Low amyloid (Aβ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease

Argyrophilic grain disease constitutes one cause of late-onset dementia. Its classification among dementia disorders is still unclear because most of the reported argyrophilic grain disease cases are associated with neurofibrillary lesions (e.g. neurofibrillary tangles) which are also typical of Alzheimer's disease. In the present study we determine whether argyrophilic grain disease is associated with the senile plaques of Alzheimer's disease. The distribution and density of senile plaques was systematically investigated in 11 demented argyrophilic grain disease cases using Abeta immunohistochemistry and stereological techniques, and the results were compared with 11 Alzheimer's disease cases. All subjects with argyrophilic grain disease exhibited neurofibrillary changes corresponding to Braak stages I-III. Three of the 11 argyrophilic grain disease cases (27%) were completely devoid of Abeta deposits. In argyrophilic grain disease cases with senile plaques, the average total plaque-load was significantly lower (1%) than in Alzheimer's disease (3.1%) (P<0. 005). The regional distribution of the senile plaques and the proportion of diffuse vs. primitive or mature plaques in argyrophilic grain disease resembled values of senile plaques reported in non-demented elderly subjects, and was significantly different from Alzheimer's disease. Similarly the immunocytochemical profile of the Abeta deposition in argyrophilic grain disease resembled that of non-demented elderly subjects rather than that of subjects with Alzheimer's disease. As all argyrophilic grain disease cases under investigation were demented, including those devoid of senile plaques, the present study further supports the thesis that dementia in argyrophilic grain disease correlates more with the density and distribution of argyrophilic grains than with associated lesions of the Alzheimer-type.     

Vascular pathology in Alzheimer's disease

Histopathologically, numerous senile plaques and neurofibrillary tangles were remarkably observed in the brain with Alzheimer's disease. At the same time, so much simple atrophy of nerve cells was evident under light microscopy. Electron microscopical observations of serial sections revealed that small blood vessels, including capillaries, had a deep relationship to the amyloid fibrils which formed the senile plaques and they had fallen into degenerative states. The vascular feet of the astroglial cells surrounding small blood vessels showed degenerative features, and many nerve cells in this area either showed various degrees of degeneration or apparently were destroyed. The atrophy of the brain with Alzheimer's disease is considered to be caused by the amyloid angiopathy of small blood vessels and the degeneration of capillaries and vascular feet. These findings strongly suggest that the major causal mechanism of Alzheimer's disease is an alteration of the blood–brain barrier. Morphology is an expression of both the structure and the function of organs in the living body. Based on this viewpoint, this review article emphasizes that the morphological changes to small blood vessels in the brain with Alzheimer's disease convey crucial information and clues for solving the underlying mechanism that causes the disease.     

阿尔茨海默病大鼠海马热休克蛋白70表达变化的研究

目的:双侧海马注射Aβ1-42建立大鼠阿尔茨海默病(AD)模型,研究其海马热休克蛋白70(HSP70)表达的变化并探讨与AD病理进程可能存在的联系。方法:48只SD大鼠随机分为模型组与生理盐水对照组,双侧海马分别注射Aβ1-42,分别于术后1天、7天、14天、21天在Y迷宫行为学测试后处死大鼠,采用RT-PCR和Western-blot方法,观察各组大鼠海马HSP70表达的变化。结果:术后14天、21天模型组学习记忆能力较对照组和术前明显减退(P<0.05)。术后模型组大鼠海马HSP70表达逐渐减少,术后7天(mRNA:0.34±0.05;蛋白:0.29±0.03)、14天(mRNA:0.32±0.06;蛋白:0.23±0.04)与对照组比较差异有统计学意义(P<0.05),至术后21天,模型组HSP70表达减少最为明显(mRNA:0.29±0.04;蛋白:0.11±0.03)(P<0.01)。结论:大鼠海马注射Aβ1-42导致HSP70表达减少,HSP70表达减少可能参与了AD的病理发展过程。     

Altered levels of microtubule proteins in brains of Alzheimer's disease patients

Summary The amount of microtubule protein present in the total soluble protein from brains of Alzheimer's disease patients and from brains of non-Alzheimer age-matched controls, were determined by radioimmunoassay. No differences were found in the amount of tubulin or microtubule-associated protein MAP2 present in either group. However, the amount of tau protein or MAP1 from the brains of Alzheimer's disease patients was about half of that present in their control counterparts.Supported by Grants from the Comisión Asesora para el Desarrollo Tecnológico y Científico and Fondo de Investigaciones Sanitarias     

Genetic-morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy

Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in beta-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5' polymorphism (LRP5') is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with the severity of CAAlep. and CAAcort., implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5'87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition.     

The contribution of cerebral vascular semicarbazide-sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer's disease

Semicarbazide-sensitive amine oxidase (SSAO) catalyses the oxidative deamination of a variety of endogenous substrates, such as methylamine and aminoacetone, to produce highly reactive aldehydes, which are capable of inducing protein cross-linkage, beta amyloid (Aβ) aggregation and advanced glycation end-product formation. In the brain, SSAO is exclusively located on the blood vessels. Deposits of Aβ, the hallmark of Alzheimer's disease (AD), are closely associated with cerebral blood vessels, that is, cerebral amyloid angiopathy (CAA). In the present study, we examined whether SSAO-mediated deamination contributes to CAA in AD. We employed immunohistochemistry to examine the colocalization of SSAO and Aβ in post mortem brains of AD patients. To assess the role of SSAO-mediated deamination in the deposition of Aβ on blood vessel walls, we developed an in vitro blood vessel model using sections of human umbilical cord. We found a strong expression of SSAO colocalized with Aβ deposits on the blood vessels in AD brains. We also demonstrated that SSAO-mediated deamination increases the deposition of Aβ onto blood vessel walls. Our results support the hypothesis that cerebral vascular SSAO-catalysed deamination contributes to CAA in AD brains.     

Alzheimer's Disease with Widespread Presence of Lewy Bodies

Abstract: Progressive mental deterioration associated with parkinsonism was observed in a 68-year-old patient in the senile period. Pathologically, evidence of senile changes was obtained consisting of degeneration of the neurons and numerous senile plaques with classical and perivascular types. Further, neuronal degeneration in the form of Lewy bodies was evidently observed in the hypothalamus, substantianigra et innominata, locus caeruleus of the vagus nerve, some nuclei in the reticular formation of the brainstem and neurons in the cerebral cortex. The clinical and pathological manifestations were those of Alzheimer's disease and Parkinson's disease. It is suggested that some common etiological factors may cause those lesions as Alzheimer's disease and Parkinson's disease.     

Prevalence and impact of cerebrovascular pathology in Alzheimer's disease and parkinsonism

OBJECTIVE: To study the prevalence and impact of cerebrovascular lesions (CVL) in Alzheimer's disease (AD) and their effects on cognitive impairment. MATERIAL AND METHODS: In study I, the prevalence of vascular lesions in a prospective series of 244 autopsy-proved AD cases (mean age 83.1+/-8.4 years) and 230 age-matched non-demented controls was examined using immunochemistry and current morphological diagnostic criteria. In study II, in 100 consecutive autopsy cases (mean age 84.3+/-9.3 years), the incidence of general and capillary cerebral amyloid angiopathy (CAA, CapCAA) was examined. RESULTS: In study I, AD cases showed significantly more frequent CVL than age-matched controls without differences in the Braak stages, but the severity of CAA was significantly higher in AD brain with associated vascular lesions. In study II, CAA was more frequent in demented than in non-demented patients, but did neither correlate with high-grade AD pathology nor with clinical dementia, whereas CapCAA correlated with both dementia and high Braak stages; the severity of both types of CAA showed only low correlation with each other. CONCLUSIONS: The present data and other studies confirm the importance of CVL in AD and Parkinson's disease without considerable impact on cognitive impairment in progressed stages of AD, and the close association of CapCAA but not of general CAA with clinical dementia and AD pathology.     

The neurochemistry of Alzheimer's disease

Our knowledge of the neurochemical pathology of AD has increased immensely the last years. Although it is now clear that mutations in the APP gene can cause some rare hereditary forms of AD, and that ApoE4 is a prominent risk factor for AD, we at present know little about the underlying cause of AD in the general population and the biochemical mechanisms by which the apolipoprotein E4 isoform affects AD pathogenesis. It is hoped that the near future will see a resolution of the current controversies in AD research, including: 1) whether APP mutations cause Alzheimer's disease by affecting Aβ deposition or the function of APP itself; 2) whether abnormal phosphorylation of tau is a central pathogenetic event, or whether it occurs as epiphenomena that reflect general neurodegeneration in a variety of disease processes; 3) Whether Aβ deposition in the brain is the central event in AD or whether it occurs as epiphenomena in a variety of brain disorders such as head trauma; and 4) whether altered tau phosphorylation occurs secondary to Aβ deposition or vice versa, and what the link is (if any) between the two processes.     

Relationships in Alzheimer's disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen

The relationship between degree of cerebral amyloid angiopathy (CAA) and the amount of smooth muscle cells (SMCs) and deposition of collagen IV fibres (COL IV) was investigated in the frontal and occipital cortex of 70 patients with autopsy confirmed Alzheimer's disease (AD). The extent of CAA was significantly greater in occipital than in frontal cortex, although SMC loss was greater in frontal than in occipital cortex. COL IV staining was significantly higher in occipital than in frontal cortex. The degree of SMC loss correlated with CAA, as Abeta40 but not as Abeta42 or total Abeta, in frontal cortex, but not in occipital cortex. Leptomeningeal arteries within occipital cortex showed significantly greater external diameter, greater wall thickness and greater luminal area than those in frontal cortex. The degree of CAA correlated with thickness of blood vessel wall and external diameter in frontal cortex, whereas extent of SMC loss correlated with thickness of blood vessel wall in occipital cortex. There were significant negative correlations between duration of disease and thickness of vessel wall, external diameter and luminal area. In patients with disease durations exceeding 10 years, external vessel diameter and thickness of the vessel wall were both halved compared with patients with durations less than 5 years; luminal area was reduced by about 75%. Blood vessels in AD undergo degenerative changes involving deposition of Abeta and COL IV with loss of SMC. SMC loss may relate to increasing Abeta deposition in early stages of disease, but this relationship may be lost with disease progression.     

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease

T. C. Dickson, H. L. Saunders and J. C. Vickers (1997) Neuropathology and Applied Neurobiology , 23, 483–491
Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease
Although the inheritance of certain apolipoprotein E (ApoE) alleles has been recognized as a genetic risk factor for Alzheimer's disease, the role of ApoE in the pathology underlying this disease is unclear. Several reports have emphasized the association of ApoE with either β-amyloid plaque formation or the development of neurofibrillary pathology. Utilization of multiple label immunohistochemical methods enabled us to examine directly the localization of ApoE immunoreactivity relative to β- amyloid plaques, dystrophic neurites and neurofibrillary tangles. In Alzheimer's disease cases, β-amyloid plaques showing high ApoE immunoreactivity were localized to layers II, III and V of the neocortex. In layer I, β-amyloid plaques were unlabelled for ApoE relative to β-amyloid. Dense core plaques labelled for β-amyloid often had only the central portions labelled for ApoE. Conversely, ApoE labelled spherical structures within some plaques were not immunoreactive for β-amyloid or dystrophic neurite markers. Unlike β-amyloid labelled plaques, all ApoE immunoreactive plaques were associated with dystrophic neurites. In preclinical Alzheimer's disease cases, most plaques were double labelled for β-amyloid and ApoE. ApoE did not label dystrophic neurites or the early stages of neurofibrillary tangle formation, indicating that ApoE may not be directly involved in neurofibrillary pathology. The specific presence of ApoE in plaques associated with dystrophic neurites in demented patients suggests that ApoE may contribute toward a higher degree of β- amyloid fibrillogenesis, enhancing the ability of certain plaques to cause damage to surrounding axons.     

Neuroimaging biomarkers of small vessel disease in cerebral amyloid angiopathy-related intracerebral hemorrhage

Aims

The significance of the correlation of computed tomography (CT)–based cerebral small vessel disease (SVD) markers with the clinical outcomes in patients with cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) remains uncertain. Thus, this study aimed to explore the relationship between SVD markers and short-term outcomes of CAA-ICH.

Methods

A total of 183 patients with CAA-ICH admitted to the Xuanwu Hospital, and Beijing Fengtai You'anmen Hospital, from 2014 to 2021 were included. The multivariate logistic regression analysis was performed to identify the correlation between SVD markers based on CT and clinical outcomes at 7-day and 90-day.

Results

Of the 183 included patients, 66 (36%) were identified with severe SVD burden. The multivariate analysis showed that the total SVD burden, white matter lesion (WML) grade, and brain atrophy indicator were independent risk factors for unfavorable outcomes at 90-day. The brain atrophy indicator was independently associated with mortality at 90-day. Severe cortical atrophy was significantly associated with early neurological deterioration.

Conclusions

The neuroimaging profiles of SVD based on CT in patients with CAA-ICH might predict the short-term outcome more effectively. Further studies are required to validate these findings and identify modifiable factors for preventing CAA-ICH development.     

Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.     

Interleukin-6 is present in early stages of plaque formation and is restricted to the brains of Alzheimer's disease patients

Interleukin-6 (IL-6) immunoreactivity has previously been shown in plaques in Alzheimer's disease (AD) and elevated IL-6 concentrations have been measured biochemically in brains of AD patients. In this study, we investigated the appearance of IL-6 immunoreactivity in AD plaques according to the stage of plaque formation. Using the Bielschowsky silver-staining method, we were able to differentiate between four types of plaques described earlier: diffuse, primitive, classic and compact. While diffuse plaques represent the early stage of plaque formation, primitive and classic plaques are thought to represent later stages of plaque development. We investigated serial sections of paraffin-embedded cortices of ten clinically diagnosed and histopathologically confirmed AD patients and ten patients with no clinical history of dementia. We found plaques in the brains of both nondemented and demented persons using the silver staining method or immunohistochemistry with antibodies against the amyloid precursor protein. In the group of clinically nondemented persons, diffuse plaques were the predominant plaque type, whereas primitive plaques formed the larger portion of lesions in the group of AD brains. IL-6 could not be detected in plaques of patients without dementia. Many IL-6-positive plaques were found in six of the AD brains and to a smaller extent in the other four AD cases. In the six cases with a large number of IL-6-positive plaques, IL-6 was found in a significantly higher ratio of diffuse plaques than expected from a random distribution of IL-6 in all plaque types. We conclude from these findings that IL-6 immunoreactivity correlates with clinical dementia and that in AD patients, an IL-6-related immunological event may contribute to plaque formation. IL-6 might be involved both in the transformation from diffuse to primitive plaques in AD as well as in the development of dementia.     

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.     

APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.     

缺血预处理模型大鼠心肌组织小分子热休克蛋白的表达*

背景：小分子热休克蛋白,尤其是热休克蛋白27和α-B晶体蛋白高表达量对于心肌组织缺血再灌注的保护作用已比较明确。但是在老龄大鼠中小分子热休克蛋白是否仍具有这种保护作用迄今仍无报道。 目的：观察热休克蛋白27和α-B晶体蛋白在青年及老年大鼠心肌缺血预处理时表达的变化。 方法：24月龄老龄大鼠及两三月龄青年大鼠在体心脏经缺血5 min、再灌注5 min(反复3次)预处理后,于0,5,15,45,60 min取左心室缺血的前壁与非缺血的后壁心肌组织分别匀浆,分离上清及沉淀蛋白,用Western Blot检测热休克蛋白27和α-B晶体蛋白在预处理不同时间可溶性蛋白及不溶性蛋白含量的改变;采用RT-PCR方法观察缺血预处理对青年及老龄大鼠热休克蛋白27和α-B晶体蛋白mRNA在不同时间点表达的改变情况,采用免疫荧光观察缺血预处理后不同时间点热休克蛋白27和α-B晶体蛋白的移位情况。 结果与结论：老龄大鼠在缺血预处理后热休克蛋白27和α-B 晶体蛋白表达量增加,表明老龄大鼠仍具有正常的基因转录及蛋白合成的能力;与青年大鼠比较,老龄大鼠缺血预处理后小分子热休克蛋白移位能力降低,从而减弱了与各相应蛋白结合的能力,限制其保护作用的发挥。提示老年大鼠心肌组织中小分子热休克蛋白丧失移位能力,可能是老年大鼠缺血预处理保护作用减弱的重要原因之一。     

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

Aims: Several observations point to the involvement of angiotensin-converting enzyme-1 (ACE-1) in Alzheimer's disease (AD): ACE-1 cleaves amyloid-β peptide (Aβ) 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 Aβ load and cerebral amyloid angiopathy (CAA). Methods: ACE-1 activity was measured in the frontal cortex from 58 control and 114 AD cases of known Aβ 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. Results: ACE-1 activity was increased in AD ( P  < 0.001) and correlated directly with parenchymal Aβ 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 Aβ, smooth muscle actin, glial fibrillary acidic protein, collagen IV, vimentin or laminin, but was similarly distributed to extracellular matrix (ECM) proteins fibronectin and decorin. Conclusions: Our findings indicate that ACE-1 activity is increased in AD, in direct relationship to parenchymal Aβ 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.