes that contribute to a gradual decline in thinking abilities. This cognitive decline is a significant contributor to the burden of the disease, often compounding any cognitive issues already present from coexisting AD pathology.
Methods for Diagnosis
A definitive diagnosis of CAA can only be established through a pathological examination of brain tissue, obtained via a brain biopsy or post-mortem autopsy. Since a biopsy is an invasive procedure, a clinical diagnosis in living patients relies heavily on characteristic findings from non-invasive brain imaging, specifically Magnetic Resonance Imaging (MRI). MRI visualizes the signs of past and current bleeding that are highly suggestive of the condition.
Key MRI Markers
The key MRI markers that point toward a CAA diagnosis include:
- Strictly lobar cerebral microbleeds, which appear as tiny, dark spots on specific MRI sequences.
- Cortical superficial siderosis, a thin line of iron deposits indicating previous, more widespread superficial bleeding.
- The presence of white matter hyperintensities, which suggest chronic small-vessel injury and ischemia.
These imaging features are integrated with a patient’s clinical history to establish a probability of CAA using a standardized set of guidelines known as the modified Boston Criteria. The Boston Criteria allow clinicians to diagnose probable CAA in a living patient without a tissue sample, based on the presence of multiple, strictly lobar hemorrhagic lesions and the patient’s age.
Treatment and Long-Term Management
Currently, there is no specific treatment or cure available that can halt the progression of CAA or remove the amyloid deposits from the cerebral vessels. Therefore, management is focused primarily on supportive care and reducing the risk of a first or recurrent intracerebral hemorrhage. This risk reduction is crucial because bleeding events are the main cause of severe disability and death in CAA patients.
The most impactful intervention is rigorous blood pressure control, as managing hypertension helps to reduce the strain on the fragile, amyloid-laden vessel walls. Patients are often treated to achieve blood pressure targets that are lower than those for the general population. Another primary management rule is the strict avoidance of medications that increase bleeding risk, particularly antiplatelet agents like aspirin and anticoagulant drugs.
These medications must be discontinued or avoided entirely unless there is a compelling and life-threatening reason to use them. Researchers are actively exploring potential new therapies, including anti-amyloid immunotherapies, but these treatments present a challenge because of the increased risk of bleeding in patients with pre-existing vascular amyloid. For a small subset of patients who develop a rare inflammatory form of CAA, immunosuppressive treatments may offer clinical and radiological improvement.