Apolipoprotein E4 genotype is not associated with short-term cognition deficits during alcohol withdrawal.

Aim of this prospective study was to investigate a possible association between the apolipoprotein E4 (ApoE4) genotype and clinically well-known cognition deficits during alcohol withdrawal. We examined 172 patients with alcohol dependence (137 men, 35 women) during withdrawal treatment. The ApoE genotype was determined in all patients using polymerase chain reaction. Cognitive function was assessed applying the c.I.-Test on day 0 (admission) and on day 7 of withdrawal treatment. Using Pearson's chi2 test we found no significant association between the ApoE4 genotype and cognition deficits for both dates (day 0: p=.463; day 7: p=.760). Moreover, multivariate logistic regression analyses revealed no significant association between presence of the ApoE4 allele and cognitive dysfunction. Even though ApoE4 plays an important role in alcoholism-related brain atrophy and cognition deficits in demented as well as in nondemented healthy elderly people, this study provides no evidence for an association with short-term cognition deficits during alcohol withdrawal.

Relation of Apo E and ACE genes to cognitive performance in chronic alcoholic patients.

Apolipoprotein E epsilon4 and ACE genes have been related to several conditions involving cognitive impairment, including Alzheimer's disease, normal ageing and cerebrovascular disease. However, it has not been established whether their genotypes are associated with alcoholism or its cognitive functioning. Genotypic distributions of 140 chronic alcoholic patients were compared with a non-alcoholic sample, and the cognitive performance of a subsample of the alcoholic subjects was assessed with standard neuropsychological tests. No differences in allele or genotype distributions of Apo E or ACE genes were found when comparing controls and alcoholics (Apo E epsilon2/2; patients 1.4%, controls 0% p < 0.06; epsilon2/epsilon3; patients 9.3%, controls 6.6% p < 0.29; epsilon2/epsilon4; patients 0%, controls 1% p < 0.31; epsilon3/epsilon3 patients 71.4%, controls 72% p < 0.89; epsilon3/epsilon4; patients 15.7%, controls 19.2%, p < 0.36; epsilon4/epsilon4; patients 2.1%, controls 1.2% p < 0.44; ACE D/D; patients 35%, controls 28.5% p < 0.14; I/D; patients 47.5%, controls 51.1% p < 0.51; I/I; patients 14.5%, controls 20.4% p < 0.19). In terms of cognitive performance, epsilon4/epsilon3 patients did better on visuoconstructive (p < 0.001) and visual memory (p < 0.04) functions compared with epsilon2/epsilon3 bearers. Furthermore, ACE D/D patients performed better on a test of abstract reasoning (p < 0.03) compared with the ACE I/I homozygous group. The cognitive results suggest that Apo E or ACE genotypes may modify the effects of ethanol on cognitive deterioration in alcoholic patients. However, the data do not support an association between the Apo E epsilon4 allele and reduced cognitive performance in alcoholism.

Apolipoprotein E epsilon 4 allele distribution in Wernicke-Korsakoff syndrome with or without global intellectual deficits.

Recent genetic studies show that the apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD). Whether this allele is associated with other dementing diseases is the next important question. The information could provide a clue to the pathogenetic role of ApoE. In the present study, patients with Wernicke-Korsakoff syndrome (WKS) of alcoholic etiology were divided into two groups according to the severity of intellectual deficits, i.e., those of "classical" Korsakoff patients with preserved intellectual function other than amnesia and those with global intellectual deficits. Genotyping showed that the frequency of ApoE epsilon 4 allele was significantly higher in the patients with global deficits, suggesting the involvement of this allele in the intellectual decline of WKS. In contrast, distributions of other two markers, alpha 1-antichymotrypsin and presenilin-1, did not differ between the two groups. These results added further support to the notion that the consequence of acute insult to the brain is influenced by the ApoE genotype, and suggested ApoE's role in the development of a certain group of "alcoholic dementia."

No association between the c2 allele at the cytochrome P450IIE1 gene and alcohol induced liver disease, alcohol Korsakoff's syndrome or alcohol dependence syndrome.

Cytochrome P450IIE1 metabolises, and is induced by ethanol. The 5' regulatory sequence of the gene is polymorphic; that identified by the c2 allele has been shown by transfection studies to confer an increased rate of transcription. A recent report indicating an association between this allele and alcohol induced cirrhosis suggests that it may contribute to the genetic vulnerability to this disease. We have examined this polymorphism in patients of western European origin with alcohol induced cirrhosis, alcohol Korsakoff's syndrome and alcohol dependence syndrome. We were unable to detect any association between this allele and any of these diseases.

Apolipoprotein E epsilon 4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan.

The apolipoprotein E epsilon 4 allele has been associated with both familial and sporadic Alzheimer's disease (AD). Given its possible role in nerve repair and growth, it is plausible that apolipoprotein E may be a common denominator in the pathogenesis of several dementing diseases. Therefore, we investigated epsilon 4 frequencies in demented and nondemented alcoholics, as well as in patients with sporadic AD and controls in Japan. No significant differences in allele frequencies was found between demented and nondemented alcoholics and controls, while a significant association was demonstrated between AD and the epsilon 4 allele. These results support a specific role of epsilon 4 in the pathogenesis of AD, rather than a more general role for epsilon 4 in dementing illnesses.

[Rationale for alcohol consumption and mitochondrial aldehyde dehydrogenase genotype in the native male population of Chukotka]. / Osobennosti potrebleniia alkogolia i genotip mitokhondrialnoi aldegidrogenazy u korennykh muzhchin Chukotki.

To study the alcohol consumption pattern and mitochondrial aldehyde dehydrogenase (ALDH2) genotype, a random sample consisting of 170 native males (Chukchee and the Eskimo), residents of 4 Chukotka settlements, was studied. According to interviews, most residents (68%) consumed alcohol once or twice a month; however during an alcohol uptake episode they consumed very high (intoxicating) doses exceeding 150 g of pure alcohol. The rates of control loss, alcohol amnesia and withdrawal syndrome were more than 50%. Twelve per cent reported inconsistent facial flushing after drinking and positive ethanol-patch test was found only in 2% of cases. Direct genotyping, using specific oligonucleotide probes, showed no atypical oriental type ALDH2. The normal genotype (ALDH2-1) was present in all the examinees from Chukotka natives (n = 87). These results explain the ability of Chukotka natives to consume high amounts of alcohol per occasion and they are in disagreement with the hypothesis that the drinking pattern among the natives is explained by specific features of alcohol-metabolising enzymes.

Cloning of human transketolase cDNAs and comparison of the nucleotide sequence of the coding region in Wernicke-Korsakoff and non-Wernicke-Korsakoff individuals.

Variants of the enzyme transketolase which possess reduced affinity for its cofactor thiamine pyrophosphate (high apparent Km) have been described in chronic alcoholic patients with Wernicke-Korsakoff syndrome. Since the syndrome has been shown to be directly related to thiamine deficiency, it has been hypothesized that such transketolase variants may represent a genetic predisposition to the development of this syndrome. To test this hypothesis, human transketolase cDNA clones were isolated, and their nucleotide and predicted amino acid sequence were determined. Transketolase was found to be a single copy gene which produces a single mRNA of approximately 2100 nucleotides. Additionally, the nucleotide sequence of the transketolase coding region in fibroblasts derived from two Wernicke-Korsakoff (WK) patients was compared to that of two nonalcoholic controls. Although nucleotide and predicted amino acid differences were detected between fibroblast cultures and the original cDNAs and among the cultures themselves, no specific nucleotide variations, which would encode a variant amino acid sequence, were associated exclusively with the coding region from WK patients. Thus, allelic variants of the transketolase gene cannot account for the biochemically distinct forms of the enzyme found in these patients nor be considered as a mechanism for genetic predisposition to the development of Wernicke-Korsakoff syndrome. Instead, the underlying mechanism must be extragenic and may be a result of differences in post-translational processing/modification of the transketolase polypeptide.

No transketolase abnormalities in Wernicke-Korsakoff patients.

Transketolase isoenzyme patterns of Wernicke-Korsakoff patients, relatives, alcoholics and controls, obtained by isoelectric focusing of purified erythrocyte transketolase, were all identical. After a series of investigations published by several authors little evidence remains to support the hypothesis of an inborn transketolase abnormality in Wernicke-Korsakoff patients.

Psychological deficit from excessive alcohol consumption: evidence from a co-twin control study.

Twenty-five pairs of monozygotic twins discordant for either the alcohol dependence syndrome or heavy drinking were studied to determine the adverse cognitive effects of alcohol. The twins and their co-twins were well-matched for premorbid history and personality but twins with high alcohol consumption performed significantly less well overall on cognitive testing than their co-twins. Impaired performance in parts of the following tests was found: visual spatial ability, visual spatial recognition, Mill Hill vocabulary, Bexley Maudsley category sorting, tactual performance. The number of years of problem drinking correlated with inferior scores on subtests of the tactual performance test. This study provides further evidence that alcohol abuse produces long-term cognitive sequelae which may not be grossly evident in clinical practice, and which may occur even at relatively low levels of intake.

Wernicke-Korsakoff syndrome in monozygotic twins: a biochemical peculiarity.

A pair of monozygotic twins, one suffering from the Wernicke-Korsakoff syndrome, verified at autopsy, and the other healthy, was studied biochemically. The erythrocyte transketolase of each twin showed abnormalities, though these differed in the two individuals. In the healthy twin, the basal transketolase was low, but responded normally to thiamine pyrophosphate (TPP) added in vitro. In the twin with the Wernicke-Korsakoff syndrome the basal level of the enzyme and its response in vitro were normal, but a period of treatment with thiamine tetrahydrofurfuryldisulphide, led to loss of the in vitro response. It is suggested that, initially, an inborn error of metabolism may have been common to both twins.

Neurobiological and genetic aspects of the etiology of alcoholism.

In contrast to humans, most animals will not voluntarily consume alcohol to the point of intoxication nor to the point of development of tolerance and physical dependence. Since there is good evidence for a genetic component to human alcoholism, we explore the possibility that the presence of alcohol in the environment during human evolution has contributed to this difference in behavior from that observed in lower animals. We then review the biologic basis for genetic influences on various aspects of alcohol-related behaviors in both humans and lower animals. Thus, the evidence for genetic influences on rate of alcohol metabolism, preference, central nervous system depressant effects. tolerance, and dependence are briefly reviewed. The technique of selective breeding for alcohol-related behavior is described and compared to the process of natural selection that may be occurring in the human population.

Genetic factors in Wernicke-Korsakoff syndrome.

The authors study the role of thiamine-deficient diets in genetic variations contributing to Wernicke-Korsakoff syndrome.

Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome.

We studied a thiamine-requiring enzyme in cultured cells from four patients with the Wernicke-Korsakoff syndrome to determine whether these patients have a genetic predilection to thiamine deficiency. Transketolase in fibroblasts from the patients with the syndrome bound thiamine pyrophosphate less avidly than control lines. The apparent Km for thiamine pyrophosphate was 195 +/- 31 micron for transketolase in extracts of the patients' cells as compared to 16 +/- 2 micron in six control lines (means +/- S.E.M.: P less than 0.001). The ranges were 146 to 281 micron for the patients and 12 to 20 micron for the controls. The abnormality in transketolase persisted through serial passages in tissue culture in cells grown in medium containing excess thiamine and no ethanol, indicating that the aberrations were genetic rather than dietary. The abnormality of transketolase in this syndrome would presumably be clinically unimportant if the diet was adequate. These patients appear to have deleterious inborn enzymatic abnormalities of a type originally postulated by Garrod.