Alzheimer Disease: Xuereb J

Mukaetova-Ladinska EB, Milne J, Andras A, Abdel-All Z, Cerejeira J, Greally E, Robson J, Jaros E, Perry R, McKeith IG, Brayne C, Xuereb J, Cleghorn A, Doherty J, McIntosh G, Milton I. · Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #18577885 No free full text.

Abstract: BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, Patterson K, Hodges JR. · Department of Clinical Neurosciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. · Brain. · Pubmed #17898010 links to  free full text

Abstract: To determine the frequency of Alzheimer's disease (AD) pathology in patients presenting with progressive focal cortical syndromes, notably posterior cortical atrophy (PCA), corticobasal syndrome (CBS), behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) (or a mixed aphasia) and semantic dementia (SD); and to compare the age of onset, evolution and prognosis in patients with focal cortical presentations of AD versus more typical AD and those with non AD pathology. From a total of 200 patients with comprehensive prospective clinical and pathological data we selected 120 : 100 consecutive cases with focal cortical syndromes and 20 with clinically typical AD. Clinical files were reviewed blind to pathological diagnosis. Of the 100 patients with focal syndromes, 34 had AD as the primary pathological diagnosis with the following distribution across clinical subtypes: all 7 of the PCA (100%); 6 of 12 with CBS (50%); 2 of 28 with bvFTD (7.1%); 12 of 26 with PNFA (44.1%); 5 of 7 with mixed aphasia (71.4%) and 2 of 20 with SD (10%). Of 20 with clinically typical AD, 19 had pathological AD. Age at both onset and death was greater in the atypical AD cases than those with non-AD pathology, although survival was equivalent. AD is a much commoner cause of focal cortical syndromes than previously recognised, particularly in PCA, PNFA and CBS, but rarely causes SD or bvFTD. The focal syndrome may remain pure for many years. Patients with atypical AD tend to be older than those with non-AD pathology.

Cook LJ, Ho LW, Wang L, Terrenoire E, Brayne C, Evans JG, Xuereb J, Cairns NJ, Turic D, Hollingworth P, Moore PJ, Jehu L, Archer N, Walter S, Foy C, Edmondson A, Powell J, Lovestone S, Williams J, Rubinsztein DC. · Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #15690550 No free full text.

Abstract: Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.

Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM. · Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2XY, UK. · Neurosci Lett. · Pubmed #15644277 No free full text.

Abstract: Divalent cations are strongly implicated in Alzheimer's disease (AD) pathogenesis, and can regulate amyloid beta-peptide aggregation. The proton-divalent cation transporters encoded by SLC11A1 (formerly NRAMP1) on chromosome 2q35, and SLC11A2 (also known as DCT1 and DMT1) on chromosome 12q13, are expressed in the brain and regulate ion homeostasis from endosomal compartments. SLC11A1 also has pleiotropic effects on pro-inflammatory responses that may be important in AD. We analyzed seven informative polymorphisms in the SLC11A1 and SLC11A2 genes encoding these divalent cation transporters in a sample of 216 late-onset AD cases and 323 age-matched controls. We found only borderline evidence (p=0.08) for an allelic association between SNP rs407135 at SLC11A2 and AD, in which the variant allele was protective (odd ratio (OR) 0.77; 95% CI 0.56-1.04) relative to the more common allele. There was no interaction with apolipoprotein E (APOE) varepsilon4, but stratification by gender showed that all of the effect of SLC11A2 was in the male patient group. No other associations with AD were observed at SLC11A1 or SLC11A2, indicating no major effect of either gene for the occurrence of AD.

Cook LJ, Ho LW, Taylor AE, Brayne C, Evans JG, Xuereb J, Cairns NJ, Pritchard A, Lemmon H, Mann D, St Clair D, Turic D, Hollingworth P, Moore PJ, Jehu L, Archer N, Walter S, Foy C, Edmondson A, Powell J, Lovestone S, Owen MJ, Williams J, Lendon C, Rubinsztein DC. · Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. · Neurosci Lett. · Pubmed #15026168 No free full text.

Abstract: Consistent deficits in the cholinergic system are evident in Alzheimer's disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.

Taylor A, Ezquerra M, Bagri G, Yip A, Goumidi L, Cottel D, Easton D, Evans JG, Xuereb J, Cairns NJ, Amouyel P, Chartier-Harlin MC, Brayne C, Rubinsztein DC. · Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK. · Am J Med Genet. · Pubmed #11803527 No free full text.

Abstract: Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin-angiotensin-aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy-confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk.

Harasty JA, Halliday GM, Xuereb J, Croot K, Bennett H, Hodges JR. · Prince of Wales Medical Research Institute, Randwick, Sydney, Australia. · Neurology. · Pubmed #11294934 No free full text.

Abstract: OBJECTIVE: To compare the pattern of cortical degeneration associated with different language deficits in cases of AD. METHODS: Cases for detailed neuropathologic analysis (Patients 1 and 2) were selected because of their detailed clinical and neuropsychological assessments of language dysfunction in AD. Patient 1 had severe phonologic impairment with relatively preserved semantic aspects of language. Patient 2 had severe semantic language impairment with relatively preserved phonologic skills. The tissue volume of cortical regions associated with speech and language function was measured using standardized three-dimensional techniques. Neuronal areal fraction was also measured from histologic tissue samples. The degree of volume atrophy and neuronal loss was calculated in comparison to control measures (n = 10 men and 11 women). Measurements more than 2 SD from controls were considered abnormal. RESULTS: Both AD cases had significant degeneration of the superior temporal gyrus and area 37. Cortical language regions affected only in Patient 1 included the anterior and posterior insula and part of Broca's area. In contrast, Patient 2 had a greater degree of degeneration in the temporal gyri and their white matter connections with the hippocampal/entorhinal complex. CONCLUSIONS: Variable patterns of neurodegeneration underlie the clinical differences observed in patients with AD. Disconnection within the temporal lobe appears associated with semantic language difficulties, whereas disconnection of the anterior and posterior language areas appears associated with phonologic and grammatical impairment.

Taylor AE, Yip A, Brayne C, Easton D, Evans JG, Xuereb J, Cairns N, Esiri MM, Rubinsztein DC. · Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. · J Med Genet. · Pubmed #11283204 links to  free full text

Abstract: OBJECTIVES: The only locus unequivocally associated with late onset Alzheimer's disease (AD) risk is APOE. However, this locus accounts for less than half the genetic variance. A recent study suggested that the A allele of the 3'UTR biallelic polymorphism in the LBP-1c/CP2/LSF gene was associated with reduced AD risk. Samples were diagnosed predominantly by clinical rather than pathological criteria. We have sought to replicate this finding in a series of necropsy confirmed, late onset AD cases and non-demented controls. METHODS: The 3'UTR polymorphism in the LBP-1c/CP2/LSF gene was typed in 216 necropsy confirmed AD cases and 301 non-demented controls aged >73 years. RESULTS: We found different LBP-1c/CP2/LSF allele distributions in our AD cases and controls (p=0.048); the A allele was associated with reduced AD risk. The allele and genotype frequencies observed in our cases and controls were similar to those previously reported. No significant effects emerged when the data were adjusted for age, sex, or apoE epsilon4 carrier status. CONCLUSIONS: Our data support LBP-1c/CP2/LSF as a candidate gene/risk factor for AD and provide justification for future studies to investigate the role of this gene in Alzheimer's disease.

Murphy T, Yip A, Brayne C, Easton D, Evans JG, Xuereb J, Cairns N, Esiri MM, Rubinsztein DC. · Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, UK. · Neuroreport. · Pubmed #11234778 No free full text.

Abstract: Alzheimer's disease (AD) pathology is characterized by beta-amyloid plaques and neurofibrillary tangles. Studies of autosomal dominant early-onset AD mutations suggest that beta-amyloid overproduction is sufficient to cause AD. Recently, the BACE gene, which encodes beta-secretase, the rate limiting enzyme in beta-amyloid formation, has been identified. Since this gene is a strong candidate gene for late-onset AD because of its function, we have characterized its genomic organization and identified two polymorphisms. Neither of these polymorphisms were associated with AD risk in genetic association studies comparing autopsy-confirmed late-onset AD cases and age-matched non-demented controls. Thus, we find no evidence that this locus influences risk for late-onset AD.

Lehmann DJ, Wiebusch H, Marshall SE, Johnston C, Warden DR, Morgan K, Schappert K, Poirier J, Xuereb J, Kalsheker N, Welsh KI, Smith AD. · Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford OX1 3QT, UK. · Neurobiol Aging. · Pubmed #11164278 No free full text.

Abstract: We first examined all the then known alleles (1997) at the HLA-A, B, Bw, C, DRB1, 3, 4 and 5, and DQB1 loci in 55 late-onset (>65y) AD cases and 73 elderly controls from Oxford. We found an association of HLA-B7 with late-onset AD (odds ratio = 3.1, corrected P = 0.04) that was limited to apolipoprotein E epsilon4-negative subjects (odds ratio = 5.1, corrected P = 0.005). We then studied linkages with Class III genes and, finally, we sought to replicate our HLA-B7 result in cohorts from Montreal and Nottingham. Altogether, we used 299 histopathologically confirmed cases of late-onset AD and 175 controls. Our initial, clear finding was not replicated in Montreal and Nottingham, however. We also failed to support any other previously reported association of AD with an HLA gene. Though we cannot exclude distinct linkages in different cohorts as an explanation of the conflicting results of HLA/AD studies, we conclude that there is no compelling evidence of a strong, direct association between late-onset AD and any HLA Class I or II allele.

Croot K, Hodges JR, Xuereb J, Patterson K. · Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom. · Brain Lang. · Pubmed #11049669 No free full text.

Abstract: We demonstrate that phonological and articulatory impairments may occur at presentation or early in the course of Alzheimer's disease, contrary to claims that these aspects of language production are relatively preserved until the final stages of this disease. Six patients with pathologically confirmed Alzheimer's disease (AD) and four patients with clinically diagnosed dementia of the Alzheimer's type (DAT) presented with one of five different clinical profiles: nonfluent progressive aphasia, mixed progressive aphasia, progressive aphasia diagnosed as DAT from neuropsychological assessment, initial amnestic syndrome with prominent phonological errors, and biparietal syndrome. Analysis of their conversational speech, single-word production, and performance of highly familiar series speech tasks such as counting revealed false start errors, phonological paraphasias, and/or articulatory difficulty. Neuropathological changes were located in left perisylvian regions consistent with speech and language impairment but atypical for Alzheimer's disease.

Narain Y, Yip A, Murphy T, Brayne C, Easton D, Evans JG, Xuereb J, Cairns N, Esiri MM, Furlong RA, Rubinsztein DC. · Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. · J Med Genet. · Pubmed #10978362 links to  free full text

Abstract: A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE epsilon4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33, 95% CI=1.14-1.53, p=0.0002).

Mukaetova-Ladinska EB, Hurt J, Jakes R, Xuereb J, Honer WG, Wischik CM. · Department of Psychiatry, University of Cambridge Clinical School, United Kingdom. · J Neuropathol Exp Neurol. · Pubmed #10888371 No free full text.

Abstract: Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.

Dahiyat M, Cumming A, Harrington C, Wischik C, Xuereb J, Corrigan F, Breen G, Shaw D, St Clair D. · Department of Mental Health, University of Aberdeen Medical School, UK. · Ann Neurol. · Pubmed #10514107 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder of later life. Genetic studies have demonstrated that the apolipoprotein E (ApoE) gene is an important susceptibility locus; however, other environmental and genetic factors operating alone or in combination with ApoE must also be involved. Among candidate genes that may contribute to this residual risk is the endothelial nitric oxide synthase (NOS3) gene. NO release from vascular endothelium accounts in large part for endothelium-derived relaxing factor bioactivity. Abnormalities of cerebral small vessels occur early in AD, and it has been demonstrated recently that beta-amyloid interacts with endothelial cells in blood vessels to produce an excess of superoxide radicals. We have genotyped 122 cases of early-onset AD (EOAD) and 317 cases of late-onset AD (LOAD) as well as 392 controls for a common structural polymorphism Glu/Asp at codon 298 in the NOS3 gene. We find a highly significant enrichment for Glu/Glu homozygotes in LOAD compared with controls. The effect appears to be independent of ApoE status. NOS3 may be a new genetic risk factor for LOAD.

Tilley L, Morgan K, Grainger J, Marsters P, Morgan L, Lowe J, Xuereb J, Wischik C, Harrington C, Kalsheker N. · Division of Clinical Chemistry, School of Clinical Laboratory Sciences, University Hospital, Queen's Medical Centre, Nottingham, UK. · Eur J Hum Genet. · Pubmed #10482954 links to  free full text

Abstract: The E4 allele of the apolipoprotein E gene (APOE) is a major risk factor for late-onset Alzheimer's disease (LOAD) but is neither necessary nor sufficient to cause the disease. In this study, we investigated polymorphisms in the presenilin-1 (PS-1), and butyrylcholinesterase (BChE) genes, which have been implicated as risk factors for LOAD. Our data-set comprised 177 AD and 118 control patients, all of whom had been histopathologically confirmed following autopsy. We have tested homozygosity for the PS-1 allele 1 and possession of the BChE-K variant in association with APOE epsilon4 as risk factors in LOAD. Our findings support an association between the PS-1 polymorphism and LOAD, finding homozygosity for allele 1 associated with an approximately two-fold increased risk. Our data also show that in subjects greater than 75 years of age possession of both BChE-K and APOE-epsilon4 alleles is associated with an increased risk of LOAD, whilst the risk associated with APOE-epsilon4 allele alone is not significant.

Cook L, Brayne CE, Easton D, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC. · No affiliation provided · Ann Neurol. · Pubmed #12402275 No free full text.

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Dow DJ, Lindsey N, Cairns NJ, Brayne C, Robinson D, Huppert FA, Paykel ES, Xuereb J, Wilcock G, Whittaker JL, Rubinsztein DC. · No affiliation provided · Nat Genet. · Pubmed #10319853 No free full text.

This publication has no abstract.