Alzheimer Disease: Edwardson JA

Kalaria RN, Ballard CG, Ince PG, Kenny RA, McKeith IG, Morris CM, O'Brien JT, Perry EK, Perry RH, Edwardson JA. · MRC-Newcastle University Centre Development in Clinical Brian Ageing, Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Novartis Found Symp. · Pubmed #11280033 No free full text.

Abstract: Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Walker MP, Ayre GA, Perry EK, Wesnes K, McKeith IG, Tovee M, Edwardson JA, Ballard CG. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #11044778 No free full text.

Abstract: Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

Moore PB, Day JP, Taylor GA, Ferrier IN, Fifield LK, Edwardson JA. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #10705162 No free full text.

Abstract: Although chromosomal abnormalities underpin some early onset cases of familial Alzheimer's disease (AD), most cases are sporadic and not associated with such abnormalities. Aluminium (Al) is a significant but controversial risk factor for sporadic AD, and studies have reported associations between Al and the principal pathological features of AD, senile plaques and neurofibrillary tangles. The present study measured gastrointestinal (GI) absorption of Al under normal dietary conditions using (26)Al tracer and accelerator mass spectrometry (AMS). Following overnight fast, 13 AD patients (aged 63-76 years) and 13 age-matched controls (aged 62-76 years) ingested a fruit drink containing 27 ng (26)Al. Plasma samples were obtained before and 1 h after the drink and from these the fraction of (26)Al absorbed across the GI tract was estimated. The GI tract rigorously excludes Al with only 0.06-0.1% of the ingested Al being absorbed. The mean fraction absorbed by AD subjects exceeded controls by a factor of 1.64 (p</=0.05, Anova). AMS is capable of determining <10(-16) g of (26)Al with many orders of magnitude more sensitivity than other techniques. Using this sensitivity, we have shown, under normal physiological conditions, that the ability of the GI tract to exclude Al is reduced in AD, possibly leading to greater systemic exposure to Al. Public health measures to limit Al dietary uptake or bioavailability may decrease the prevalence of AD in the community and should be considered.

Elson JL, Herrnstadt C, Preston G, Thal L, Morris CM, Edwardson JA, Beal MF, Turnbull DM, Howell N. · Mitochondrial Research Group, School of Neurology, Neurobiology, and Psychiatry, The University of Newcastle upon Tyne, and Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Hum Genet. · Pubmed #16408223 No free full text.

Abstract: We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer's disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.

Vollbach H, Heun R, Morris CM, Edwardson JA, McKeith IG, Jessen F, Schulz A, Maier W, Kölsch H. · Department of Psychiatry, University of Bonn, Bonn, Germany. · Ann Neurol. · Pubmed #16130094 No free full text.

Abstract: Alterations in cholesterol homeostasis influence the risk for Alzheimer's disease (AD). Apolipoprotein A1 is the major apolipoprotein of the high-density lipoprotein and is involved in reverse cholesterol transport. Variation in the apolipoprotein A1 gene (APOA1) might influence the function of the protein, and thus brain cholesterol metabolism, leading to an increased risk for AD. Two polymorphisms of APOA1, a G/A substitution at position -75bp and a C/T and G/A base substitution at position +83bp or +84bp, or both, in the APOA1 promoter, have been described. We investigated the effect of these polymorphisms on the risk for AD in 427 AD patients and 500 healthy control subjects of German and English descent. The A allele of the APOA1 -75bp G/A polymorphism was associated with an increased risk for AD in subjects with an age at onset of 66 years or younger. Further data analysis indicated that AD patients homozygous for the A allele at position -75bp presented with disease onset 8 years earlier than carriers of at least one G allele. No influence of the +83/84bp polymorphism on the risk for AD was observed. These results suggest that variants of APOA1 might influence the onset and the risk for AD.

O'Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O'Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson JA, Morris CM, McKeith IG. · MRC Building, MRC/University of Newcastle Centre Development for Clinical Brain Ageing, Newcastle upon Tyne, NE1 3BZ, UK. · Pharmacogenetics. · Pubmed #12668920 No free full text.

Abstract: OBJECTIVES: To determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood. METHODS: We examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment. CONCLUSIONS: These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.

Singleton AB, Wharton A, O'Brien KK, Walker MP, McKeith IG, Ballard CG, O'Brien J, Perry RH, Ince PG, Edwardson JA, Morris CM. · Medical Research Council/University of Newcastle upon Tyne, Centre Development in Clinical Brain Ageing, MRC Building, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #12411758 No free full text.

Abstract: Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) epsilon4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the epsilon4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E epsilon4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast to previous studies, no association of the epsilon4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the epsilon4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the epsilon4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the epsilon4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO epsilon4 allele with AD as a common risk factor, but that there are differences in the way the epsilon4 allele affects the phenotypic expression of disease.

Hussain RI, Ballard CG, Edwardson JA, Morris CM. · MRC Building, Institute for the Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK. · Neurosci Lett. · Pubmed #11750985 No free full text.

Abstract: Genetic studies in Alzheimer's disease (AD), have indicated that the apolipoprotein E locus (APO E) is a major susceptibility factor, but that it can only account for approximately 50% of AD cases. Several other studies have attempted to identify additional genetic loci associated with disease development, often based on a candidate gene approach. As several lines of evidence indicate that oxidative stress and free radical damage occur in AD, the transferrin gene (TF) has been suggested as a candidate locus for AD since it is the major transport protein for iron, which itself is a major factor in free radical generation. Previous studies have shown elevated TF C2 allele frequencies in AD, this being specifically associated with carriers of the APO E varepsilon4 allele. We have therefore determined the influence of the common polymorphisms in TF, C1 and C2, in dementia. The frequency of the C2 allele was not significantly associated with AD. Stratification of cases according to the APO E varepsilon4 allele showed a highly significant excess of the C2 allele in AD cases without the varepsilon4 allele, contrasting with previous studies. Given the contrasting findings between reports of altered TF C2 allele frequencies, the TF locus would not appear to be a strong risk factor for AD in this population.

Singleton AB, Gibson AM, McKeith IG, Ballard CG, Edwardson JA, Morris CM. · CAMRC Building, Institute for the Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK. · Neurosci Lett. · Pubmed #11297817 No free full text.

Abstract: Evidence suggests that vascular and inflammatory components may be important in the aetiology of dementia and genetic risk factors affecting these processes may therefore influence disease development. Recently, polymorphisms in the endothelial constitutive nitric oxide synthase 3 (NOS3) and also the inducible nitric oxide synthase gene (NOS2A) have been suggested to lead to increased risk of Alzheimer's disease (AD) or dementia with Lewy bodies. We have studied the relationship of both these NOS gene polymorphisms to development of AD and dementia with Lewy bodies and find no evidence for association with either condition. We conclude that NOS gene polymorphisms do not alter disease risk in the majority of late-onset dementia cases.

Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM. · Department of Neurology, The University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #10908912 No free full text.

Abstract: ARTICLE ABSTRACT: The authors analyzed the relationship between nuclear genetic risk factors (apolipoprotein E genotype) and mitochondrial DNA (mtDNA) sequence variants in pathologically proved cases of AD (n = 185), dementia with Lewy bodies (DLB; n = 84), and control subjects (n = 179). Specific European mtDNA haplogroups and the A4336G mutation were not associated with an increased risk of AD. mtDNA haplogroup H was overrepresented in the DLB patients when compared with control subjects. Additional studies are needed to clarify the significance of the association.

Twist SJ, Taylor GA, Weddell A, Weightman DR, Edwardson JA, Morris CM. · MRC Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Westgate Road, University of Newcastle, NE4 6BE, Newcastle upon Tyne, UK. · Neurosci Lett. · Pubmed #10822138 No free full text.

Abstract: Epidemiological studies indicate that oestrogen improves memory and may delay the onset of Alzheimer's disease (AD) in postmenopausal women. Furthermore, evidence from experimental studies suggests beneficial effects of oestrogen on several pathogenic mechanisms implicated in AD. We have therefore measured the levels of oestradiol and testosterone in control and AD brains. The results show that in control brain, oestradiol levels are 3.5 fold higher in females than males, though testosterone levels are equivalent. In AD, oestradiol levels were not significantly increased compared to those in control brain, while testosterone levels were unaffected in AD. The results do not support the hypothesis that a lack of oestrogen is a contributory factor in AD.

Gibson AM, Singleton AB, Smith G, Woodward R, McKeith IG, Perry RH, Ince PG, Ballard CG, Edwardson JA, Morris CM. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neurology. · Pubmed #10668708 No free full text.

Abstract: OBJECTIVE: Analysis of AD has revealed that the apolipoprotein E locus (APOE) cannot account for all of the genetic risk associated with AD. Whole genome scanning in AD families suggests that a chromosome 12 locus may contribute significantly to disease development. The alpha2-macroglobulin gene (A2M) has been suggested as a candidate locus for AD based on analysis of familial AD. METHOD: We determined, in 195 neuropathologically verified AD cases and 107 age-matched control subjects, the association of two common polymorphisms in A2M (a pentanucleotide deletion 5' to the bait domain exon, and a valine-1000-isoleucine polymorphism in the thiolester site of the protein). RESULTS: Evidence was observed for linkage disequilibrium between the deletion and Ile1000 polymorphisms. No evidence was observed for an association between the thiolester polymorphism and AD alone or when accounting for the APOE-epsilon4 allele. No alteration in the frequency of the bait domain deletion was observed, although a small excess (4%) of deletion homozygotes was found in the AD group, which were absent in the control population. CONCLUSIONS: The A2M deletion polymorphism at most accounts for a small fraction of the genetic contribution toward AD, and this is small compared with APOE. Furthermore, reverse transcriptase PCR of A2M RNA from the brains of patients homozygous for the deletion polymorphism showed that the bait domain exon still is present in the RNA. This suggests that the A2M deletion polymorphism may be nonfunctional and that the chromosome 12 AD locus is situated elsewhere.

Neill D, Curran MD, Middleton D, Mawhinney H, Edwardson JA, McKeith I, Ballard C, Morris C, Ince P, Jaros E, Perry R. · Institute For The Health Of The Elderly, Newcastle General Hospital, Newcastle Upon Tyne, UK. · Neurosci Lett. · Pubmed #10568518 No free full text.

Abstract: The allele frequency of the HLA-DRB1 gene was compared between groups of 48 clinically diagnosed elderly Alzheimer's disease (AD) cases and 44 pathologically confirmed elderly control cases. Specific primers were used to PCR amplify the highly polymorphic second exon of HLA-DRB1 using DNA extracted from blood samples or frozen brain tissue. The allele type was identified using sequence specific oligonucleotide probes. The results showed an increased frequency of DRB1*03 (P < 0.006) and decreased frequency of DRB1*09 (P < 0.049) in the AD cases compared with the controls. The results suggest that DRB1*03 is associated with an increased risk and DRB1*09 a possible decreased risk for the development of late-onset AD with first detectable clinical symptoms occurring at age 75 years or greater.

Singleton AB, Gibson AM, McKeith IG, Ballard CA, Perry RH, Ince PG, Edwardson JA, Morris CM. · MRC Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neuroreport. · Pubmed #10380971 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second most common cause of dementia in the elderly after Alzheimer's disease (AD). The apolipoprotein E gene (APOE) is a major risk factor, but can only account for approximately 50% of AD cases. Whole genome scanning in late-onset AD families has suggested that a locus on chromosome 12 may contribute significantly to disease development. Recently the alpha2-macroglobulin gene (A2M) on chromosome 12 has been suggested as a candidate locus for AD. We therefore determined the influence of two polymorphisms in A2M, a pentanucleotide deletion 5' to the bait domain exon, and a valine to isoleucine polymorphism in the thiolester site of the protein, in AD and DLB cohorts. No evidence was observed for an association between the thiolester or deletion polymorphisms and AD or DLB alone or when accounting for the APOE epsilon4 allele. We did, however, identify a non-significant excess of deletion homozygotes in the AD and DLB groups. This genotype accounted for 4% of disease cases but was absent in the control population. Given that the A2M deletion polymorphism is non-functional, the chromosome 12 AD/DLB locus may be situated elsewhere and not with these A2M polymorphisms.

Atkinson A, Singleton AB, Steward A, Ince PG, Perry RH, McKeith IG, Fairbairn AF, Edwardson JA, Daly AK, Morris CM. · Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Pharmacogenetics. · Pubmed #10208640 No free full text.

Abstract: The similarities between the clinical and pathological findings of dementia with Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex, and their significance for pathogenesis is unresolved. It is likely that DLB shares common disease determinants with both Alzheimer's disease and Parkinson's disease. Clinically DLB shows the presence of dementia similar, though not identical, to that found in Alzheimer's disease. A parkinsonian movement disorder is present in a proportion of DLB cases. Pathologically DLB shows senile plaques, as with Alzheimer's disease, and also substantia nigra neurone loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's disease, but this is absent in Parkinson's disease. An elevated frequency of the CYP2D6*4 allele has been found in Parkinson's disease and we have therefore genotyped a large series of clinically and neuropathologically confirmed cases of DLB, Alzheimer's disease, Parkinson's disease and age-matched control individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with respect to the Apolipoprotein E epsilon4 also did not show any significant associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major genetic determinant of DLB and the results place DLB with Alzheimer's disease rather than Parkinson's disease on a genetic level.

Middleton D, Mawhinney H, Curran MD, Edwardson JA, Perry R, McKeith I, Morris C, Ince PG, Neill D. · Northern Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, UK. · Neurosci Lett. · Pubmed #10203251 No free full text.

Abstract: The frequency of various allele types of the class I Major Histocompatibility Complex (MHC) genes HLA-A and HLA-B were compared between pathologically confirmed groups of late and early-onset Alzheimer's disease (AD) and a control group. DNA was extracted from frozen brain tissue and the highly polymorphic second and third exons of the HLA-A and HLA-B genes were independently PCR amplified using specific primers. Individual allele types were identified using sequence-specific oligonucleotide probes. The results showed that the main frequency differences occurred between the late-onset AD and the control group however none of these reached statistical significance.