Leptomeningeal arteries on the surface of the cerebral hemispheres are most commonly affected by CAA, arteries in the cerebral cortex are less affected, and capillaries are even less frequently involved by CAA. Medium-sized leptomeningeal arteries often have a patchy deposition of Aβ in the media or in the adventitia on the outer aspects of the artery wall (Figure 1a) 23. Small arteries may show dense accumulation of Aβ in the tunica media (Figure 1a), or as seen in an artery entering the cerebral cortex in Figure 1b, there may be a reticular pattern of Aβ deposition that reflects the accumulation of Aβ in the basement membranes of the smooth muscle cells in the tunica media 4524.

Aβ is detectable by thioflavin staining or by immunohistochemistry mainly in the walls of leptomeningeal arteries with a diameter of less than 60 μm 4, but this reveals only part of the picture. Biochemical investigations have detected Aβ in intracranial vessels as large as the basilar and middle cerebral arteries in individuals as young as 20 years of age (the youngest tested) and increasing sharply in those from 50 to 70 years of age 25. Aβ was undetectable in the walls of extracranial blood vessels 25. In transgenic mouse models of Aβ-CAA, there is heavy deposition of Aβ in the walls of leptomeningeal arteries, but involvement may start with the larger arteries at the base of the brain 26. Veins do not appear to be involved in CAA, although deposits of Aβ are found attached to the walls of veins when CAA of leptomeningeal arteries is severe; this may be due to flakes of amyloid detaching from artery walls in the subarachnoid space and attaching to veins 23.

Aβ may be deposited in the whole or part of the circumference of the wall of cortical arteries (Figure 2a). When arteries are viewed in a longitudinal plane, however, deposition of amyloid is often discontinuous along the length of the vessel (Figure 2b). Transverse bands (Figure 2c) reflect the deposition of amyloid in basement membranes surrounding smooth muscle cells in the tunica media 4. A similar patchy distribution is seen in the walls of leptomeningeal arteries 427. The discontinuous nature of the amyloid deposits in CAA means that estimating the true incidence and severity of CAA is probably most accurately performed on isolated cerebral vessels rather than on sections of brain 27.

Aβ is frequently deposited in the glia limitans that surrounds arteries in the cortex. However, it is unlikely that Aβ drains directly from the glia limitans into the artery wall 28 as the adjacent artery wall may lack Aβ (Figure 2d), and in the less severely involved vessels, there is discontinuity across the artefactual space 28 that separates Aβ in the artery wall from deposits in the glia limitans (Figure 2d-f). ApoE is also deposited in the glia limitans and co-localises with the Aβ 22. The ligand in the glia limitans to which the Aβ binds is not known and it may be that Aβ is taken up by astrocytes 22. Dystrophic neurites are also seen in the perivascular glia limitans, although again the reason is not clear 1. At the surface of the cerebral cortex, deposition of Aβ may be seen in the glia limitans remote from artery walls 4 (Figure 2f), which suggests that the deposits are due to an inherent property of the glia limitans rather than related to perivascular drainage of Aβ.

Deposition of Aβ in basement membranes in artery walls appears to impair the perivascular drainage of ISF and solutes from the brain 35, but it has other effects. Smooth muscle cells are lost from artery walls in CAA and replaced by amyloid (Figure 2g, h), and the affected vessels may show severe degenerative changes that are associated with cerebral haemorrhage 29.

Deposits of Aβ in capillary walls are much less common than Aβ deposits in the walls of cortical and leptomeningeal arteries 30. Capillary CAA is seen mostly in areas that are devoid of Aβ plaques 3132, and the Aβ in the capillary walls is mainly Aβ42 30.

Capillaries with no Aβ in their walls may be closely associated with diffuse plaques of Aβ (Figure 3a). In CAA, insoluble Aβ is deposited in the basement membranes of capillary endothelia (Figure 3b-d) and as excrescences or Drusen (Figure 3c-h) that are smooth and globular (Figure 3c, d, f), irregular (Figure 3e) or filamentous (Figure 3g, h). Drusen are continuous with Aβ in the capillary basement membrane. Both types of pericapillary deposit of Aβ can be demonstrated in paraffin sections (Figure 3c-e), in smear preparations of brain 28 (Figure 3f-h) or on vessels isolated by digesting away the surrounding brain tissue 4. The consolidated globular Drusen (Figure 3c, d, f) may be older than the filamentous deposits of Aβ where the strands of amyloid are in the extracellular spaces of the brain parenchyma through which solutes diffuse to reach the drainage pathways in the capillary walls 333.

Perivascular lymphatic drainage pathways by which ISF and solutes drain from the brain have been defined in experimental animals 3937, and Aβ is deposited in those pathways in CAA as its drainage fails with age (Figure 4). Fluorescent tracers injected into the striatum of the mouse brain initially spread diffusely through the brain parenchyma, but within 5 minutes, the tracers are located in the capillary basement membranes and in the basement membranes around smooth muscle cells in the tunica media of arteries 3. Tracers are taken up in small amounts by vascular smooth muscle cells and by perivascular macrophages along the lymphatic drainage route 3. Lymphatic drainage of ISF along artery walls appears to be almost completely separate from CSF 7. Only 15% of radioactive tracer injected into the ISF is recoverable from the CSF, and the majority of tracer drains to the cervical lymph nodes 9 at a rate equivalent to lymphatic drainage from other tissues 9. Radioactive tracers injected into the brain were located in the adventitia of intracranial arteries but were absent from the walls of the carotid artery in the neck 9. This suggests that solutes draining from the brain pass along the walls of intracranial arteries but leave the carotid artery wall at the base of the skull en route to the cervical lymph nodes 79.

Figure 4 summarises the major mechanisms and routes for the elimination of Aβ from the brain. Observations from tracer studies and from CAA (Figures 1, 2, 3) suggest that, as Aβ leaves the brain, it initially diffuses with ISF and other solutes through the narrow and tortuous extracellular spaces of the grey matter 33338 (Figure 4). It then enters the bulk drainage pathways in the 100- to 150-nm-thick endothelial basement membranes in the walls of capillaries 32833 to drain out of the brain along basement membranes in the tunica media of cortical and leptomeningeal arteries 5.

Basement membranes of the arterial endothelium are not involved in the drainage of fluorescent tracers and do not contain stainable Aβ in CAA 35 (Figure 4). This may be one reason why CAA in older patients and in those with AD is not accompanied by catastrophic arterial thrombosis. Although capillaries may be occluded and reduced in number in AD 39, thrombotic occlusion of arteries in AD is not as widespread as CAA.

Tracer studies suggest that fluid and solutes move to the adventitia of leptomeningeal arteries and from there to the lymph nodes at the base of the skull 79. In CAA, Aβ is detected by immunohistochemistry mainly in the tunica media of smaller leptomeningeal arteries but is present in the adventitia on the outer aspects of medium-sized leptomeningeal arteries 23, suggesting that Aβ follows the same lymphatic drainage route as tracers in experimental animals 79. Restriction of Aβ to the walls of intracranial arteries and its absence from the walls of the extracranial carotid artery 25 suggest that Aβ drains from the wall of the carotid artery to lymph nodes related to the artery at the base of the skull 40. The pattern of deposition of Aβ in the basement membranes of capillary and artery walls in CAA indicates that there is a failure of lymphatic drainage of Aβ and suggests that the failure is related to age changes in artery walls.

As arteries age, fibrous tissue increases in the tunica intima and tunica media (arteriosclerosis and arteriolosclerosis) and arteries become stiffer 23. Such age changes may interfere with the motive force for transport of ISF and solutes, like soluble Aβ, out of the brain. Theoretical models suggest that the contrary (reflection) wave that follows the pulse wave in arteries is the motive force that drives ISF and solutes out of the brain along perivascular pathways in the direction opposite to the flow of blood in the lumen 8. Stretching of the basement membrane with expansion of the artery during systole may be the valve that prevents reflux during the subsequent pulse wave 23. If the pulse wave is the motive force for perivascular drainage of Aβ, then stiffening of artery walls with age may interfere with that force.

Vascular basement membrane changes that occur with age and defects in innervation of cerebral vessel may also play roles in the pathogenesis of CAA 823. Overproduction of transforming growth factor-beta-1 in transgenic mice results in changes in vascular basement membranes and induces CAA 41. Furthermore, experimental cholinergic deafferentation of arteries within the brain, induced by the destruction of the nucleus basalis, results in CAA that resolves with re-innervation 42. These observations emphasise the need to view the lymphatic drainage pathways as a dynamic entity in the context of the whole neurovascular unit 43.

Capillary CAA is much less common than CAA in leptomeningeal or cortical arteries and has been associated with severe dementia 44 and with APOE ε4 genotype 31. However, this does not explain the pathogenesis of capillary CAA. An association between capillary CAA and thrombotic occlusion of cortical arteries has been reported 32, and there is an increase in capillary CAA in the brains of patients treated with immunotherapy 45. In both of these instances, capillary CAA is associated with a paucity or absence of Aβ plaques in the surrounding brain parenchyma and the deposition of Aβ in capillary walls. In the immunised patients with AD, there is an increase in Aβ42 in the walls of blood vessels, suggesting that it is derived from plaque Aβ 46. It seems that the removal of Aβ from plaques by microglia, activated by either ischaemia or immunisation, results in an overload of the drainage pathways in capillary walls by which Aβ drains from the brain.

Arranged along the pathway for the drainage of soluble Aβ from the brain is an array of enzymes and mechanisms for the elimination of Aβ (Figure 4) 1. Enzymes that degrade Aβ are present in the brain parenchyma and in artery walls 1. Mechanisms that mediate absorption of Aβ into the blood via capillary endothelium or uptake of Aβ by smooth muscle cells are also present in the walls of cerebral blood vessels 1.

Neprilysin, angiotensin-converting enzyme and insulin-degrading enzyme are among the Aβ-degrading enzymes to which Aβ is exposed as it diffuses through the extracellular spaces of grey matter in the brain and along the perivascular drainage pathways 1. Neprilysin can hydrolyse monomeric and oligomeric forms of Aβ40 and Aβ42. However, abnormal forms of Aβ that result from the Flemish, Dutch, Italian and Arctic mutations in the APP gene are not cleaved by neprilysin and these familial disorders are associated with severe CAA and early-onset cerebral haemorrhage or dementia 10. Neprilysin is produced by pyramidal neurons and by smooth muscle cells in the walls of arteries 47; a reduction of neprilysin in artery walls is associated with severe CAA in AD and in transgenic mice 4748. Other enzymes that degrade Aβ in the walls of cerebral arteries are also deficient or less active in AD 1.

Absorption of Aβ into the blood, mediated by low-density lipoprotein receptor-related protein-1 (LRP-1) located in capillary endothelium 4349, is a major mechanism for elimination of Aβ from the brain 43 and is six times faster than lymphatic drainage 50. LRP-1 also mediates the entry of Aβ into vascular smooth muscle cells, where it is degraded 43. Failure of LRP-1-related elimination of Aβ with age 49 or in conditions of hypoxia 43 may also increase the flow of soluble Aβ into perivascular drainage pathways already compromised by age changes in the artery walls themselves 23.

There is evidence that the perivascular macrophages that take up tracer draining along perivascular pathways 3 also degrade Aβ 51. In APP transgenic mice that overproduce human Aβ, stimulation of perivascular macrophages reduces the severity of CAA whereas depletion of these cells increases the severity of CAA 51. Enzymic and absorptive mechanisms appear to fail with age 1. Such a failure may be a factor that aggravates CAA in older patients and in those with AD by diverting more Aβ into the ageing perivascular drainage pathways 23.

Figure 5 summarises the role of impaired lymphatic drainage of the brain and CAA in the accumulation of Aβ in the brain in AD. Diffusion of Aβ through the extracellular spaces of the brain and along the drainage pathways in artery walls 5657 is impaired by plaques of Aβ in the brain 5859. CAA also restricts the drainage of Aβ along perivascular pathways as seen in tg2576 transgenic mice in which plasma levels of Aβ fall and levels of Aβ in the brain rise as CAA develops 60.

There is evidence that the failure of elimination of Aβ and fluid from the brain correlates with CAA in human AD. First, severe CAA correlates with severe dementia 61. Second, high levels of soluble Aβ40 in brain parenchyma, with up to a threefold increase, distinguish demented patients with AD from non-demented patients, even though the non-demented patients may have high numbers of insoluble Aβ plaques in their brains 62. Third, accumulation of fluid in cerebral white matter (leukoaraiosis) in AD has been correlated with the severity of CAA 27, suggesting that Aβ in artery walls may block the perivascular drainage of fluid and solutes from white matter as well as from grey matter.

These observations suggest that one of the main pathogenetic roles of insoluble Aβ is to block the elimination of fluid and solutes from the brain. This may result in the accumulation of toxic soluble fibrillar oligomers of Aβ in the brain in AD 63. But it may equally well result in the accumulation of other soluble metabolites and the loss of homeostasis of the neuronal environment with consequent impairment of neuronal function.

The reported prevalence of CAA in histological studies of brains of patients with AD varies from 90% to 96% 1. However, the true prevalence of CAA in AD may be significantly underestimated in histological and immunohistochemical surveys in which little account may be taken of the long length of the perivascular drainage pathways, the patchy nature of Aβ deposits and the relative insensitivity of immunohistochemistry as a method for detecting Aβ compared with biochemical techniques 23. Methods using isolated cerebral arteries, stained for amyloid, may give better estimates of the true prevalence and distribution of CAA in AD 427, and a greater understanding of the dynamics and pathophysiology of perivascular drainage should help to resolve any current discrepancies in the role of CAA in the aetiology of AD.

In addition to the accumulation of insoluble and soluble Aβs in the brain in AD, hyperphosphorylated tau accumulates as neurofibrillary tangle (NFT) in neurons and as neuropil threads and dystrophic neurites in neuronal processes 64. Explaining how the accumulation of tau relates to the deposition of Aβ in the brain has presented a challenge for many years. In transgenic mice that overexpress both APP and tau, the deposition of Aβ in the brain precedes and accelerates the accumulation of intracellular tau 65. Furthermore, a recent study suggests that failure of elimination of tau from the extracellular spaces of the brain may play a role in the intracellular accumulation of tau 66. In AD, tau inclusions first appear in neurons in the transentorhinal cortex and then spread to the hippocampal formation and neocortex 64. Cognitive impairment ensues as tau inclusions reach the hippocampus, and neocortical tau inclusions are a hallmark of the later and more severe stages of AD 64. Injections of fibrillary tau transfer the propensity to form NFT in mice 66, which suggests that interference with the disposal of tau from the extracellular spaces when lymphatic drainage pathways are blocked by CAA may be a factor in the formation and spread of NFT in the human brain in AD.