Magdalini Tsolaki

Relationship between Helicobacter pylori infection and Alzheimer disease

The authors investigated the association between Helicobacter pylori infection (Hp-I) and Alzheimer disease (AD) by using histology for diagnosis of Hp-I. Fifty patients with AD and 30 iron deficiency anemic control participants without AD were included. The histologic prevalence of Hp-I was 88% in patients with AD and 46.7% in controls (p < 0.001).

ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease

Increased formation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimers disease (AD). High cellular cholesterol load promotes Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.

Age and diagnostic performance of Alzheimer disease CSF biomarkers

Objectives: Core CSF changes in Alzheimer disease (AD) are decreased amyloid β1–42, increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. Methods: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43–89 years) and 304 controls (67, 44–91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43–89 years) followed for at least 2 years, or until dementia diagnosis. Results: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. Conclusion: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

The Role of Apolipoprotein E in Cognitive Decline and Delirium after Bypass Heart Operations

Cognitive decline and delirium are common complications after heart bypass surgery. Based on the reported role of the APOE-ε4 allele in neurodegenerative diseases, we studied its association with these complications. A neuropsychological test battery consisting of the Mini Mental State Examination, the Wechslers Memory Scale Revised, the Brief Psychiatric Rating Scale, and the Delirium Rating Scale was applied to 137 APOE-genotyped patients on admission and 1 month after bypass surgery. We correlated the APOE (apolipoprotein E) polymorphism with the postoperative test outcome by taking into account all factors known to influence cognitive capacity after heart surgery. There was a significant decline in all test results 1 month after surgery and a high frequency of postoperative delirium. Neither this decline nor the frequency of delirium was associated with the APOE-ε4 allele. This study confirms the high incidence of cognitive decline and delirium after coronary surgery, but it does not support the role of the APOE-ε4 allele in the occurrence of these complications.

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease

A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of β-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimers disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4–0.8).

Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease.

There is an urgent need for the identification of Alzheimer’s disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10–0.48, P=4.19E−04; ChE 34:0, OR=0.152, 95% CI=0.05–0.37, P=2.90E−04; ChE 34:6, OR=0.126, 95% CI=0.03–0.35, P=5.40E−04; ChE 32:4, OR=0.056, 95% CI=0.01–0.24, P=6.56E−04 and ChE 33:6, OR=0.205, 95% CI=0.06–0.50, P=2.21E−03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.

Cholesterol 25-Hydroxylase on Chromosome 10q Is a Susceptibility Gene for Sporadic Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5′ region of CH25H revealed three common haplotypes, CH25Hχ2, CH25Hχ3 and CH25Hχ4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hχ4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain Aβ deposits in carriers of CH25Hχ4 and CH25Hχ3 haplotypes, whereas no Aβ deposits were present in CH25Hχ2 carriers. Together, these results are compatible with a role of CH25Hχ4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain Aβ deposition.

Association study of cholesterol-related genes in Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples.

Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease

A recent study demonstrated a significant genetic association between the ATP‐binding cassette transporter A2 (ABCA2) and the risk for Alzheimers disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early‐onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population‐dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.

Saitohin gene is not associated with Alzheimer’s disease

Background: The deposition of tau protein in neurofibrillary tangles constitutes an important feature of many neurodegenerative disorders, including Alzheimer’s disease. A polymorphic gene, saitohin (STH), nested within the tau gene (microtubule associated protein tau, MAPT), was recently identified and an association of a non-synonymous polymorphism in STH with increased risk for Alzheimer’s disease was suggested. Objective and methods: To test the above hypothesis in a case–control association study of two independent white populations within Switzerland and Greece, comparing genotype and allele frequencies from 225 Alzheimer’s disease patients and 144 healthy control subjects. Results: No differences in allelic or genotypic distributions between Alzheimer’s disease patients and controls was found in the individual samples (Swiss/Greek) or in the combined sample. Stratification for the presence of apolipoprotein E (APOE) ε4 allele, sex, or age did not show significant effects in the populations studied, nor was there an effect on the age of onset. Conclusions: No evidence was found for an association of the non-synonymous polymorphism (Q7R) in STH and Alzheimer’s disease. This finding is in line with earlier studies showing no association between MAPT and Alzheimer’s disease.