Diagnosis of cerebral amyloid angiopathy with cerebral hemorrhage by enzyme linked immunosorbent assay (ELISA) of cystatin C in the cerebrospinal fluid

The lower level of cystatin C in cerebrospinal fluid (CSF) is one of the useful diagnostic markers of hereditary cerebral hemorrhage with amyloidosis in Iceland. We attempted to establish an assay to determine the level of cystatin C in CSF for diagnosis of CAA due to the deposition of cystatin C in CSF for diagnosis of CAA due to the deposition of cystatin C. We carried out the sandwich enzyme immunosorbent assay with the use of monoclonal mouse anti-cystatin C and polyclonal rabbit anti-cystatin C antibodies. CSF from nine cases of cerebral hemorrhage and fifty reference cases with other neurological diseases were examined. Four patients with cerebral hemorrhage showed a low level of cystatin C and clinical manifestations suggestive of CAA. Our study showed the feasibility of using ELISA for the diagnosis of cerebral amyloid angiopathy that causes cerebral hemorrhage with the deposition of cystatin C.     

No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition

To investigate the relationship between cerebral amyloid angiopathy (CAA) and cystatin C, we studied five CAA patients on whose cerebral blood vessels colocalization of cystatin C and β-protein was recognized immunohistochemically. One patient was suspected as familial CAA and the other patients were sporadic cases. Two patients had low concentration of cystatin C in their cerebrospinal fluid (CSF) as we have previously reported in CAA patients. Enzyme-linked immunosorbent assay (ELISA) revealed that cystatin C and β-protein have been included at the ratio of about 1∶100 in the crude amyloid fibrils of one patient. Using a monoclonal antibody (MAb) against cystatin C, we performed affinity chromatography and immunoblotting on her amyloid fibril fraction. Eluate showed a band with a mol wt of 14,000 and the N-terminal 14 amino acid residues of 14-kDa protein were identical with that of cystatin C. This molecular weight is not identical to that of the truncated form of cystatin C deposited in hereditary cerebral hemorrhage with amyloidosis in Iceland (HCHWA-I), but that of normal cystatin C. DNA sequence analysis of five patients whowed no point mutations in the cystatin C gene. Cystatin C and β-protein colocalization, which was recognized in amyloid lesions of CAA, suggests that cystatin C deposition may be related to β-protein deposition. We hypothesize that cystatin C deposition in sporadic cerebral amyloid angiopathy with cystatin C deposition (SCCAA) involves a different mechanism from that in HCHWA-I, which may be related to low CSF concentration of cystatin C without amino acid substitutions.     

Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease

Introduction - Inflammatory processes are suspected in the pathomechanism of Alzheimer's dementia (AD) but the serum and cerebrospinal fluid (CSF) levels of inflammatory cytokines are not yet determined in the different forms of the disorder. Subjects and methods - Interleukin-6 (IL-6) levels were examined in the sera and CSF of patients with mild-moderate and severe stage of late onset sporadic type of AD and in the sera of demented Down syndrome (DS) probands with similar stages of AD and compared with data of age-matched healthy controls. Results - Normal serum IL-6 levels were found in the mild-moderate stage, but significantly increased levels were found in the severe stage of both dementia groups. The CSF concentrations remained within the normal range in all groups. Positive correlations between the serum IL-6 levels and age and the severity of the disease were present. Conclusion - These findings suggest a disease stage dependent general activation of the immune system both in sporadic AD and in DS with AD.     

Oligoclonal immunoglobulin bands in cerebrospinal fluid of patients with Alzheimer''s disease and vascular dementia

We examined serum and cerebrospinal fluid (CSF) of 16 patients with Alzheimer's disease (AD), 28 patients with vascular dementia (VD), their age-matched controls and multiple sclerosis (MS) patients in order to evaluate the humoral immune response within the central nervous system both quantitatively and qualitatively. Intra-blood-brain barrier (BBB) protein synthesis was calculated by CSF IgG index. The presence of oligoclonal banding (OCB) was investigated with agarose isoelectric focusing (IEF) followed by immunoblotting with antihuman IgG. No patient with AD and only 4 patients with VD had slightly elevated IgG indexes, and no statistically significant differences in the indexes were found between the two groups. No bands were found in the CSF of AD patients but 3 VD patients had OCB in both serum and CSF. One VD patient had bands in serum but no bands in CSF. No kappa or lambda free light chains were found in those demented patients with demonstrable bands in the CSF and serum. No OCB were found in control sera and CSF. For comparison, the majority of patients with MS had OCB in CSF. Thus, no consistent increase of intrathecal protein synthesis was found in patients with AD and VD. Methodological differences explain at least part of the conflicting results published earlier.     

The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer's disease

BACKGROUND/AIMS: Attempting to improve the cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD), the neurofilament heavy chain isoform, NfH(SMI35) was compared to other CSF markers [total tau, phospho-tau, amyloid beta 1-42 (Abeta42), the ratio of amyloid beta fragments Abeta42/Abeta40 (Abeta ratio)]. METHODS: CSF levels were determined in patients with AD (n = 109), mild cognitive impairment (MCI, n = 25), frontotemporal dementia (n = 15), vascular dementia (VD, n = 41), and controls (n = 58). RESULTS: CSF NfH(SMI35) was elevated in AD and VD as compared to controls (p < 0.05). Total tau was higher in AD as compared to controls (p < 0.05). CSF phospho-tau was elevated in AD as compared to controls and VD (p < 0.05 each). CSF Abeta42 and Abeta ratios in AD were lower than in MCI and controls (p < 0.05 each). CONCLUSION: The diagnostic potential of NfH(SMI35) is not superior to that of other CSF markers.     

Absence of the cystatin C amyloid in the cerebral amyloid angiopathy, senile plaque, and extra-CNS amyloid deposits of aged Japanese

Amyloid protein in Icelandic patients with hereditary cerebral amyloid angiopathy (CAA) is a variant of cystatin C. Immunoreactivities of the cystatin C and other amyloid proteins were investigated in CAA and other senile amyloid deposits in the Japanese sporadic aged cases including patients with dementia of Alzheimer type, and compared with those in Icelandic hereditary CAA. Compared with positive reaction of cystatin C in Icelandic hereditary CAA, no immunoreactivity of cystatin C was found in senile amyloid deposits of the Japanese aged including CAA. Immunoreactivity of the amyloid beta protein was negative in Icelandic hereditary CAA, for which CAA and senile plaque amyloid in the Japanese senile brains were positive. Our data suggest that the cystatin C amyloid would be present only in hereditary CAA, but not in the CAA and other senile amyloid deposits of the sporadic aged cases.     

CSF tau protein and β-amyloid (1–42) in Alzheimer''s disease diagnosis: discrimination from normal ageing and other dementias in the Greek population

Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's disease (AD). In order to evaluate their diagnostic potential in clinical practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15 patients with non-AD neurodegenerative dementias (NAND), six patients with vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and a sensitivity of 82% in differentiating AD from normal ageing, whilst the corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67 and 82%, respectively. Tau was better in differentiating AD, from normal ageing (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values comparable or even better than tau for differentiating AD from normal ageing (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and definitely better than any of the candidate markers alone, for differentiating AD from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful adjuvant to clinical criteria for dementia diagnosis.     

血及脑脊液β-淀粉样蛋白对老年期痴呆鉴别诊断的意义

目的:探讨血及脑脊液中β-淀粉样蛋白(β-AP)对老年期痴呆主要包括老年性痴呆(AD)、血管性痴呆(VD)及其他原因所致的痴呆(OD)的鉴别诊断意义。方法:采用平衡饱和竞争放射免疫分析法对55例不同类型的痴呆患者及30例正常对照者血清及脑脊液(CSF)中β-AP进行测定。结果:在正常对照组,随着观察者年龄的增长,血清β-AP含量缓慢增高,CSF中β-AP含量缓慢下降(r分别为0.56,0.52,均P<0.01)。不同病因痴呆患者血清β-AP含量均高于对照组,其中AD组最明显;CSF中β-AP含量在AD组最低,明显低于对照组(P<0.01),在VD组最高,接近对照组(P>0.05)。AD组中的重度痴呆患者,其β-AP含量在血清中升高最明显,同时在CSF中降低也最显著。结论:血清及CSF中β-AP含量变化的测定,可能有助于各型痴呆的鉴别诊断及AD患者病情轻重的判断,但这种变化具重叠性。     

β淀粉样蛋白与生长因子变化与老年性痴呆致病因素的研究

目的：检测血清β淀粉样蛋白（β－ＡＰ）和多肽生长因子含量变化,探讨其在Ａｌｚｈｅｉｍｅｒ病（ＡＤ）和血管性痴呆（ＶＤ）发病机制中的可能作用。方法：采用放射免疫分析法（ＲＩＡ）检测临床诊断为ＡＤ患者８例,ＶＤ患者１５例及６３例缺血性脑血管病（ＩＣＶＤ）患者血清β－ＡＰ、转化生长因子α（ＴＧＦ－α）和类胰岛素样生长因子Ⅱ（ＩＧＦ－Ⅱ）的水平,同时与健康对照组比较。结果：ＡＤ与ＶＤ患者β－ＡＰ、ＴＧＦ－α和ＩＧＦ－Ⅱ水平明显高于ＩＣＶＤ组和健康对照组,均具有显著性差异。ＩＣＶＤ患者血清β－ＡＰ、ＴＧＦ－α和 ＩＧＦ－Ⅱ水平亦明显高于对照组,其中以脑梗塞后遗症（ＳＣＩ）和椎基底动脉供血不足（ＶＢＩ）组增高十分明显,与对照组比较差异显著（Ｐ＜０．０５）。ＡＤ与 ＶＤ患者 ３项测定指标之间具有明显的正相关。结论：①β－ＡＰ可能是ＡＤ和ＶＤ发病的危险因素。②引起ＡＤ和ＶＤ神经元毒性作用进而导致痴呆．这可能与ＴＧＦ－α和ＩＧＦ－Ⅱ增多有关。③β－ＡＰ与ＴＧＦ－α、ＩＧＦ－Ⅱ密切相关,在老年斑形成过程中可能起重要作用。     

Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view

Amyloid deposition can take place in the walls of arteries, arterioles, and, less often, capillaries and veins of the central nervous system, a phenomenon known as cerebral amyloid angiopathy (CAA). The major clinicopathological manifestations of CAA include cerebral hemorrhage, ischemic lesions, and dementia. CAA may be classified according to the amyloid protein deposited. In the most common form, sporadic CAA, and in CAA related to sporadic Alzheimer disease (AD). A beta deposition is characteristic. CAA can also be severe in variants of familial AD caused by mutations of the amyloid-beta precursor protein or presenilin-1 genes in which deposition of A beta variants and/or wild-type A beta occurs. Other amyloid proteins involved in familial CAAs include 1) the mutant cystatin C (ACys) in hereditary cerebral hemorrhage with amyloidosis of Icelandic type, 2) variant transthyretins (ATTR) in meningo-vascular amyloidoses, 3) mutated gelsolin (AGel) in familial amyloidosis of Finnish type, 4) disease-associated prion protein (PrP(Sc)) in a variant of the Gerstmann-Str?ussler-Scheinker syndrome, and 5) ABri and ADan in CAAs observed in the recently described BRI2 gene-related dementias, familial British dementia and familial Danish dementia, respectively. This review addresses issues related to the correlation between morphology, biochemistry, and genetics, and briefly discusses both the pathogenesis and animal models of CAAs.     

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.     

New laboratory markers in diagnosis of alzheimer dementia

Abstract

Objectives: The aim of our work was to assess the role of tau protein, beta amyloid and cystatin C in diagnosis of Alzheimer dementia (AD) and other neurodegenerative diseases (NDs).

Methods: The levels of tau protein, beta amyloid and cystatin C were assessed in a set of 79 patients with ND (38 men and 41 women; aged 22–90 years; mean, 61.6 ± 15.6 years) and in a control group of 79 subjects with a healthy central nervous system (38 men and 41 women; aged 20–91 years; mean, 61.5 ± 15.1 years).

Results: When compared with the subjects in the control group, a statistically significant decrease in tau protein levels was found in patients with ND, an increase in tau protein levels in patients with AD and an increase in cystatin C cerebrospinal fluid/serum index in the ND + AD group.

Discussion: Our work only confirmed the previously reported results in part. Although tau protein seems to be a quite reliable marker of AD, the role of beta amyloid in AD diagnosis remains at the least questionable. In the case of cystatin C, our results would seem to confirm the views of certain authors that cystatin C will probably not become a new 'revolutionary' marker contributing to differential diagnostics.     

Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults

OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.     

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.     

Higher cathepsin B levels in plasma in Alzheimer's disease compared to healthy controls

Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.     

Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.     

Apolipoprotein D in the aging brain and in Alzheimer's dementia

Apolipoprotein D (apoD) levels were examined in the temporal cortex as well as an assessment of the location of apoD positive cells within the brain by immunohistochemical and biochemical methods in young control (YC), aged control (AC), and Alzheimer's demented (AD) probands. Scattered apoD positive astrocytes and oligodendrocytes were found throughout the white matter by immunohistochemistry. ApoD immunoreactivity was also observed in the cerebellar oligodendrocytes of the YC group. There was faint positive apoD staining in scattered cortical astrocytes and a few neurons in the same group. In contrast, some of the AC and all of the AD probands had intense and frequent apoD immunostained cortical astrocytes and pyramidal neurons. The cortical senile plaques and neurofibrillary tangles were apoD immunonegative. No quantitative differences were found between the cortical apoD levels in the AC and AD groups, determined by immunoblotting. ApoD detected in the brain tissue was different in molecular weight (29 kDal) from that seen in CSF or in the serum (32 kDal). Our results indicate apoD is present in the human brain, especially in glial cells, and has increased abundance in the elderly and AD subjects.     

CSF biomarker profile and diagnostic value in vascular dementia

Background and purpose:  The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (τ_T) or hyperphosphorylated at threonin-181(τ_P-181) form and beta amyloid peptide 1–42 (Aβ42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD.
Methods:  The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls.
Results:  Alzheimer's disease and MD showed increased levels of τ_T, τ_P and reduced levels of Aβ42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying ≥85% of patients, either in the form of a discriminant function or in the form of the τ_T × τ_P-181/Aβ42 formula.
Conclusions:  Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.     

脑脊液中β淀粉样蛋白检测对老年期痴呆的诊断意义

目的　研究阿尔茨海默病（AD）和血管性痴呆（VD）患者脑脊液(CSF)中β淀粉样蛋白（Aβ或βA     

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 beta-amyloid peptide (Abeta) 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 Abeta 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.