Severe Cerebral Amyloid Angiopathy Research Articles

Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta) peptides in leptomeningeal and cortical blood vessels, affects the majority of patients with Alzheimer's disease (AD). Evidence suggests that vascular amyloid deposits may result from impaired clearance of neuronal Abeta along perivascular spaces. We investigated the role of perivascular macrophages in regulating CAA severity in the TgCRND8 mouse model of AD. Depletion of perivascular macrophages significantly increased the number of thioflavin S-positive cortical blood vessels. ELISA confirmed that this increase was underscored by elevations in total vascular Abeta(42) levels. Conversely, stimulation of perivascular macrophage turnover reduced cerebral CAA load, an effect that was not mediated through clearance by microglia or astrocytes. These results highlight a function for the physiological role of perivascular macrophages in the regulation of CAA and suggest that selective targeting of perivascular macrophage activation might constitute a therapeutic strategy to clear vascular amyloid.

Cerebral amyloid angiopathy: micro‐haemorrhages demonstrated by magnetic resonance susceptibility‐weighted imaging

Cerebral amyloid angiopathy: micro‐haemorrhages demonstrated by magnetic resonance susceptibility‐weighted imaging

Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review

BackgroundDeposition of amyloid-β (Aβ) in vessel walls of the brain as cerebral amyloid angiopathy (CAA) could be a major factor in the pathogenesis of dementia. Here we investigate the relationship between dementia and the prevalence of CAA in older populations. We searched the literature for prospective population-based epidemiological clinicopathological studies, free of the biases of other sampling techniques, which were used as a comparison.MethodsTo identify population-based studies assessing CAA and dementia, a previous systematic review of population-based clinicopathological studies of ageing and dementia was employed. To identify selected-sample studies, PsychInfo (1806–April Week 3 2008), OVID MEDLINE (1950–April Week 2 2008) and Pubmed (searched 21 April 2008) databases were searched using the term "amyloid angiopathy". These databases were also employed to search for any population-based studies not included in the previous systematic review. Studies were included if they reported the prevalence of CAA relative to a dementia classification (clinical or neuropathological).ResultsFour population-based studies were identified. They showed that on average 55–59% of those with dementia displayed CAA (of any severity) compared to 28–38% of the non-demented. 37–43% of the demented displayed severe CAA in contrast to 7–24% of the non-demented. There was no overlap in the range of these averages and they were less variable and lower than those reported in 38 selected sample studies (demented v non-demented: 32–100 v 0–77% regardless of severity; 0–50 v 0–11% for severe only).ConclusionCAA prevalence in populations is consistently higher in the demented as compared to the non-demented. This supports a significant role for CAA in the pathogenesis of dementia.

Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice: Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via γ-Secretase Inhibition

The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-beta peptide (Abeta), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Abeta but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Abeta can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Abeta on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Abeta improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Abeta cause cerebrovascular dysfunction, that mechanisms other than Abeta-induced alteration in vessel integrity are responsible, and that anti-Abeta therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.

Consequence of Aβ immunization on the vasculature of human Alzheimer's disease brain

A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.

Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances

The role of cerebral amyloid angiopathy (CAA) in the pathogenesis of Alzheimer's disease (AD) is not fully understood. Here, we studied whether CAA is associated with alterations in microvascularisation in transgenic mouse models and in the human brain. APP23 mice at 25–26 months of age exhibited severe CAA in thalamic vessels whereas APP51/16 mice did not. Wild-type littermates were free of CAA. We found CAA-related capillary occlusion within the thalamus of APP23 mice but not in APP51/16 and wild-type mice. Magnetic resonance angiography (MRA) showed blood flow alterations in the thalamic vessels of APP23 mice. CAA-related capillary occlusion in the branches of the thalamoperforating arteries of APP23 mice, thereby, corresponded to the occurrence of blood flow disturbances. Similarly, CAA-related capillary occlusion was observed in the human occipital cortex of AD cases but less frequently in controls. These results indicate that capillary CAA can result in capillary occlusion and is associated with cerebral blood flow disturbances providing an additional mechanism for toxic effects of the amyloid β-protein in AD.

Severe cerebral amyloid angiopathy in Alzheimer's disease is associated with frequent old microinfarcts

To investigate whether the presence of severe cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) was associated with a higher prevalence of old microinfarcts (OMIs) than in AD without significant CAA, 6 AD brains with severe CAA were selected, together with 12 age‐matched AD brains without significant CAA, from the Alzheimer's Disease Research Center Tissue Bank. Immunohistochemistry for CD68 was employed to highlight ≤5 mm foci of macrophage‐infiltrated tissue destruction (i.e. OMIs) in formalin‐fixed paraffin‐embedded tissue blocks taken from various regions of the cerebral cortex/white matter and cerebellum (range 13–21, mean 16.3 blocks per brain in the AD/CAA group; range 7–21, mean 14.7 blocks per brain in the AD group; p = 0.39, 2‐tailed Student's t‐Test). OMIs, manually counted by light microscopy, were observed in all of 6 AD/CAA brains, and in 2 out of 12 AD brains (p = 0.0015, 2‐tailed Fisher's Exact Test). The number of OMIs per block ranged from 0.14 to 1.76 (mean 0.74) in the AD/CAA group, and from 0 to 0.12 (mean 0.02) in the AD group (p = 0.02, 1‐tailed Student's t‐Test). Using Perl's iron staining, old microhemorrhages were occasionally seen in both groups. In conclusion, OMIs are frequent in AD with severe CAA, which may contribute to a vascular component of cognitive impairment. This work was supported by the grants P50 AG16570, P01 AG12435 and the Sarkaria Chair in Diagnostic Medicine (H.V.V.).

Cerebral amyloid angiopathy in Lewy body disease

While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson's disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid beta (Abeta) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Abeta plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology.

Angiotensin‐converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE‐1 to cerebral amyloid angiopathy

Several observations point to the involvement of angiotensin-converting enzyme-1 (ACE-1) in Alzheimer's disease (AD): ACE-1 cleaves amyloid-beta peptide (Abeta) in vitro, the level and activity of ACE-1 are reportedly increased in AD, and variations in the ACE-1 gene are associated with AD. We analysed ACE-1 activity and expression in AD and control brains, particularly in relation to Abeta load and cerebral amyloid angiopathy (CAA). ACE-1 activity was measured in the frontal cortex from 58 control and 114 AD cases of known Abeta load and CAA severity. The distribution of ACE-1 was examined immunohistochemically. In five AD cases with absent or mild CAA, five with moderate to severe CAA and five controls with absent or mild CAA, levels of vascular ACE-1 were assessed by quantitative immunofluorescence. ACE-1 activity was increased in AD (P < 0.001) and correlated directly with parenchymal Abeta load (P = 0.05). Immunohistochemistry revealed ACE-1 in neurones and cortical blood vessels - in the intima but most abundant perivascularly. Cases with moderate to severe CAA had significantly more vessel-associated ACE-1 than did those with little or no CAA. Perivascular ACE-1 did not colocalize with Abeta, smooth muscle actin, glial fibrillary acidic protein, collagen IV, vimentin or laminin, but was similarly distributed to extracellular matrix (ECM) proteins fibronectin and decorin. Our findings indicate that ACE-1 activity is increased in AD, in direct relationship to parenchymal Abeta load. Increased ACE-1, probably of neuronal origin, accumulates perivascularly in severe CAA and colocalizes with vascular ECM. The possible relationship of ACE-1 to the deposition of perivascular ECM remains to be determined.

Association of the Glutathione S-transferase Omega-1 Ala140Asp Polymorphism With Cerebrovascular Atherosclerosis and Plaque-Associated Interleukin-1α Expression

Glutathione S-transferase omega-1 is a multifunctional enzyme. The Asp/Asp genotype of the Ala140Asp polymorphism of the GSTO1 gene has been alleged to increase the risk of vascular dementia. The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism. The severity and expansion of atherosclerosis in the circle of Willis vessels, cerebral small vessel disease, and cerebral amyloid angiopathy were studied in a sample of 79 autopsy cases. Genotyping of the GSTO1 Ala140Asp polymorphism as well as immunohistochemistry for glutathione S-transferase omega-1 was performed. Carriers of the GSTO1 Asp/Asp genotype presented with more severe and widespread atherosclerosis than noncarriers. However, there was no effect on small vessel disease expansion and cerebral amyloid angiopathy severity. Immunohistochemically, we detected interleukin-1 alpha expressing macrophages in the lipid core of atherosclerosis plaques exhibiting glutathione S-transferase omega-1-positive material. GSTO1 Asp/Asp carriers showed larger areas of atherosclerosis plaques containing interleukin-1 alpha-positive material than carriers of the GSTO1 Ala-allele. The GSTO1 Asp/Asp genotype presumably modulates the severity and expansion of atherosclerosis in the circle of Willis. The cellular colocalization of glutathione S-transferase omega-1 and interleukin-1 alpha suggests a functional interaction between both proteins which in part might explain the function of glutathione S-transferase omega-1 in the pathogenesis of cerebral atherosclerosis.

Small heat shock proteins associated with cerebral amyloid angiopathy of hereditary cerebral hemorrhage with amyloidosis (Dutch type) induce interleukin-6 secretion

In hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), severe cerebral amyloid angiopathy (CAA) is associated with an inflammatory reaction. Small heat shock proteins (sHsps) are molecular chaperones and association of HspB8 with CAA in HCHWA-D has been observed. The aims of this study were to investigate (1) if other sHsps are associated with the pathological lesions in HCHWA-D brains, (2) if the amyloid-β protein (Aβ) increases production of sHsps in cultured cerebral cells and (3) if sHsps are involved in the cerebral inflammatory processes in both Alzheimer's disease (AD) and HCHWA-D. We conclude that Hsp20, HspB8 and HspB2 are present in CAA in HCHWA-D, and that Aβ did not affect cellular sHsps expression in cultured human brain pericytes and astrocytes. In addition, we demonstrated that Hsp20, HspB2 and HspB8 induced interleukin-6 production in cultured pericytes and astrocytes, which could be antagonized by dexamethasone, whereas other sHsps and Aβ were inactive, suggesting that sHsps may be among the key mediators of the local inflammatory response associated with HCHWA-D and AD lesions.

Molecular Imaging With Pittsburgh Compound B Confirmed at Autopsy

To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of beta-amyloid (Abeta) in postmortem tissue analysis. Patient A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose (18)F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan. Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Abeta plaques. Biochemical measures revealed a positive correlation between Abeta levels and regional PiB binding. This report confirms that PiB detects Abeta in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.

Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology

Cerebral amyloid angiopathy (CAA) is defined by β-amyloid peptide (Aβ) depositions in cerebral vessels and is associated with Alzheimer disease (AD). It has been suggested that severe CAA is an independent risk factor for cognitive decline. 171 autopsy brains underwent standardized neuropathological assessment, the patients age ranged from 54 to 104 years (mean age: 83.9 years, +/− 9.2, 59.6% female, 56.1% clinically demented). Using immunohistochemistry, the severity of Aβ depositions in vessels was assessed semiquantitatively in the frontal, frontobasal, hippocampal, and occipital region, respectively. CAA was present in 117 cases (68.4%), with the occipital region being affected significantly stronger than other regions. The overall incidence of CAA was significantly higher in cases with high grade neuritic AD pathology (ADP) compared to those with low grade or no ADP. The severity of CAA significantly increased with increasing ADP, with CAA in the occipital region increasing significantly stronger than that in other regions. The association of CAA and clinical dementia failed to remain statistically significant when adjusting for concomitant ADP. However, in cases devoid of any ADP CAA was significantly associated with the presence of clinical dementia. These results indicate a strong association of AD with CAA, but do not unequivocally support reports suggesting CAA to be an independent risk factor for cognitive decline, except for a subgroup of demented patients lacking any ADP.

Caveolin‐1 and ‐2 and their relationship to cerebral amyloid angiopathy in Alzheimer's disease

Cerebral amyloid angiopathy (CAA) affects over 90% of patients with Alzheimer's disease (AD) and increases the risk of cerebral haemorrhage and infarction. Caveolae--cholesterol-enriched plasmalemmal microinvaginations--are implicated in the production of amyloid beta peptide (Abeta). Caveolin-1 (CAV-1) is essential for the formation of caveolae. Caveolin-2 (CAV-2) is expressed at the plasma membrane only when in a stable hetero-oligomeric complex with CAV-1. CAV-1 and CAV-2 are highly co-expressed by endothelium and smooth muscle. Recent studies suggest that down-regulation of CAV-1 causes a reduction in alpha-secretase activity and consequent accumulation of Abeta. We have used quantitative immunohistochemical techniques to assess the relationship between CAV-1 and CAV-2 with respect to Abeta accumulation in the cerebral vasculature in a series of post mortem brains. CAV-1 and CAV-2 were co-expressed within the tunica media and endothelium of cerebral blood vessels. There were regional differences in CAV-1 immunolabelling, which was significantly greater in the frontal cortex and white matter than in the parietal lobe (in both control and AD cases) or the temporal lobe (in AD alone). However, CAV-1 labelling in AD did not differ from that in controls in any of the three lobes examined. Assessment of CAV-1 labelling in relation to the severity of CAA showed CAV-1 to be significantly increased in the frontal white matter in a subgroup of AD cases with absent/mild CAA compared with controls with absent/mild CAA and to AD cases with moderate/severe CAA, but the latter groups did not show significant differences from one another. CAV-1 labelling did not vary with age, gender, APOE genotype, post mortem delay or brain weight. Only segments of blood vessels with particularly abundant Abeta and extensive loss of smooth muscle actin showed loss of CAV-1 and CAV-2 from the tunica media. Within these vessels endothelial CAV-1 was preserved and discontinuous CAV-2 labelling was noted along the outer aspect of the vessel wall. Our findings suggest that alterations in the expression of vascular CAV-1 and CAV-2 are unlikely to play a role in the development of CAA in AD.

Decreased Expression and Activity of Neprilysin in Alzheimer Disease Are Associated With Cerebral Amyloid Angiopathy

Neprilysin (NEP) degrades amyloid-beta (Abeta) and is thought to contribute to its clearance from the brain. In Alzheimer disease (AD), downregulation of NEP has been suggested to contribute to the development of cerebral amyloid angiopathy (CAA). We examined the relationship among NEP, CAA, and APOE status in AD and elderly control cases. NEP was most abundant in the tunica media of cerebrocortical blood vessels and in pyramidal neurons. In homogenates of the frontal cortex, NEP protein levels were reduced in AD but not significantly; NEP enzymatic activity was significantly reduced in AD. Immunohistochemistry revealed a reduction of both vascular and parenchymal NEP. The loss of vessel-associated NEP in AD was inversely related to the severity of CAA, and analysis of cases with severe CAA showed that levels of vascular NEP were reduced to the same extent in Abeta-free and Abeta-laden vessels, strongly suggesting that the reduction in NEP is not simply secondary to CAA. Possession of APOE epsilon4 was associated with significantly lower levels of both parenchymal and vascular NEP. Colinearity of epsilon4 with the presence of moderate to severe CAA precluded assessment of the independence of this association from NEP levels. However, logistic regression analysis showed low NEP levels to be a significant independent predictor of moderate to severe CAA.

Phenotype associated with APP duplication in five families

Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Abetax-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.

Cerebral amyloid angiopathy presenting with vasculitic pathology

We present an elderly patient with an unusual extensive multifocal central nervous system mass lesion, with dramatic imaging changes but only minor disturbance of cerebral function. Cerebral biopsy revealed an unexpected finding of severe cerebral amyloid angiopathy with secondary florid vasculitic appearances, which is a very rare but recognised association. Immunosuppression has produced significant sustained clinical and radiological remission.

Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia

Vascular dementia (VaD) has occasionally been associated with cerebral amyloid angiopathy (CAA), but the prevalence and significance of this counterintuitive relationship are poorly known. Therefore, we investigated the presence and characteristics of CAA in brains of VaD cases. We examined temporal and parietal regions of the cerebral cortex of 26 consecutive VaD cases from the Lund Longitudinal Dementia Study. We carried out immunohistochemistry and routine stainings, determined Apolipoprotein E (ApoE) genotypes, and obtained clinical characteristics on the studied group for retrospective analysis. CAA was marked in eight out of 26 cases, and correlated strongly with the presence of cortical microinfarcts, both in the temporal lobe and in the parietal lobe. Based on comparisons with eight age-matched VaD cases without CAA, the clinical records suggested that VaD cases with CAA as a group exhibited less pronounced neurological symptoms. A clear contribution of the ApoE genotype could not be identified. Based on a combination of the clinical and pathological data, we suggest that microinfarcts in the cerebral cortex associated with severe CAA may be the primary pathological substrate in a significant proportion of VaD cases. Future studies should be undertaken to confirm or dismiss the hypothesis that these cases exhibit a different symptom profile than VaD cases without CAA.

A 50-Year-Old Man With Acute-Onset Generalized Seizure

A 50-Year-Old Man With Acute-Onset Generalized Seizure

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type

The amyloid beta-protein (Abeta) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid-life onset and dementia. The mutation does not affect total Abeta production but may alter the Abeta1-42:Abeta1-40 ratio, and affect the proteolytic degradation of Abeta and its transport across the blood-brain barrier. Abeta E22Q aggregates faster into more stable amyloid-like fibrils than wild-type Abeta. Non-fibrillar Abeta(x-42) deposits precede the appearance of fibrils and the deposition of Abeta(x-40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA-D CAA. Parenchymal Abeta deposition is also enhanced in the HCHWA-D brain with non-fibrillar membrane-bound Abeta(x-42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends to decrease with age. Neurofibrillary degeneration is absent or limited. HCHWA-D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA- or Abeta-related factors for cognitive deterioration in HCHWA-D remains to be determined.