Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?

We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer's disease. We genotyped 417 affected sib-pairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multipoint linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of epsilon4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant.

Norwegian Twin Registers and Norwegian twin studies--an overview.

The Norwegian Twin Registers include several sets of population-based sub-registers, and covers twin pairs born between 1895 and today. Except for the missing birth years 1960 to 1967, the register is almost complete. Most of the register contains information about both same-sexed and opposite-sexed twin pairs, except for twin pairs born between 1946 and 1960, where only same-sexed twins are registered. In a substantial part of the register, information about zygosity is obtained, mainly by a mailed questionnaire and in some cases supported by DNA testing. These are the birth years 1915 to 1960 and the birth years 1967 to 1979. Zygosity information is further obtained in the different twin studies derived from the twin register. In 1990 the whole register was made available in a computerized form. Several twin studies have been derived from the different parts of the register. In this article, studies from the two earliest parts of the register are reviewed and grouped by recruitment specifics. Finally, future plans for the register and twin studies are discussed.

The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study.

BACKGROUND: This study compares the relative importance of heredity and environment in the development of Alzheimer disease and vascular dementia. The relationship between apolipoprotein E and dementia is also tested. METHODS: A total of 23,000 cognitively impaired subjects from Norwegian institutions for the elderly were identified, and their files were checked against the records of 26,000 twin pairs from the Norwegian Twin Register. A sample of 72 twin pairs was selected and thoroughly investigated clinically. The mean age of the sample was 80 years. RESULTS: The pairwise concordance rate for Alzheimer disease was 78% (7/9) among monozygotic and 39% (9/23) among dizygotic twin pairs. The probandwise concordance rate was 83% (10/12) among monozygotic and 46% (12/26) among dizygotic twin pairs. There was no significant difference in the rate of apolipoprotein E epsilon 4 allele between twin pairs concordant and discordant for Alzheimer disease. By using tetrachoric correlations, the estimated heritability was approximately 0.6. Environmental factors shared by cotwins seemed to explain most of the remaining variance. In vascular dementia, there was no significant difference in pairwise concordance rates among monozygotic (1/6 [17%]) and dizygotic (4/16 [25%]) twin pairs or in probandwise concordance rates among monozygotic (2/7 [29%]) and dizygotic (5/17 [29%]) twin pairs. CONCLUSION: Heredity is the major causal factor in late onset Alzheimer disease, whereas environmental factors dominate in vascular dementia.

[Geriatric psychiatry--a specialty gaining recognition]. / Alderspsykiatri--et fagfelt som finner sin plass.

Services for elderly, mentally ill people have developed in response to changing needs in society. In 1990 most of the 650 beds allocated to elderly patients in psychiatric hospitals were occupied by long-term care patients. Outpatient programmes hardly existed. In 1995 about 400 beds were allocated to geriatric psychiatry. They were served by 40 physicians and 20 psychologists. Out-patients' clinics were established. Most of the in-patients were short-term admissions. Nowadays, departments of geriatric psychiatry define themselves as diagnostic and short-term units. About a third of the in-patients suffer from dementia, a third from depression, and a third from various other psychiatric disorders. The authors recommend that a special unit for geriatric psychiatry should be established in every county in Norway. Funds should be allocated for professorships at all universities.

[Geriatric psychiatry--a specialty within psychiatry]. / Alderspsykiatri--en spesialisert form for psykiatri.

The aim of this article is to describe the prevalence of mental disorders in the elderly and how the psychiatric services for these patients ought to be organized in Norway. Geriatric psychiatry is a special branch of psychiatry. Its areas of concern are the assessment and treatment of mental disorders which frequently occur in the elderly. The most prevalent psychiatric disorders are depression and dementia. Functional psychosis and anxiety disorders are less prevalent, but nevertheless disorders causing great concern. Psychiatric morbidity frequently coexists with physical illness. An elderly patient suffering from a mental disorder often has a combination of psychological, social and physical needs. The resources allocated to psychiatric services for old people are scarce. Efforts should be made to establish a special unit for geriatric psychiatry in every county in Norway. Each unit should serve approximately 150-200,000 inhabitants, and should consist of both an in-patients' and an out-patients' clinic. It is recommended that there should be 1 to 1.5 beds per 1000 elderly aged 65 years and over.

Apolipoprotein E type epsilon4 allele, heritability and age at onset in twins with Alzheimer disease and vascular dementia.

The apolipoprotein E (APOE) epsilon4 allele is a risk factor in Alzheimer disease (AD), but not in vascular dementia (VaD). We have investigated whether the epsilon4 allele is more common in twin pairs concordant for AD, compared with those discordant for AD, and whether the epsilon4 allele is more common in AD twins than in VaD twins. In addition, we have investigated the relationship of the epsilon4 allele and the age at onset in AD and VaD. APOE genotype was analysed in 29 senile demented twin pairs. The epsilon4 allele was associated with AD and not with VaD. However, there was no difference in the frequency of the APOE epsilon4 allele in concordant (33.3%) and discordant (31.3%) AD dizygotic twin pairs. Age at onset in AD was significantly lower in epsilon4 homozygotes than in individuals with one or no copies of epsilon4 (62.4 vs. 73.5, p<0.01). In concordant AD twin pairs, the epsilon4 allele frequency was somewhat higher in the twins with earlier onset (41.7% vs. 25%), but the difference was not statistically significant. In the VaD group the age at onset was not significantly different between individuals with or without epsilon4 in their genotypes.

Heredity in dementia of the Alzheimer type.

Family, twin and linkage studies in Alzheimer's disease are reviewed. Several of these studies appear to be burdened with sources of error, mainly related to sampling and clinical diagnoses. It was previously thought that early-onset cases of Alzheimer's disease were heavily genetically influenced, whereas late-onset cases were sporadic. The author questions whether this difference is mainly due to methodological error.

Use of twin cohorts for research in Alzheimer's disease.

The causes of Alzheimer's disease (AD) remain a mystery despite the recent identification of several putative environmental risk factors and the discovery of several linked genetic loci and point mutations associated with the disease. Particularly uncertain is the generalizability of the genetic findings to the common forms of disease encountered in clinical practice or population research. Twin studies of AD can illuminate causal mechanisms, both genetic and environmental. This consensus document explores the rationale for such twin studies, as well as a number of methodologic problems that render them difficult to implement or interpret. We review existing twin studies of AD and note several ambitious new studies. Finally, we delineate several practical strategies for the near future of twin research in AD.

Were Langfeldt's schizophreniform psychoses really affective?

Langfeldt's cases of schizophreniform psychoses were reclassified according to the ICD-9 and DSM-III-R diagnostic systems. The main purpose was to reexamine the validity of his concept of 'schizophreniform psychoses' to see whether it supported the existence of a 'third psychosis', and whether his material could be helpful in identifying good prognostic features in schizophrenia. Most of the schizophreniform psychoses turned out to be affective disorders with psychotic features. The number of other psychotic disorders was too small to facilitate a more thorough examination.

Langfeldt's schizophreniform psychoses fifty years later.

As a result of follow-up studies published in 1937 and 1939, Langfeldt divided schizophrenia into two groups; 'typical schizophrenia' which had a poor outcome, and the 'schizophreniform psychoses' which had a less typical clinical picture of schizophrenia and a good outcome. Langfeldt's cases of schizophreniform psychoses were reclassified according to the ICD-9 and DSM-III-R diagnostic systems. Most of the schizophreniform psychoses did not appear 'schizophrenia-like' at all, but turned out to be mainly affective disorders. Those included in Langfeldt's diagnosis of 'schizophreniform psychoses' were found to be too heterogenous to validate the existence of this syndrome.