Blog – A vascular element of Alzheimer’s: Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy is the deposition of amyloid-β in the blood vessels of the brain, and an incredibly common co-pathology of Alzheimer’s disease. However, we don’t hear as much about it as the typical plaques and tangles. My new postdoc project has a large focus on cerebral amyloid angiopathy (or CAA), and I thought it was a great opportunity to share some of my newfound interest and understanding of this area with the dementia researcher community.

Amyloid-β plaques are one of the hallmark pathologies of Alzheimer’s disease. These plaques result from the aggregation and deposition of the amyloid-β peptide, which is produced through the sequential cleavage of the amyloid precursor protein in neuronal membranes. However, unlike plaques, which are deposited throughout the parenchymal tissue of the brain amongst neurons and glia, CAA occurs when amyloid-β is deposited within the walls of blood vessels. CAA can affect vessels in both the meninges, the protective tissues which surround the brain, and in the cerebrum. CAA occurs primarily in arterioles but can also occur in capillaries. The amyloid-β begins to accumulate in the media of a vessel, near the smooth muscle wall. Over time, with progressive deposition, the integrity of the vessel can become impaired. As with plaque deposition in Alzheimer’s disease, the cause of CAA has been linked to both the overproduction of (in genetic causes of Alzheimer’s disease), or the failure to clear, amyloid-β.

In post-mortem brain tissue, CAA can be detected by staining for amyloid-β and examining vessels of the leptomeninges and parenchyma. Classifications can be made on the severity of CAA with mildly affected vessels having less than the entire diameter positive for amyloid-β, and more severely affected vessels being largely covered in amyloid-β, demonstrating fracturing or double-barrelling of vessel walls. On post-mortem examination, upward of 90% of individuals who had Alzheimer’s disease will have some vessels affected by CAA, however, the prevalence and severity vary hugely. Although a common comorbidity of Alzheimer’s disease generally, certain genetic forms of Alzheimer’s disease, such as those caused by familial autosomal dominant mutations, or Down syndrome, tend to have higher levels of more severe CAA.

But what are the consequences of CAA? The integrity of blood vessels can be damaged by CAA, resulting in adverse outcomes such as brain bleeds in the form of microhaemorrhages. Neuroimaging can be used to show evidence of CAA, which is associated with cerebral microbleeds, white matter hyperintensities and cortical superficial siderosis, among other features. CAA can occur during healthy aging, but as it is often a co-pathology of Alzheimer’s disease, and can therefore be can be asymptomatic in the context of pre-existing cognitive decline, and only identified post-mortem. If symptomatic, CAA is associated with symptoms of brain bleeds, such as headaches and nausea. There are rare hereditary cases of CAA, such as Dutch or Icelandic familial mutations, where stroke occurs more frequently than in Alzheimer’s disease in the general population. A further rare condition that can occur in certain individuals is CAA-related inflammation, which results from localised perivascular inflammation caused by amyloid-β deposition in blood vessels and has a more acute onset of symptoms.

So why is CAA so important in the context of current Alzheimer’s disease research? Well, this comes down to the recently approved anti-amyloid-β monoclonal antibody therapies, such as Lecanemab and Donanemab. These drugs, which have been approved as safe to use by the MHRA in the UK (but not currently covered by the NHS), have been shown to moderately slow cognitive decline in people who are at the early-stages of Alzheimer’s disease. This means staying cognitively stable for a longer period of time, between 6-12 months. However, a major controversy surrounding these drugs is the commonly occurring side effect known as ARIA – amyloid related imaging abnormalities. ARIA occurs as either a haemorrhage event (ARIA-H) or as oedema (ARIA-E), both of which were detected by MRI in participants of clinical trials for these drugs. ARIA occurred with about a 20-25% incidence in patients participating in trials for both therapies. Although many cases of ARIA are asymptomatic, it can be associated with some mild symptoms such as headache and dizziness, and in extreme cases, stroke.

Why ARIA is happening is not fully clear, but hypotheses within the field indicate that this is likely due to the presence of CAA in the vasculature in treated individuals. Whether ARIA is being caused by the direct removal of CAA and subsequent vessel damage, by amyloid-β removal from the parenchyma via the vessels causing localised inflammation events, or by a broad inflammatory response that disturbs vessel integrity, is not currently known. It may be a combination of these events and vary between individuals. A recent study showed the direct binding of Lecanemab to CAA in post-mortem brain material from individuals who had Down syndrome-Alzheimer’s disease. However, how and if these antibodies bind to CAA in a living individual with Alzheimer’s disease needs more exploration.

What is clear is that understanding the role of CAA in ARIA will be very important when considering who should be treated with these therapies. Moreover, understanding a person’s risk for CAA, in the absence of specific CAA biomarkers, will be necessary in the immediate future for those being considered for currently available monoclonal antibodies. Overall, these new therapies shed light on the importance of considering the vascular element of Alzheimer’s disease, and remind us of the complex and heterogeneous nature of disease pathologies and processes.

Clíona Farrell

Author

Dr Clíona Farrell is a Postdoctoral Researcher in the UK Dementia Research Institute at University College London. Her work focuses on understanding neuroinflammation in Down syndrome, both prior to, and in response to, Alzheimer’s disease pathology. Originally from Dublin, Ireland, Clíona completed her undergraduate degree in Neuroscience in Trinity College, and then worked as a research assistant in the Royal College of Surgeons studying ALS and Parkinson’s disease. She also knows the secret behind scopping the perfect 99 ice-cream cone.

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