The inflammation-sensitive protein alpha 1-anti-chymotrypsin neutralizes fibrillar aggregation and cytotoxicity of the beta-amyloid peptide more effectively than alpha 1-antitrypsin.

OBJECTIVES: A neuroinflammatory process, triggered by amyloid-beta (Abeta)-peptide, is thought to play a central role in the neurodegenerative process leading to Alzheimer's disease (AD). Abeta(25-35) retains the functionality of Abeta(42) and was employed to investigate the effects of inflammation-sensitive proteins (ISPs) alpha1-antichymotrypsin (A1ACT) and alpha1-antitrypsin (A1AT) on fibrillar aggregation and cytotoxicity. DESIGN AND METHODS: Inhibitory concentrations of the ISPs were determined in an established human red blood cell lysis model of Abeta-cytotoxicity. For studies of Abeta-fibrillar aggregation CSF levels of A1ACT (0.041 microM)/A1AT (0.11 microM) were incubated with Congo Red dye 25 microM+Abeta(25-35) 10 microM noting the formation of visible aggregates and spectrophotometric changes over 24 h. RESULTS: A1ACT at CSF reported levels inhibited fibrillar aggregation and cytotoxicity while A1AT at CSF reported levels failed to cause a similar inhibition. CONCLUSIONS: A1ACT neutralizes fibrillar aggregation and cytotoxicity of Abeta-peptide more effectively than A1AT. Both proteins are known to be co-deposited with Abeta within senile plaques of AD brains.

Transthyretin inhibition of amyloid beta aggregation and toxicity.

OBJECTIVES: The aim of this study was to investigate transthyretin (prealbumin) effects on Abeta25-35-induced cytotoxicity. DESIGN AND METHODS: In view of the well-recognized literature data demonstrating that Abeta25-35 fibrillar aggregates cause in vitro cytotoxicity to human red blood cells and apoptotic changes to SK-N-BE neuroblastoma cells in cultures (ultrastructural evidence), we tested transthyretin effects on these two experimental models. RESULTS: Incubation of Abeta25-35 with transthyretin (at transthyretin concentrations equal to CSF physiological levels) demonstrated both inhibition of red blood cells lysis and neutralization of SK-N-BE neuroblastoma cells ultrastructural apoptotic changes. Moreover, transthyretin was shown to be able to inhibit the formation of fibrillar macroaggregates of Abeta25-35. CONCLUSIONS: The findings imply that experimental systems investigating Abeta-induced cytotoxicity consider the protective interaction of transthyretin with Abeta; an interaction to be considered also in vivo in view of the fact that transthyretin immunoreactivity has been previously demonstrated in amyloid plaques of brains from Alzheimer's disease patients.

Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease.

BACKGROUND: Multiple genes have been provisionally associated with Alzheimer's disease, including the coding polymorphisms in exons 8 and 13 in the low density lipoprotein receptor gene (LDLR), situated on chromosome 19p13.2. METHODS: The sample groups consisted of 180 AD patients and 141 control spouses. We carried out genotyping of LDLR8 and LDLR13. RESULTS: The LDLR8 GG genotype was common, found in 84% of the unaffected control subjects and 91% of the AD patients in our study. There was a ninefold elevation in risk associated with GG:CC versus A- and T- among APOE4+ subjects when compared with APOE4- subjects (odds ratio 9.3; 95% confidence interval 1.8 to 48.2). With the additional information on LDLR polymorphism, we defined an overall 12 fold elevation in risk for APOE4 in combination with LDLR GG:CC (11.9; 2.8 to 50.0; Fisher's exact test, p = 0.0002; standard power 0.999), compared with other subjects lacking all three of these polymorphisms. CONCLUSION: These results imply a functional interaction between ApoE and LDL receptor proteins that determines risk for Alzheimer's disease.

Cystatin C as a risk factor for Alzheimer disease.

Cystatin C, a protease inhibitor with widespread distribution, is upregulated in response to injury. Levels are elevated in the brains of patients with Alzheimer disease (AD). We compared frequencies for the CST 3 exon 1 polymorphism in patients with AD and controls. A proportional odds model indicated that the CST 3 A and APOE4 combination carried a high risk: a 14-fold elevation for men and 16-fold for women. These risks apply to risk at ages older than 64 years and to a shift in onset to ages younger than 65 years.

Grade-of-membership sibpair linkage analysis maps IDDM11 to chromosome 14q24.3-q31.

We demonstrate the use of Grade-of-membership (GoM) (Manton et al. 1994) for sibpair linkage analysis: GoM was used to map the IDDM11 locus to the region of chromosome 14q24.3 identified by Field et al. (1996). Haplotype groups were constructed from sib pair information on the number of shared alleles. The sample consisted of 578 sibling pairs found in 246 multiplex IDDM families. Both siblings were diabetic in 53% of the pairs (AA). Pair members could share 0, 1 or 2 alleles IBS at each of eight linked marker loci spanning IDDM11. Three model-based groups best represented the data on allele sharing: the groups corresponded to 'No', 'One' and 'Two' shared haplotypes for the region. Group 'Two' was larger (37% vs. 25%, p < 0.0001) and more homogeneous (p < 0.0001) than expected by chance consistent with the IDDM11 locus being a determinant of diabetes in multiplex families. Genetic linkage of IDDM to the region was demonstrated by a 19% increase in the proportion of AA pairs over the haplotype groups: 'No', 42%; 'One', 49%; 'Two', 61%, p = 0.0005, representing a 43% relative increase.

Density profiles of Alzheimer disease regional brain pathology for the huddinge brain bank: pattern recognition emulates and expands upon Braak staging.

Density profiles of Alzheimer's disease (AD) regional brain pathology were constructed for 249 subjects in the Huddinge Brain Bank. Counts per square millimeter for neurofibrillary tangles (NFT), diffuse plaques (DP), and neuritic plaques (NP) in 38 areas were investigated using a pattern recognition technique called GoM. The seven distributional profiles of AD neuropathology emulated and expanded upon Braak staging illustrating induction (Groups 1-3) and clinical progression (Groups 4-7). Normal aging represented limited AD changes, few NFT in the entorhinal cortex and hippocampal CA1 (Group 1). The threshold for possible AD was NFT in the subiculum (Group 2), found with DP in the neocortex. Temporal medial NFT was the threshold for probable AD (Group 4). The 'oldest-old', often demented without brain atrophy, had extensive entorhinal/CA1 NFT and cortical DP, but few cortical NFT or NP (Group 5). A second subtype 'disconnection' (Group 6) lacked AD pathology for a specific set of subcortical and cortical areas. Accumulation of NFT in first-affected areas continued through end-stage disease (Group 7), with apparent rapid transition of DP to NP in the cortex during clinical progression. The evolution of AD is a highly ordered sequential process. Pattern recognition approaches such as GoM may be useful in better defining the process.

Is sitting-while-at-work associated with low back pain? A systematic, critical literature review.

OBJECTIVES: To present a critical review and evaluate recent reports investigating sitting-while-at-work as a risk factor for low back pain (LBP). METHODS: The Medline, Embase and OSH-ROM databases were searched for articles dealing with sitting at work in relation to low back pain for the years 1985-97. The studies were divided into those dealing with sitting-while-working and those dealing with sedentary occupations. Each article was systematically abstracted for core items. The quality of each article was determined based on the representativeness of the study sample, the definition of LBP, and the statistical analysis. RESULTS: Thirty-five reports were identified, 14 dealing with sitting-while-working and 21 with sedentary occupations. Eight studies were found to have a representative sample, a clear definition of LBP and a clear statistical analysis. Regardless of quality, all but one of the studies failed to find a positive association between sitting-while-working and LBP. High quality studies found a marginally negative association for sitting compared to diverse workplace exposures, e.g. standing, driving, lifting bending, and compared to diverse occupations. One low quality study associated sitting in a poor posture with LBP. CONCLUSIONS: The extensive recent epidemiological literature does not support the popular opinion that sitting-while-at-work is associated with LBP.

Stroke and apolipoprotein E epsilon4 are independent risk factors for cognitive decline: A population-based study.

BACKGROUND AND PURPOSE: Stroke and apolipoprotein E epsilon4 (ApoE epsilon4) are individually important risk factors for cognitive decline, including Alzheimer disease. It has been suggested that ApoE epsilon4 multiplies the risk for cognitive decline following stroke. In a population-based sample, using well-defined sensitive cognitive measures, this study investigates whether cognitive decline following stroke is worse for patients who carry the ApoE epsilon4 allele. METHODS: Subjects were participants in the Longitudinal Aging Study Amsterdam (LASA). The sample consisted of 1224 subjects, aged 62 to 85 years, who participated in the 3-year follow-up examination and for whom ApoE and stroke data were complete. We assessed cognitive decline using the Mini-Mental State Examination, the Auditory Verbal Learning Test (memory: immediate and delayed recall), and the Coding Task (information processing speed). The effects of stroke and ApoE epsilon4 on cognitive decline were evaluated with ANOVA and multiple logistic regression analysis, adjusted for age, sex, education, and baseline cognition. RESULTS: A synergistic effect modification for stroke and ApoE epsilon4 on cognitive decline was not observed. Unexpectedly, instead, stroke patients carrying the epsilon4 allele demonstrated a nonsignificantly lowered risk for Mini-Mental State Examination decline (OR=0.3; 95% CI 0.1 to 1.1). ApoE epsilon4 was associated with declines in information processing speed (OR=1.5; 95% CI 1.1 to 2.1) and small declines for immediate and delayed recall. CONCLUSIONS: Stroke and ApoE epsilon4 may impair cognition through distinct nonsynergistic mechanisms. The slowing of information processing speed for ApoE epsilon4 carriers was more evident than impairment in memory.

Incidence of dementia in relation to stroke and the apolipoprotein E epsilon4 allele in the very old. Findings from a population-based longitudinal study.

BACKGROUND AND PURPOSE: Both stroke and the apolipoprotein E (APOE) epsilon4 allele increase the risk of dementia. However, the interaction between stroke and APOE on dementia is still unclear. We addressed this topic by using a longitudinal design. METHODS: We followed up a community cohort of 1301 subjects aged >/=75 years, who did not have dementia at baseline. Among them, 92 subjects had a history of stroke (from 3 months to 16 years before baseline interview). After the 3-year follow-up, 224 dementia cases had been diagnosed. During the period of follow-up, 91 subjects had a first occurrence of stroke (incident stroke). The APOE genotype was known for 985 subjects. Cox proportional hazards regression models were constructed to estimate the risk for dementia in terms of relative risks (RRs) for stroke and the APOE epsilon4 allele, with adjustment for age, sex, education, systolic blood pressure, antihypertensive medication use, and heart disease. RESULTS: In the entire study population, RRs for dementia related to history of stroke and incident stroke were 1.7 (95% CI, 1.1 to 2.6) and 2.4 (95% CI, 1.6 to 3.5), respectively, after adjustment for all potential confounders. Subjects with stroke that occurred within 3 years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2), whereas those with stroke occurring >3 years before baseline had RR of dementia of 1.1 (95% CI, 0.6 to 2.3). Among those with APOE information, individuals with only history of stroke (that occurred within 3 years before baseline) had RR of 3.1 (95% CI, 1.4 to 6.6), individuals with only the APOE epsilon4 allele had RR of 1.7 (95% CI, 1.1 to 2.5), and individuals with both factors had RR of 5.3 (95% CI, 2.1 to 13.4). The corresponding figures when incident stroke was examined instead of history of stroke were 2.3 (95% CI, 1.3 to 4.1), 1.7 (95% CI, 1.1 to 2.4), and 4.6 (95% CI, 2.0 to 10.6), respectively. The RR of interaction term for history of stroke and APOE epsilon4 was 1.1 (95% CI, 0.3 to 3.8; P=0.8). The corresponding figure was 1.2 (95% CI, 0.4 to 4.4; P=0.7) for incident stroke and APOE epsilon4. Furthermore, the RRs of dementia without any stroke and dementia with stroke in relation to APOE epsilon4 were 1.6 (95% CI, 1.1 to 2.3) and 1.2 (95% CI, 0.6 to 2.4), respectively. In addition, the APOE epsilon4 allele was not significantly related to the occurrence of stroke (RR=0.8; 95% CI, 0.5 to 1.5). CONCLUSIONS: A relatively fresh stroke is a risk factor for dementia. APOE epsilon4 increases the risk of dementia without stroke but not dementia with stroke. Our data do not support a multiplicative effect of stroke and the APOE epsilon4 allele on the risk of dementia. However, both factors seem to have an additive effect on the risk of dementia. The APOE epsilon4 allele does not increase the risk of stroke in this Swedish elderly population.

Coding of occupation for the "young cohort" of the Danish twin register. A resource for future epidemiologic research.

OBJECTIVES: Information on health-related outcomes and exposures is available in user-friendly computerized format for the "young cohort" of the Danish Twin Register born 1953-82. We incorporated occupation information within the database to facilitate future job-related studies. METHODS: Occupation information for the 29,430 twins responding to a mailed questionnaire in 1995 was coded according to DISCO-88. The subjects were classified in three ways depending on the information available: directly from the 2,196 job titles listed in the DISCO-88 handbook, according to a set of predetermined rules, or by consensus if ambiguous information was provided. Two percent (2%) of the sample was recoded independently by two investigators to demonstrate coding consistency. RESULTS: Occupation could be directly coded using job titles for 61% of the sample; 15% were coded according to a set of rules or by consensus; 24% could not be coded. The recoded sample was 99% in agreement with the original coding. CONCLUSION: Occupation information has been incorporated within the extensive health-related database for the "young cohort" of the Danish Twin Register. This resource is available to researchers for future studies concerning occupation, health, and heredity using (1) the existing data (2) via linkage to other Danish databases, or (3) by contacting selected subjects directly.

Molecular pathogenesis of apolipoprotein E-mediated amyloidosis in late-onset Alzheimer's disease.

Apolipoprotein E (apoE) epsilon4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer's disease (AD). In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid beta protein (Abeta). However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms by which apoE might enhance Abeta deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces lysosomal accumulation of Abeta and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other is the extracellular pathway in which apoE-containing lipoproteins are trapped by Abeta1-42 deposits mobilizing soluble Abeta peptides and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest a chaperone-like function for the apoE molecule

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy.

HIV produces a chronic viral infection of the central nervous system that elicits chronic glial activation and overexpression of glial cytokines that are also implicated in Alzheimer disease (AD) pathogenesis. A genetic risk factor for AD is the E4 isoform for apolipoprotein E (APOE). Here we compare the frequency of neurologic symptoms for subjects with and without the E4 isoform (E4(+)and E4(-), respectively) in an HIV cohort. Compared with E4(-) subjects, twice as many E4(+) subjects were demented (30% compared with 15%) or had peripheral neuropathy (70% compared with 39%) at least once, and they had threefold more symptomatic examinations (13% compared with 3% and 42% compared with 14%, respectively)(P < 0.0001). Thus, neurologic symptoms for HIV-infection and AD are linked through an etiologic risk factor. Long-term survivors of HIV infection with E4 may be at high risk for AD; conversely, gene-viral interactions may speed AD pathogenesis.

The role of APOE polymorphisms in late-onset dementias.

Epidemiologic and laboratory results consistently implicate the APOE gene in the pathogenesis of late-onset Alzheimer's disease (AD): the epsilon 4 allele increases risk in a dose-dependent fashion, while epsilon 2 confers protection. Individuals are susceptible for AD in varying degrees depending on which combination of APOE alleles has been inherited, APOE promoter polymorphism and other factors. Deposition of both senile plaques and neurofibrillary tangles, the pathologic hallmarks of AD, are enhanced by epsilon 4 from the earliest lesions onward--diffuse plaques consisting of A beta 1-42 and neurofibrillary tangles in the entorhinal cortex. Transgenic APOE mice carrying an APP mutation and 0, 1 or 2 copies of APOE showed dose-related increases in plaque deposition in the hippocampus and cortex, a clear indication that APOEp promotes A beta deposition. The presence of each additional APOE epsilon 4 allele leads to an earlier onset of the histopathological process of about 1 decade, on average. The association of both types of AD-related changes with the occurrence of epsilon 4 suggests that the APOE polymorphism causally contributes to the pathogenesis of AD.

Psychotic symptoms and apolipoprotein E genotypes in an elderly population.

BACKGROUND: Psychotic symptoms have been found to be more common in demented elderly persons. Genetic variation in the apolipoprotein E (APOE) gene is reported to be associated with variation in the risk of Alzheimer's dementia. This study reports on variables associated with psychotic symptoms including APOE, in demented and nondemented elderly persons. METHODS: A population of 668 elderly persons was examined. APOE genotype was available in 309 individuals. RESULTS: Psychotic symptoms were found to be associated with dementia, a previous psychiatric history, female gender, being less educated, disability in daily living and institutionalisation. In the nondemented group, psychotic symptoms were equally common in subjects with or without the epsilon 4 present. In the demented subjects, psychotic symptoms were slightly more common, although not significant, in subjects without the epsilon 4 genotype. CONCLUSIONS: There was no statistical significant difference in APOE genotype between subjects with and without psychotic symptoms, stratified by dementic diagnosis.

Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+.

The aim of this study was to define the co-occurrence of depression and dementia in relation to apolipoprotein E (APOE) polymorphism. Physicians extensively examined 806 persons aged 78 years and over. DNA was extracted from peripheral white blood cells, and APOE genotype was determined using a microsequencing method on microtiter plates. The prevalence of dementia was 22.8% and was found to increase with the number of epsilon 4 alleles present. Depression was found in 11.4% of the demented subjects compared to 3.5% of the nondemented subjects. The overrepresentation of depression in demented subjects was found for each of the common genotypes. Depression was not strongly associated with APOE polymorphism. In spite of the association between dementia and APOE polymorphism, as well as dementia and depression, there was no association between APOE polymorphism and depression.

No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes.

BACKGROUND: Recent findings of a reduced cerebral metabolic rate of glucose (CMRGlu) in at-risk relatives of patients with Alzheimer disease (AD) who carry the apolipoprotein E (APOE) epsilon 4 allele suggest a causative role for the E4 isoform in cognitive changes that lead to AD. It is not known whether epsilon 4 allele-associated deficits exist in patients with clinical AD. OBJECTIVE: To determine whether distinct patterns of cerebral hypometabolism exist in patients who carry the epsilon 4 allele. PATIENTS AND METHODS: Information on the CMRGlu and APOE genotype was available for 46 patients at a memory disorders clinic: 31 patients were diagnosed as having probable AD, 3 demented patients did not meet criteria for AD, and 12 patients had mild memory complaints. Positron emission tomography with the use of 18F-fludeoxyglucose was used to calculate the CMRGlu in the frontal and temporoparietal regions of the cortex. Estimates were standardized to the sensorimotor area of the cortex. Linear regression models were constructed to relate the APOE genotype to the CMRGlu, adjusting for cognitive status (ie, the Mini-Mental State Examination score). RESULTS: Distinct patterns of the CMRGlu did not emerge for patients with different APOE genotypes. Bilateral deficits in the CMRGlu were found in the patients with AD. Left-right asymmetry was found in 8 of 12 patients with mild memory complaints: 7 of 8 had CMRGlu ratio less than 0.85 in the left side of the temporoparietal region of the cortex. CONCLUSIONS: The APOE epsilon 4 allele does not appear to be associated with specific deficits in brain metabolism in patients with AD despite evidence that the epsilon 4 allele is associated with preclinical alterations. This finding is consistent with previous epidemiologic results that have demonstrated a higher risk for AD in carriers of the epsilon 4 allele, but no change in the rate of progression of AD.

Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more.

BACKGROUND AND PURPOSE: We investigated apolipoprotein E polymorphism stroke risk in a population sample of 1810 persons aged 75 years or more in Stockholm (the Kungsholmen Project). Information on cognition at cohort inception (from 1987 to 1989) and on stroke occurrence (from 1969 to 1994) is available for the cohort. In the cohort, cognitive impairment is associated with the epsilon 4 allele, and longer survival in subjects aged > or = 85 years with good cognition is associated with the epsilon 2 allele and the absence of epsilon 4. METHODS: We compared stroke incidence in the 1077 of 1124 genotyped subjects who carried epsilon 2/3, epsilon 3/3, or epsilon 3/4 and estimated the proportion of cognitive impairment attributable to stroke. RESULTS: Risk of stroke did not vary with apolipoprotein E polymorphism (P = .82): 24% of 87 incident stroke patients during follow-up compared with 25% of 827 subjects with normal cognition and no stroke diagnosis at baseline carried the epsilon 3/4 genotype. An estimated 9% of cognitive impairment was attributable to stroke. Notably, a reduced epsilon 3/4 frequency of 20% was found in subjects who survived a prior stroke and were included in the cohort, and risk of hemorrhagic stroke tended to be associated with the presence of the epsilon 3/4 genotype and the absence of epsilon 2/3. CONCLUSIONS: This population-based study indicates that apolipoprotein E polymorphism is not a risk factor for ischemic stroke in subjects aged > or = 75 years (although it might possibly influence survival after stroke occurrence and be a risk factor for infrequent hemorrhagic stroke) and that approximately 10% of cognitive impairment in this age group is attributable to stroke.

Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families.

An association between the epsilon 4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset Ad families. We found an association of familial AD to the APOE epsilon 4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE epsilon 4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis.