Alzheimer's disease (AD) is the most common type of dementia and is characterised pathologically by the intraneuronal accumulation of neurofibrillary tangles (NFT) containing tau and ubiquitin, and by the extracellular accumulation of amyloid-β (Aβ) in brain tissue and in artery walls as cerebral amyloid angiopathy (CAA). Many studies have correlated the severity of dementia in AD with the number and distribution of NFTs, the number of plaques of insoluble Aβ, and the levels of soluble Aβ in the brain [as reviewed by [1
]]. Relatively few studies, however, have investigated the relationship between dementia and the key pathological change of CAA.
CAA is the deposition of the amyloid peptides, of which Aβ is the most common, in the media and adventitia of small to medium-sized cerebral and leptomeningeal arteries, and less commonly in the walls of capillaries and veins [2
]. The occipital lobe is most often involved, the frontal, parietal and temporal lobes less so and the cerebellum least; CAA is rare in the thalamus, basal ganglia and white matter [6
]. Scholz [8
] first emphasized the presence of CAA, suggesting that the pathological feature was associated with 'senility'. However, CAA was only reported to be a risk factor for dementia in the 1980s [9
]. There has since then been increasing evidence to support this proposal [12
] and CAA is now thought to play a significant role in the production of dementia [14
]. Hereditary and sporadic types of CAA have been defined [17
] however this review focuses on the common sporadic CAA found in the old.
The cause and effects of CAA have generated much debate especially in relation to dementia [19
]. CAA represents the failure of elimination of Aβ along the perivascular pathways that serve as the lymphatic drainage channels for the brain [20
]. Soluble tracers injected into the mouse striatum drain out of the brain along basement membranes of capillary and artery walls [21
]. In CAA, Aβ is deposited in the very same perivascular drainage pathways outlined, in capillary and artery walls, in the injection studies in mice. This suggests that there is a failure of elimination of Aβ along ageing cerebral and leptomeningeal arteries [20
]. Stiffening of artery walls with age and cerebrovascular disease may be a key element in reducing the elimination of Aβ from the brain in the elderly and in AD [20
]. Transgenic mice that overproduce Aβ only in the brain develop CAA [19
] which further supports the hypothesis that, in CAA, Aβ is entrapped in the perivascular pathways by which fluid and solutes drain from the brain [20
Two major consequences arise from CAA. First: arteries weakened by deposits of Aβ in their walls tend to rupture and result in CAA-related intracerebral haemorrhage [26
]. Second: blockage of perivascular drainage pathways by Aβ may be associated with accumulation of Aβ in the brain. Ultimately it is increased levels of soluble Aβ that correlates with cognitive decline in patients with AD [28
]. It is possible that drainage of other soluble metabolites from the brain may also be impeded in CAA. This would result in a loss of homeostasis in the neuronal extracellular environment that could contribute to cognitive decline in AD [20
CAA has been related to other neuropathological markers of dementia including neuritic plaques and NFTs [30
]. The amount of phospho-tau in neurites was found to be greater in grey matter surrounding cerebral vessels affected by CAA than in grey matter away from affected vessels [33
]. The relationship between CAA and other neuropathologies is not simple however, and there is great heterogeneity in CAA severity in brains with AD-type pathology [34
]. CAA has been reported to affect cognition/dementia status independently of other neuropathological markers of dementia [3
]. However, in one study CAA was found to be associated with dementia only in those who lacked any AD-type pathology [37
Assessing the possible impact of CAA or any neuropathological marker of dementia is best done using a sample that closely reflects the population at risk [38
]. The vast majority of studies assessing the relationship between CAA and dementia have assessed selected samples (e.g., necropsy and hospital patients) which do not reflect the population at risk, in terms of either clinical or age profiles. Many of these studies have had access to limited clinical information, which further limits the interpretation of results. Thus, although CAA has been reported to play a significant role in the causation of dementia, it is unknown whether this is partly an artefact of using highly selected samples and/or the predominant use of neuropathological dementia classifications such as AD (which most likely relates to CAA closer than clinical diagnoses). The role of CAA in dementia at a population level is uncertain.
Our aim in this study was to investigate the importance of CAA in relation to dementia in a population-based context. We have addressed this by systematically reviewing previous studies that have assessed the relationship between CAA and dementia in prospectively sampled population-based cohorts of elderly people. For comparison, we have systematically reviewed studies of CAA on selected samples.