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Biomedical subjects

L Lannfelt

Publications and source records attributed to L Lannfelt.

At least 91 records · Page 5Linked to original sources
PubMed1996

Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition.

OBJECTIVE: To quantify the influence of apolipoprotein E (APOE) polymorphism on cognition and survival in a population sample aged 75 years or older. DESIGN: The Kungsholmen Project established a cohort of 1810 residents in a district in Stockholm, Sweden, aged 75 years or older in 1987. Information on cognition at cohort inception is available for all subjects. Subjects were followed up for mortality to January 1, 1995. SUBJECTS: Included in this study are 1077 subjects (of 1124 genotyped for APOE) with the common epsilon 2/3, epsilon 3/3, and epsilon 3/4 APOE genotypes. RESULTS: The odds of cognitive impairment for the epsilon 3/4 vs epsilon 3/3 genotype declined with age: 4.8 for age 75 through 79 years; 1.7 for age 80 through 84 years; and 1.0 (i.e., no association) for age 85 years or older. Despite this association, APOE polymorphism did not significantly predict survival in subjects younger than 85 years, nor did it predict survival in subjects 85 years or older who were cognitively impaired. Instead, survival varied fourfold with respect to APOE polymorphism in those 85 years or older who had good cognition: Mortality in subjects with the epsilon 2/3 genotype was half that in those who carried the epsilon 3/3 genotype (hazard ratio, 0.5; 95% confidence interval, 0.2 to 0.9), and mortality in subjects with the epsilon 3/4 genotype was twice that in those who carried the epsilon 3/3 genotype (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.5). This fourfold variation resulted in 2-year differences in survival. CONCLUSIONS: The minor sequence variation in the apolipoprotein E isoforms resulted in a fourfold difference in the risk of death among the oldest old (age > or = 85 years) with good cognition. The observed variation in mortality was unlikely to have been caused by cognitive impairment, as APOE polymorphism was not a risk factor for cognitive impairment in this age group.

Age Factors↗
PubMed1996

Lack of association between schizophrenia and the apolipoprotein E epsilon 4 allele.

The association between the epsilon 4 allele of the apolipoprotein E (APOE) gene and Alzheimer's disease (AD) has been reported. In order to examine if the epsilon 4 allele may play a role also in schizophrenia, another mental disorder, patients (n = 87) and control subjects (n = 57) were genotyped for APOE. No significant difference was found between the groups. The data indicate that the APOE gene is not of major importance for the genesis of schizophrenia.

Adult↗
PubMed1996

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Alzheimer Disease↗
PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗
PubMed1996

Genetics of Alzheimer's disease.

Alzheimer's disease (AD) is characterised neuropathologically by the accumulation of neuritic plaques and neurofibrillary tangles as well as by cerebrovascular amyloid deposition and neuronal cell loss. The major component of neuritic plaques and cerebrovascular amyloid is a 40-42 amino acid peptide termed beta-amyloid, derived as a proteolytic fragment from the large amyloid precursor protein (APP), a membrane-bound protein expressed in most tissues. The last few years have seen considerable advances in understanding the pathogenesis of Alzheimer's disease through genetic studies. The importance of the beta-amyloid peptide in the pathogenesis of AD has been strengthened by the identification of pathogenic mutations in the APP gene on chromosome 21.

Aged↗
PubMed1996

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.

Aged↗
PubMed1996

Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene.

Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in the amyloid precursor protein (APP) gene using the end-specific monoclonal antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively. In cases of APP717 mutation the predominant A beta species within plaques terminate at A beta 42(43) with relatively little A beta 40 being present. The total amount of A beta deposited as A beta 42(43) is significantly greater than in sporadic Alzheimer's disease, consistent with the suggestion that this mutation might influence the processing of APP so as to produce more of the highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major peptide in plaques is also A beta 42(43), although the proportion of plaques containing A beta 40, and the total A beta load is similar to that in sporadic Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder, however, parenchymal deposits are exclusively A beta 42(43). Although the various APP mutations may influence the type, quantity, and location of A beta deposited, the predominant, and possibly the initial, species deposited in the brain parenchyma is A beta 42(43).

Adult↗
PubMed1996

[Important current genetic findings in schizophrenia].

Twin and adoption studies have yielded convincing evidence of the involvement of genetic factors in the aetiology of schizophrenia. A genetic link with chromosome 6 reported just over a year ago has since been confirmed by other research groups. There is reason to hope that one or more schizophrenia genes will be identified in the next few years.

Chromosomes, Human, Pair 6↗
PubMed1995

Amyloid beta-peptide in cerebrospinal fluid in individuals with the Swedish Alzheimer amyloid precursor protein mutation.

The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid beta-peptide (A beta) and in recent years, pathogenic mutations in the amyloid precursor protein (APP) gene have been discovered in some AD families. The APP670/671 mutation, found in a Swedish AD family, has revealed over-production of A beta as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A beta levels in cerebrospinal fluid (CSF) from APP670/671 mutation-carriers and non-carriers. A correlation was seen between decrease in A beta levels and duration of disease although no difference was found in levels of A beta between the groups (14.5 +/- 3.3 ng/ml versus 14.9 +/- 2.3 ng/ml).

Adult↗
PubMed1995

Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

The major component of the cerebral plaques in Alzheimer disease is the beta-amyloid peptide, but serine proteinase inhibitors like alpha 1-antichymotrypsin (ACT) are also present. Their role in the pathogenesis of amyloid formation is unsettled. In addition to their function as proteinase inhibitors, serine proteinase inhibitors can interact with various hydrophobic compounds, a reaction accompanied by a transition from the stressed to the relaxed conformation. We report here on the ability of ACT to regulate the formation of beta-amyloid fibrils in vitro. In a molar ratio of 1:10 (ACT to beta-amyloid) ACT inhibits beta-amyloid fibril formation. Furthermore, ACT promotes rapid disaggregation of beta-amyloid fibrils when added in the same molar ratio to preformed beta-amyloid fibrils. These processes are accompanied by increased thermostability of ACT and loss of its biological activity, consistent with a conformational transition of ACT from the stressed to the relaxed state. The influence of ACT on beta-amyloid fibril formation may be an example of a hydrophobic interaction between the beta-amyloid peptide and the hydrophobic domain C terminal to the reactive center of ACT.

Alzheimer Disease↗
PubMed1995

Increased cerebrospinal fluid tau in patients with Alzheimer's disease.

One of the pathological features in Alzheimer's disease (AD) is neurofibrillary tangles in the brain. The main constituent of tangles is the microtubuli-associated protein tau in a hyperphosphorylated state. Tau is also released into cerebrospinal fluid (CSF), and in this study we have used an enzyme linked immunosorbent assay to measure tau in CSF from AD and control cases. Our findings show that tau levels in AD cases are significantly elevated compared to healthy control individuals. We suggest that tau may serve as a biochemical marker of Alzheimer's disease.

Aged↗
PubMed1995

Amyloid precursor protein mutation at codon 713 (Ala-->Val) does not cause schizophrenia: non-pathogenic variant found at codon 705 (silent).

In some families with early-onset Alzheimer's disease (AD) pathogenic mutations have been found in exons 16 and 17 of the amyloid precursor protein (APP) gene. One case of schizophrenia has been described with a mutation at codon 713. We have developed a single strand conformation polymorphism (SSCP) method that detects mutations in these exons and investigated 98 AD cases and 56 elderly healthy controls. An earlier reported mutation at codon 713 in a healthy control and a previously undescribed polymorphism at codon 705 in a sporadic case of AD were found. These mutations are probably not related to disease pathogenesis.

Aged↗
PubMed1995

Apolipoprotein epsilon 4 allele and disease progression in patients with late-onset Alzheimer's disease.

A random sample of 60 late-onset Alzheimer's disease (AD) cases from a population-based study were apolipoprotein E (apoE) genotyped and clinically examined with a 3-year interval. The epsilon 4 allele carriers had a significantly lower age of disease onset compared to non-epsilon 4 carriers. However, no significant differences were observed between epsilon 4 allele carries and non-carriers for Mini-Mental State Examination (MMSE) test scores at the first examination, in spite of a longer disease duration in the epsilon 4 allele carriers. After 3 years, MMSE test scores were still not significantly different between epsilon 4 carries and non-carriers but more than twice as many non-carriers had died. All other clinical features were similar between epsilon 4 allele carriers and non-carriers. This study indicates that the epsilon 4 allele is associated with a better prognosis of the disease in late-onset AD but that there are probably factors other than the epsilon 4 allele that are important for the AD phenotype.

Age of Onset↗
PubMed1995

Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: effects of the Swedish Alzheimer's disease APP 670/671 mutation on binding levels.

We have characterised the muscarinic receptor subtypes found in human skin fibroblasts and compared binding levels in cell lines from members of the Alzheimer's disease family with the Swedish amyloid precursor protein (APP) 670/671 mutation. Binding studies with [3H] quinuclidinyl benzilate ([3H]QNB) and the M2/M4 selective antagonist [3H] (+/-)-5,11-dihydro-11-([(2-[(di-propylamino)methyl]-1- piperidinyl]ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one ([3H]AF-DX 384) revealed the presence of a single population of muscarinic receptors on lysed fibroblast membranes. [3H]QNB binding was displaced by a number of selective muscarinic ligands with a rank order of potency: atropine > himbacine > methoctramine > (+/-)-p-fluoro-hexahydro-sila-difenidol hydrochloride > pirenzepine > muscarinic-toxin-3. APP 670/671 mutation carrying cell lines showed 25-35% lower levels of muscarinic receptors labelled with [3H]QNB, [3H]N-methyl scopolamine and [3H]AF-DX 384, compared to controls. This difference was not statistically significant due to large individual variation. It is concluded that muscarinic receptors on adult skin fibroblasts are predominantly of the M2 subtype. Since these cells do not possess M1 and M3 receptor subtypes, they are unlikely to provide a good model for studying muscarinic receptor regulation of APP processing.

Aged↗