Plasma and cerebrospinal fluid alpha1-antichymotrypsin levels in Alzheimer's disease: correlation with cognitive impairment

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer's disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.     

Serological alpha 1-antichymotrypsin in Down's syndrome and Alzheimer's disease.

alpha 1-Antichymotrypsin (ACT) is a serine protease inhibitor that is markedly elevated in the serum and cerebrospinal fluid of patients with Alzheimer's disease (AD). Patients with Down's syndrome are known to develop neuropathological changes of AD by age 40 years and many become demented. Therefore, in the present study, we obtained serum ACT levels from patients with Down's syndrome and AD, diagnosed by autopsy or clinically, and healthy control subjects. Newman-Keuls' multiple range test revealed a significantly greater (p less than 0.01) mean ACT level in the Autopsy AD (906.4 +/- 94.64 mg/L) and Clinical AD (745.00 +/- 59.95 mg/L) groups in contrast to the Old Control group (531.00 +/- 23.05 mg/L). The mean ACT level of the Down's Syndrome group (513.33 +/- 14.73 mg/L) was not significantly different from that of the Young Control subjects. Furthermore, we did not observe a positive correlation of ACT levels with age in the Down's Syndrome group, in spite of the age-dependent premature increase in neuropathological changes of AD that are known to occur in patients with Down's syndrome. A positive correlation between serum ACT levels and the density of plaques or tangles, neuropathological hallmarks of AD, in brains of patients with AD also did not exist. Thus, our results suggest that ACT levels may not parallel the development of the classical neuropathological hallmarks of AD.     

Alpha 1-antitrypsin and alpha 1-antichymotrypsin are in the lesions of Alzheimer's disease.

We performed immunocytochemistry to localize alpha 1-antichymotrypsin and alpha 1-antitrypsin in tissue sections of Alzheimer disease patients. Our results show that both serine protease inhibitors are localized in neurofibrillary tangles and senile plaques. Using various monoclonal and polyclonal antibodies, immunolabeling was evident in formalin, methacarn or acetone-fixed sections. Brief pretreatments of sections with either formic acid or guanidine-HCl were also necessary to reveal clear immunostaining of the lesions with two of the antibodies. We suggest that both alpha 1-antitrypsin and alpha 1-antichymotrypsin may be functionally involved in the pathogenesis of the lesions of Alzheimer's disease. Like alpha 1-antichymotrypsin, the major cell producing alpha 1-antitrypsin is likely to be astrocytes since the protein was localized there and astrocytes are involved in both lesions.     

Apolipoprotein E and α1-antichymotrypsin polymorphism in Alzheimer's disease

A recent observation has shown that a common polymorphism in the α₁-antichymotrypsin (ACT) gene modifies the apolipoprotein E (ApoE) ε4-associated Alzheimer's disease (AD) risk identifing the combination of the ACT/AA and ApoE ε4/ε4 genotypes as a potential susceptibility marker for AD. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE ε4/ε4 genotypes. The frequency of ApoE ε4/ε4 homozygosity in the AD sample resulted highest for the ACT/TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE ε4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.     

No effect of the α1-antichymotrypsin A allele in Alzheimer's disease

The apolipoprotein E (ApoE)-ε4 allele is associated ina dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-ε4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported anassociation between Alzheimer's disease and the A allele ofα1-antichymotrypsin (Aact) gene, which was not confirmed in a largerseries more recently analysed. The ApoE and Aact genotypes wereanalysed in 314 patients with Alzheimer's disease and 173 healthycontrols, confirming the dose dependent effect of the ApoE-ε4 allele.Nevertheless, even using odds ratios adjusted for age and sex, therewas no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-ε4 allele associated risk for Alzheimer's disease.

     

Association of an interleukin 1 alpha polymorphism with Alzheimer's disease

BACKGROUND: Retrospective epidemiologic studies suggest that individuals exposed to anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs have a lower probability of developing AD as well as an older age at onset for the illness. Neuroinflammation may play an important role in the pathogenesis of AD. Interleukin 1 (IL-1), a potent proinflammatory cytokine, is colocalized immunohistochemically to neuritic plaques, a requisite neuropathologic feature for AD. A polymorphism in the 5'-flanking regulatory region at -889 of the IL-1 alpha gene (a C-to-T transition designated as IL-1A[-889] allele 2) may cause an overexpression of IL-1 alpha, a finding shown to be associated with inflammatory diseases. The IL-1A(-889) allele 2 polymorphism may be associated with AD pathogenesis. METHODS: A total of 259 patients with AD and 192 nondemented control subjects were included from two different centers (Indianapolis, IN, and Munich, Germany). Genotyping for APOE alleles and IL-1A(-889) allele 2 was performed by PCR-based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by center-, gender group-, and age group-stratified Mantel-Haenszel odds ratios, CI, and p values. RESULTS: The allele frequency of IL-1A(-889) allele 2 was 46% in clinically diagnosed patients with probable AD versus 34% in control subjects from the combined centers. CONCLUSION: The authors found an increased risk for AD with an estimated Mantel-Haenszel odds ratio of 1.68 (95% CI 1.1 to 2.6; p = 0.022) for heterozygous carriers and 7.2 (95% CI 2.0 to 24.5; p = 0.003) for individuals homozygous for IL-1A(-889) allele 2. They found no evidence for an interaction between the IL-1A and the apoE epsilon 4 polymorphisms (carriers and homozygotes), age, or gender with regard to conferred risk. The data strongly support an association between the IL-1A(-889) allele 2, especially in homozygotes, and later-onset AD.     

Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.     

Alpha-1-antichymotrypsin gene polymorphism and risk for sporadic Alzheimer's disease in a German population

The A allele of a common A-T polymorphism in the signal peptide of alpha(1)-antichymotrypsin gene (ACT) has been reported to contribute a two- to threefold increased risk to Alzheimer's disease (AD) patients who carry the apolipoprotein E epsilon4 (APOE epsilon4) genotype. Since the ACT expression in AD brains is enhanced in particular in areas that develop amyloid plaques, the ACT polymorphism is considered to be a good candidate gene. We have analyzed this polymorphism in 102 AD patients and 191 matched controls, all originating from Western Germany. No statistically significant differences in allele frequencies and in genotype distribution of ACT could be shown between AD patients and controls. When we analyzed the polymorphism in APOE epsilon4 carriers, no overrepresentation in our AD group could be shown for the ACT*AA genotype carriers. Copyrightz1999S.KargerAG,Basel     

Lack of genetic associations of alpha-1-antichymotrypsin polymorphism with alzheimer-type neuropathological changes or sporadic Alzheimer's disease.

To elucidate the influence of the alpha1-antichymotrypsin (ACT) polymorphism on Alzheimer-type neuropathological changes and the development of sporadic Alzheimer's disease (AD), we studied the relationship between the ACT polymorphism and the severity of Alzheimer-type neuropathological changes in the brains from AD patients and nondemented subjects. There was no association of the ACT polymorphism with Alzheimer-type neuropathological changes in AD or nondemented individuals. ACT polymorphism was not associated with the development of AD. These results remained nonsignificant when the ACT genotype groups were divided into subgroups according to the apolipoprotein E (ApoE) epsiolon4 status. Our study shows that the ACT polymorphism has no effect on Alzheimer-type neuropathological changes or the development of AD, either alone or in combination with ApoE epsiolon4.     

Post-stroke dementia is associated with alpha(1)-antichymotrypsin polymorphism

BACKGROUND AND PURPOSE: Alpha-1-antichymotrypsin (ACT) is an acute phase protein involved in inflammatory reaction, promoting the assembly of beta amyloid protein into filaments and contributing to its resistance to proteolytic digestion. The aim of our study was to determine ACT signal peptide polymorphism (A/T) as a possible risk factor for post-stroke dementia (PSD). METHODS: 142 consecutive ischemic stroke patients and 188 controls were included in this study. Pre-stroke dementia (PRESD) was evaluated using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). The diagnosis of the post-stroke dementia (PSD) was established according to DSM-IV criteria. The ACT gene (A/T) polymorphism was determined by PCR-RFLR. RESULTS: Both ACT-TT genotype and T-allele were significantly more prevalent in patients with PSD than in non-demented stroke patients, controls or patients with PRESD. After adjustment for age, gender, and vascular risk factors, both the ACT-TT genotype and T-allele remained independently associated with PSD. CONCLUSION: Our findings suggest that ACT polymorphism (A/T) is a risk factor for PSD.     

Apolipoprotein E and alpha-1-antichymotrypsin genotypes do not predict time to psychosis in Alzheimer's disease

Psychotic symptoms occurring in Alzheimer's disease (AD + psychosis, AD + P) are a marker for a more rapidly deteriorating phenotype. We have developed a polygenic model of AD + P risk, conditioned on the presence of AD. Whether risk genes for AD itself contribute to AD + P risk is not established, although our model predicts they will not. The most important identified genetic determinant of sporadic, late-onset AD is the apolipoprotein E epsilon 4 allele (APOE4). The effect of APOE4 on AD phenotype is to reduce the age of onset of AD. Prior studies examining the association of APOE4 with AD + P have reported conflicting results. However, no prior studies have examined if APOE4 reduces time to onset of psychosis in AD. The objective of this study was to examine the effect of APOE4 and alpha1-antichymotrypsin/AA (ACT/AA) genotypes on time to psychosis onset in subjects with AD. A longitudinal study of psychosis incidence in 316 subjects with AD with no history of current or prior psychotic symptoms at entry was undertaken. APOE and ACT genotyping was conducted per established protocols. Data were analyzed by survival analysis and Cox proportional hazards models. There were no significant associations of APOE or ACT genotypes with time to psychosis onset and no significant interaction of these genotypes with time to psychosis onset. There remained no significant associations after covarying for age, age of AD onset, degree of cognitive impairment, gender, race, and education. This is the first study to examine the genetic prediction of psychosis onset in AD. The findings support the hypothesis that these two genetic determinants of AD risk do not contribute to the risk of development of psychotic symptoms in AD.     

Blood levels of alpha-1-antichymotrypsin and risk factors for Alzheimer's disease: effects of gender and apolipoprotein E genotype

Concentrations of alpha(1)-antichymotrypsin (ACT) were measured in serum or plasma samples from 137 patients with late-onset probable Alzheimer's disease (AD) and 89 controls. Levels of ACT from sera or plasma from both AD or controls were different, being highest in serum samples. Increased levels of serum or plasma ACT and normal levels of C-reactive protein (CRP) were found in AD. Differences in serum ACT levels between AD and controls were statistically significant, while those in plasma ACT were not. ACT serum levels were higher in women with AD that in female and male controls. Apolipoprotein E (APOE) genotypes did not independently affect blood ACT levels in both AD and controls; although, among AD patients, female AD patients with APOE 4,4 showed the highest level of serum ACT. The gender effect appeared to be prominent, since female AD patients with APOE 3,3 had similar ACT levels to those of female AD patients with APOE 4,4.     

Association of early-onset Alzheimer's disease with an interleukin-1alpha gene polymorphism

Overexpression of the pluripotent cytokine interleukin-1 (IL-1) by microglial cells correlates with formation of neuritic beta-amyloid plaques in Alzheimer's disease (AD). We evaluated polymorphisms in the genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist cytokines, and tested their association with the occurrence and age at onset of sporadic AD. We found a strong association between the IL-1A T/T genotype and AD onset before 65 years of age (odds ratio, 4.86), with carriers of this genotype showing an onset of disease 9 years earlier than IL-1A C/C carriers. A weaker association with the age at onset was also shown for the IL-1B and IL-1RN genes. These data suggest either a direct effect of the IL-1 gene family, mainly IL-1A, on the clinical onset of AD, or a linkage dysequilibrium with an unknown locus relevant to AD on chromosome 2.     

An immunocytochemical study of alpha 1-antichymotrypsin in the senescent cerebral amyloid

An immunocytochemical study of alpha 1-antichymotrypsin (alpha 1ACT) was performed in order to demonstrate its localization and the relationship between alpha 1ACT and senescent cerebral amyloid. We examined 5 brains with dementia of the Alzheimer type (SDAT), a peripheral nerves of familial amyloidotic polyneuropathy (variant transthyretin type, FAP) and dorsal root ganglions of a primary amyloidosis with peripheral neuropathy (AL type, PA). Avidin-biotin-peroxidase complex method and double immunoenzymatic staining method (peroxidase-antiperoxidase method combined with avidin-biotin-alkaline phosphatase complex method) were used. Anti-beta protein serum was used as the marker of cerebral amyloid. About 98% of senile plaques had alpha 1ACT like-immunoreactivity (alpha 1ACTI). All types of plaques showed the immunoreactivity: Core and peripheral of typical plaques, primitive plaques, core plaques and amorphous cerebral amyloid deposits. Although, a part of a senile plaque showed beta protein like-immunoreactivity alone and the other part had alpha 1ACT, many remainder part of a senile plaque had both immunoreactivity. Of the other pathological changes of SDAT, eosinophilic tangles and cerebrovascular amyloid were positive, in contrast, intracellular tangles, granulovacuolar degeneration and Hirano body were negative. The amyloid from FAP had weak alpha 1ACTI and diffusely stained. alpha 1ACTI was seen in the peripheral margin of the amyloid from PA. These results indicate that alpha 1ACT is closely associated with senile plaques formation.     

Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits

Neuropsychologic and pathologic data are presented for a group of 11 patients with a clinical diagnosis of probable Alzheimer's disease (AD) according to recently proposed criteria. In all cases, the diagnosis was verified by cortical biopsy. In addition, increased cortical plaque counts were associated with greater deficits in language production and comprehension and poorer performance on an index of global mental status. These results suggest that a clinical diagnosis of AD is very accurate when patient selection is restricted to typical cases and that language deficits may provide a useful indicator of severity of disease in AD patients.     

Lack of association between alpha1-antichymotrypsin polymorphism and late-onset depressive disorder

Late-onset depressive disorder (LOD) has been thought to be associated with dementia. Recently, it was reported that the position-15 (alanine) polymorphism of the alpha1-antichymotrypsin gene (ACT*A) was a risk factor for Alzheimer's disease. We wondered whether the ACT*A allele frequency might be elevated in LOD. ACT genotyping was performed as described by Kamboh et al. (Kamboh, M.I., Sanghera D.K., Ferrell R.E., DeKosky, S.T., 1995. APO* E4-associated Alzheimer's disease risk is modified by alpha1-antichymotrypsin polymorphism. Nature Genetics 10, 486-488) in 153 patients with depressive disorders and 107 healthy controls. The patients were subdivided into those with early-onset and late-onset, using 50 years as the cut-off age. There was no statistically significant difference in the age of onset of depressive disorders according to the ACT genotype. There was also no significant association between early-/late-onset depressive disorders and the ACT genotype. In addition, there was no association between the apolipoprotein E epsilon 4 allele and the ACT genotype in LOD. Our results suggest that there is no association between the ACT*A allele and LOD.     

Distribution of the protease inhibitor alpha 1-antichymotrypsin in cerebral and systemic amyloid.

We performed immunocytochemical staining to study the distribution of serum protease inhibitors in cerebral and systemic amyloid deposits. In beta-protein amyloid deposits in Alzheimer's disease, Down's syndrome, age-related cerebral amyloidosis, sporadic cerebral amyloid angiopathy and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, antibody to alpha 1-antichymotrypsin (ACT) stains senile plaques and vascular deposits. Immature plaques or preamyloid deposits, identified by their positive staining for beta-protein and negative staining for Congo red, which represents the earliest recognizable stages of amyloid deposition, are also labeled. We did not detect ACT in other chemically different forms of cerebral and systemic amyloid. None of the other inhibitors in this study, i.e. antithrombin III and alpha 2-macroglobulin, was detected in the amyloid deposits. Neurons and glial cells throughout the central nervous system in normal and amyloid-containing brains also bind ACT antibody. The results emphasize the close association of ACT with one type of cerebral amyloid (beta-amyloid diseases) as well as the failure to detect such an association in other chemically different forms of cerebral and systemic amyloids.