Ulrike Mann

INCREASED LIPOPROTEIN OXIDATION IN ALZHEIMER'S DISEASE

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimers disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

High Prevalence of Pathogenic Mutations in Patients with Early-Onset Dementia Detected by Sequence Analyses of Four Different Genes

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer’s disease

Because increased oxidation is an important feature of Alzheimers disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.

Depression in Alzheimer’s Disease Might Be Associated with Apolipoprotein E ε4 Allele Frequency in Women but Not in Men

The association between depression and apolipoprotein E (apoE) was investigated in 137 out-patients with Alzheimer’s disease. An ICD-10 diagnosis of depression was found in 21.1% of all patients. There was a good correlation between clinicians’ diagnoses and blinded rating by the Montgomery-Åsberg Depression Rating Scale (r = 0.70). In male patients, apoE 3/3 was detected in 34.1%, 3/4 in 38.6%, 4/4 in 13.6%, 2/4 in 6.8% and 2/3 in 6.8% of cases. In female patients, apoE 3/3 was detected in 35.5%, 3/4 in 45.2%, 4/4 in 12.8%, 2/4 in 3.2% and 2/3 in 3.2% of cases. When analyzing the variance of gene dosage effect, the frequency of the apoE Ε4 allele was significantly increased in depressed women but not in men. This effect remained stable in stepwise regression analysis when depression as the dependent variable was tested against the independent variables age, age of onset, duration of disease, cognitive status and years of school education.

High Frequency of Mutations in Four Different Disease Genes in Early‐Onset Dementia

Abstract: Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early‐onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH‐patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.

Reply to Croes et al.

To the Editor:Croes et al. (2000xCroes, EA, Dermaut, B, van der Cammen, C, van Broeckhove, C, and van Duijn, CM. Genetic testing should not be advocated as a diagnostic tool in familial forms of dementia. 2000; 67: 1033–1035See all References2000 [in this issue]) make the point that genetic testing as a diagnostic tool shows poor performance in differential diagnosis in general medical practice. We fully agree with this comment. Therefore, one of the goals of our study (Finckh et al. 2000xHigh prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Finckh, U, Muller-Thomsen, T, Mann, U, Eggers, C, Marksteiner, J, Meins, W, Binetti, G, Alberici, A, Hock, C, Nitsch, RM, and Gal, A. Am J Hum Genet. 2000; 66: 110–117Abstract | Full Text | Full Text PDF | PubMed | Scopus (131)See all References2000) was to establish criteria that would increase the chance of identifying a pathogenic mutation in the setting of a specialized clinic. Indeed, among patients who had both onset at an early age and positive family history for early-onset dementia (EOD), diagnostic sequencing identified disease-relevant mutations in >50% of the patients analyzed by us. Another notable result of our study was the finding of four prion mutations among the 36 EOD patients, which suggested that atypical forms of prion disease may remain underdiagnosed. This assumption is supported by independent observations, such as those made by two coauthors of the letter by Croes et al. (2000xCroes, EA, Dermaut, B, van der Cammen, C, van Broeckhove, C, and van Duijn, CM. Genetic testing should not be advocated as a diagnostic tool in familial forms of dementia. 2000; 67: 1033–1035See all References2000), who found a PRNP insertion mutation in a patient with both prion disease and ante mortem diagnosis of familial Alzheimer disease (FAD) (Dermaut et al. 1998xSee all References1998).We agree with Croes et al. that assessment of the relevance of previously unknown mutations is a difficult issue. Nonetheless, in recent screening studies of FAD, 72%–83% of the sequence changes corresponded to pathogenic mutations already reported (Kamimura et al. 1998xFamilial Alzheimers disease genes in Japanese. Kamimura, K, Tanahashi, H, Yamanaka, H, Takahashi, K, Asada, T, and Tabira, T. J Neurol Sci. 1998; 160: 76–81Abstract | Full Text | Full Text PDF | PubMed | Scopus (28)See all References1998; Campion et al. 1999xEarly-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Campion, D, Dumanchin, C, Hannequin, D, Dubois, B, Belliard, S, Puel, M, Thomas-Anterion, C, Michon, A, Martin, C, Charbonnier, F, Raux, G, Camuzat, A, Penet, C, Mesnage, V, Martinez, M, Clerget-Darpoux, F, Brice, A, and Frebourg, T. Am J Hum Genet. 1999; 65: 664–670Abstract | Full Text | Full Text PDF | PubMed | Scopus (357)See all References1999). In our study, 58% of the mutations had been previously described by others. Repeated identification of any given rare mutation in a rare disorder, together with the absence of the mutation in control probands, significantly increases the likelihood that it has causative effects.We were pleased to see that Croes et al. agree with our conclusion that E318G in PS1 is a nonpathogenic polymorphism and that they reemphasize the importance of a careful and critical analysis of the literature. The importance of early and disease-specific diagnosis of EOD as a way of identifying treatable forms of dementia is an issue separate from our assertion that diagnostic sequencing of the four known EOD genes may provide important information for proper clinical and genetic counseling in the early phases of the disorder.