Cerebral amyloid angiopathy (CAA) ­– should it be a contraindication for drugs like lecanemab?

Early in my career as a neurologist, probably about 1990, I was asked to consult on a 62-year-old, previously healthy woman who had had a large brain hemorrhage. She had no apparent risk factors such as high blood pressure, aneurysms or anticoagulants like warfarin, and she had no cognitive impairment suggestive of dementia.  She had a good recovery from the brain hemorrhage and was able to return to her regular job as a secretary.  Two years later she had a second bleeding episode in a different lobe of her brain. This time she had cognitive problems that did not improve.  An angiogram was unremarkable. A spinal tap showed elevated protein and white blood cells in her spinal fluid suggesting the possibility of inflammation in her brain, so I recommended treatment with steroids thinking she might have primary CNS vasculitis, an inflammatory disease of cerebral blood vessels. The steroids didn’t help, and she became progressively impaired and died a year later. The autopsy revealed that she had cerebral amyloid angiopathy (CAA), and she also had many amyloid plaques and neurofibrillary tangles throughout her brain consistent with Alzheimer’s disease.

CAA is vascular disease of the brain in which beta-amyloid is deposited in the walls of small arteries and capillaries. The amyloid replaces smooth muscle cells causing vessel wall thickening and stiffness resulting leaks and reduced blood flow in these small blood vessels. Tiny hemorrhages and small strokes are seen surrounding the affected blood vessels.  In the elderly, CAA is a major cause of bleeding in the various lobes of the brain. It can occur sporadically or in families. There is often but not always overlap with Alzheimer’s disease. The beta-amyloid in vessel walls in CAA is usually the shorter peptide fragment, Aβ40 (40 amino acids in length), compared to that in the amyloid plaques of Alzheimer’s disease, Aβ42. Pathological evidence of CAA is found in in over half of brains that have Alzheimer’s amyloid plaques and neurofibrillary tangles.

Although the first symptom of CAA can be a catastrophic brain hemorrhage in an elderly patient, personality changes, particularly apathy, may occur much earlier. As in Alzheimer’s disease, apathy in CAA appears to be caused by damage to neural circuits in the prefrontal cortex. In the absence of major bleeding or a biopsy, CAA is surprisingly difficult to detect during life. Currently the best test is an MRI protocol called susceptibility weighted imaging. This is a sequence that is particularly sensitive to blood and other iron-containing compounds that distort the local magnetic field. Although the SWI-MRI is not completely specific for blood, the distribution of these black dots around blood vessels correlates very well with the presence at autopsy of microhemorrhages associated with CAA. Although MRI-SWI is the best test for CAA at present, it can only detect CAA if there has been leakage of blood from these damaged blood vessels. The location and number of so-called white matter hyperintensities as seen on FLAIR MRI images may also support the diagnosis. Sensitivity of these MRI techniques for detecting CAA is probably about half that of examining the brain at autopsy. We really can’t yet detect the early stages of CAA during life.

Although there is no treatment for CAA, people who have it are at increased risk for major bleeding in the brain. In patients with a known history or even a suspicion of CAA, I believe that anti-amyloid monoclonal antibodies like lecanemab should not be given.  People who have had ARIA-H (amyloid-related imaging abnormalities with microhemorrhages) during treatment with an anti-amyloid monoclonal antibody may have CAA, and they should be closely monitored by MRI if the drug is continued. Caution should also be used in the use of blood-thinning drugs like warfarin or the clot-busting medication tissue plasminogen activator (t-PA) as these may increase the chance of a potentially fatal hemorrhage in those with CAA.