Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

Polymorphisms of the gene encoding the inflammatory cytokine interleukin-6 determine the magnitude of the increase in soluble interleukin-6 receptor levels in Alzheimer's disease. Results of a pilot study.

Interleukin-6 (IL-6) is a multifunctional cytokine involved in the pathogenesis of Alzheimer's disease (AD). The effects of IL-6 are mediated through a specific receptor complex made up of a ligand binding glycoprotein (gp80 or IL-6R) and a signal transducing glycoprotein (gp130). Conflicting results have been reported concerning altered IL-6 or soluble IL-6R (sIL-6R) levels in serum and CSF in AD. This study investigated whether genetic heterogeneity determines the magnitude of the difference in IL-6 and sIL-6R levels in AD. Fifty-eight AD patients and 25 control subjects were included. Plasma and CSF IL-6 and sIL-6R levels were measured and the IL-6 variable number of number repeats ( IL-6vntr) and IL-6 promoter ( IL-6prom) genotypes were determined. sIL-6R levels in plasma and CSF were higher in AD patients than in control subjects. This elevation was striking among non-carriers of the IL-6vntr*C allele and among subjects homozygous for the IL-6prom*C allele whereas no difference in plasma and CSF sIL-6R levels was observed among carriers of the IL-6vntr*C allele and among subjects with the IL-6prom*CG and IL-6prom*GG genotypes. We conclude that plasma and CSF levels of sIL-6R are significantly increased in AD patients and that the magnitude of increase is determined by the IL-6 genotype.

Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease.

Cholesterol and 24S-hydroxycholesterol are involved in the pathogenesis of Alzheimer's disease (AD). Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24S-hydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C --> T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A --> G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C --> T polymorphism was associated with an increased 24S-hydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain.

CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects.

In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau(231)) in CSF correlate with progression of cognitive decline. High CSF p-tau(231) levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-epsilon 4 carrier status were predictive as well. Our data indicate that an increased p-tau(231) level is a potential risk factor for cognitive decline in patients with MCI.

The insulin gene VNTR polymorphism in Alzheimer's disease: results of a pilot study.

Insulin (INS) and insulin-like growth factors include different polypeptides involved in growth and development. Possibly they play a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). A variable number of tandem repeats (VNTR) polymorphism at the human INS 5'-flanking region consisting of three distinct allele classes has been shown to influence the tissue-specific expression of INS and the insulin-like growth factor 2 (IGF-2). Since alterations in the expression of INS or IGF-2 might be relevant in AD, we investigated the association between the INS VNTR polymorphism and the risk for AD. We found no association between the INS VNTR genotype and the risk for AD (p = 0.873). However, survival analysis revealed that class III homozygotes of the INS VNTR polymorphism had an earlier initial onset in patients suffering from early AD (p = 0.002). Our preliminary results suggest, that genetically determined alterations of the INS/IGF-2 metabolism might modify the course of AD. Further studies are warranted to confirm these data in larger study samples.

Physical disorders and causes of death in relatives of Alzheimer's disease patients.

BACKGROUND: Genetic risk factors are important in Alzheimer's disease (AD). These risk factors might also predispose for other disorders. This might lead to a familial coaggregation of AD and other disorders, e.g. Down's syndrome or Parkinson's disease. In the present study the risk of physical disorders in relatives of AD patients, of depressed patients and of control subjects were compared. METHODS: Family history and, if possible, interview information on physical disorders and causes of death in relatives of 146 patients with AD, 168 patients with major depression (MD) and 136 controls was collected. Statistical comparisons were performed using chi-square tests and, if necessary, logistic regression analysis accounting for age, gender and interview status. RESULTS: In contrast to our hypotheses, there was no increased risk of cerebrovascular disease, Down's syndrome, haematological malignancies or Parkinson's disease in relatives of AD patients compared with relatives of patients with MD and of controls. The explorative analysis revealed that congenital malformations, i.e. malformations of the heart or of the extremities, were slightly increased in relatives of AD patients. Relatives of patients with AD or MD were at increased risk of dying as a result of accidents, in most cases falls in advanced age, and relatives of patients with MD were at slightly increased risk of dying from gastroenterologic diseases, in most cases complications of peptic ulcers. CONCLUSION: The results do not support a major overlap between the genetic risk of AD and the genetic risk of cerebrovascular disease, Down's syndrome, haematological malignancies or Parkinson's disease. The finding of an increased risk of congenital malformations in relatives of AD patients needs further replication before it can be stated. The increased risk of dementia or depression with cognitive impairment in elderly relatives of patients with AD or MD increases the risk of accidents like falls. The genetic risk of depression in relatives of patients with MD could have a negative influence on the prognosis of peptic ulcera.

24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia.

The brain is the most cholesterol-rich organ in the human body. Accumulation of excess cholesterol in hippocampal neurons promotes the cleavage of the amyloid precursor protein (APP) into amyloidogenic components with the consequence of the acceleration of neuronal degeneration. Conversion of cholesterol to 24S-hydroxycholesterol mediated by cholesterol 24S-hydroxylase (CYP46) is the major pathway for the elimination of brain cholesterol and the maintenance of brain cholesterol homeostasis. We examined whether cerebrospinal fluid (CSF) 24S-hydroxycholesterol levels differ between patients with dementia, patients with mild cognitive impairment (MCI), and cognitively intact control subjects. Plasma and CSF concentrations of 24S-hydroxycholesterol and cholesterol in 32 patients with Alzheimer's disease (AD), 11 patients with vascular dementia, seven patients with MCI, and seven cognitively intact control subjects were measured by combined gas-chromatography/mass spectrometry. We show elevated concentrations of 24S-hydroxycholesterol in the CSF of AD patients and we interpret this finding as a consequence of increased cholesterol turnover in the central nervous system during neurodegeneration. The observed influence of the apolipoprotein E epsilon4 (APOE4) allele on CSF 24S-hydroxycholesterol concentrations with a gene-dosage effect suggests the existence of a link between the AD risk factor APOE4 and CNS cholesterol metabolism. The elevation of CSF 24S-hydroxycholesterol appears to occur early in the disease process, since patients with mild cognitive impairment had also increased CSF concentrations of this compound. We believe that the CSF concentration of 24S-hydroxycholesterol is altered in AD-related neurodegeneration and thus, CSF 24S-hydroxycholesterol may be a marker for monitoring the onset and progression of the disease.

Fertility and number of children in patients with Alzheimer's disease.

Oestrogen therapy has been suggested to have protective effects against Alzheimer's disease. The effects of natural exposure to oestrogen in cognitive disorders have rarely been studied. Assuming that nulliparous women have a higher exposure to natural oestrogen, it could be hypothesised that these women might have a lower risk of Alzheimer's disease than women who have had children. The fertility and number of children in 106 women with a diagnosis of Alzheimer's disease was examined and compared with that of 189 female subjects from two control groups with subjects without dementia. As additional control, the same comparisons were carried out for 40 male patients with Alzheimer's disease and 105 male control subjects. In female subjects, having had children was found to be associated with a diagnosis of Alzheimer's disease. This was not the case in male subjects. The number of children did not seem to affect the risk of Alzheimer's disease, neither in female nor in male subjects. Natural exposure to oestrogen seems to reduce the risk of Alzheimer's disease in women.

Seasonal distribution of births in patients with Alzheimer's disease and elderly depressive patients.

Winter births have been associated with a higher risk of Alzheimer's disease (AD) and other psychiatric disorders. In the present investigation, this putative association was examined in a sample of gerontopsychiatric patients. An analysis of the quarterly birth rates of 83 patients with AD, 78 elderly depressive patients with an early onset and 74 patients with a late onset of the depressive disorder, 48 patients with both AD and depression (co-morbid patients) and 107 healthy control subjects, revealed no particular seasonal distribution for any of the diagnostic groups. In AD and co-morbid patients, controlling for the ApoE genotype did not change this finding. Logistic regression analysis revealed the expected findings that increasing age and the presence of the ApoE4 allele were associated with a higher risk of dementia. Younger age and female gender were identified as risk factors for a depressive disorder. A winter birth (birth in the first three months of the year) was not associated with any of the diagnostic subgroups. We concluded that in our sample a seasonal distribution of births was not found to increase the risk for AD or geriatric depression.

Inter-rater reliability of family history information on psychiatric disorders in relatives.

The family history method in psychiatric family studies is an important and necessary way of obtaining information on family members who are not available for personal interview. Studies on the validity of this method have shown that family history information on psychiatric disorders in relatives is neither accurate nor sensitive but highly specific. However, its inter-rater reliability has rarely been assessed, even though this is a prerequisite for adequate validity. In the present investigation we examined the inter-rater reliability of family history information obtained with a semi-structured and symptom-oriented interview. Forty informants were interviewed twice by two different raters within 3 and 20 days. The inter-rater reliability was found to be good for dementia (kappa=0.82, 95% CI=0.61-1.00), alcohol related disorders (kappa=0.93, 95% CI=0.80-1.00), for depressive disorders (kappa=0.72, 95% CI=0.42-1.00), anxiety disorders (kappa=0.75, 95% CI=0.41-1.00) and any psychiatric disorder (kappa=0.79, 95% CI=0.66-0.91). We concluded that the family history interview is a useful family study instrument that can be applied reliably by different raters for frequent psychiatric disorders.

Subthreshold depressive and anxiety disorders in the elderly.

The aims of the present study were to compare the current and lifetime prevalences for major and subthreshold affective disorders in elderly subjects in the general population, to assess the influence of demographic variables on prevalence rates, and to examine co-morbidity between these disorders. Major and subthreshold disorders were diagnosed in 286 subjects (aged >/= 60 years). Four-point-nine percent of the subjects had a lifetime diagnosis of major depression, 31.8% either minor or recurrent brief depression, 6.6% a major anxiety disorder, and 18.5% a subthreshold anxiety disorder. The risk for current and lifetime subthreshold anxiety was higher in females than in males, the lifetime prevalence for subthreshold anxiety disorders was increased in elderly subjects and subjects with low professional levels. Increased co-morbidity between major and subthreshold depressive and anxiety disorders could not be observed. In the elderly, subthreshold depressive and anxiety disorders are frequent, more so than major affective disorders. The presence of subthreshold anxiety disorders, but not subthreshold depression, is influenced by age, gender, and previous professional level. Further research focusing on detection, evaluation of risk factors and the relevance for the quality of life in the elderly general population is needed.

Advanced parental age: a risk factor for Alzheimer's disease or depression in the elderly?

BACKGROUND: Advanced parental age has been suggested as a risk factor for Alzheimer's disease (AD) as well as for other psychiatric disorders. In the present investigation, a sample of gerontopsychiatric patients was examined for a possible parental age effect. STUDY POPULATION AND METHODS: Eighty-three patients with AD, 154 elderly patients with depressive episodes, and 48 comorbid patients (AD and depressive episode) as well as 107 age-matched healthy control subjects from the general population were included in the investigation. Information on the years of birth of the parents was derived from personal or family history information. RESULTS: The mean maternal and paternal ages at the time of birth of the index subject were not significantly different for the different diagnostic subgroups or for the control sample. CONCLUSION: There was no evidence in our sample that advanced parental age increases the risk of AD or depression in the elderly.