Alzheimer Disease: Lovestone S

Lovestone S, Hardy J. · No affiliation provided · Neurology. · Pubmed #12105301 No free full text.

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Lovestone S. · No affiliation provided · Neurology. · Pubmed #10599757 No free full text.

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Hooper C, Killick R, Lovestone S. · King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, UK. · J Neurochem. · Pubmed #18088381 No free full text.

Abstract: Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline-directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD), an observation that has led us to coin the 'GSK3 hypothesis of AD'. According to this hypothesis, over-activity of GSK3 accounts for memory impairment, tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated microglial-mediated inflammatory responses; all of which are hallmark characteristics of AD. If our 'GSK3 hypothesis of AD' is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.

Lovestone S, Francis P, Strandgaard K. · S. Lovestone, NIHR Biomedical Research Centre, South London and Maudsley NHS Trust and King's College London, London SE5 8AF, UK. · J Nutr Health Aging. · Pubmed #17653500 No free full text.

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Lovestone S, Güntert A, Hye A, Lynham S, Thambisetty M, Ward M. · Institute of Psychiatry, MRC Centre for Neurodegeneration Research and NIHR Biomedical Research Centre, KCL, London, UK. · Expert Rev Proteomics. · Pubmed #17425458 No free full text.

Abstract: Alzheimer's disease is the scourge of the modern, aging world: a costly, damaging disease that robs the elderly of their ability to function as well as their memories. Three decades of progress have resulted in a deep understanding of the pathological processes and a range of targets for therapy, many of which have advanced to late-stage clinical trials. Proteomics has contributed greatly to these advances and will continue to have a growing role in determining the nature of the pathological lesions in the brain. In addition, proteomics (both gel based and gel free, mass spectrometry based), is likely to play an increasing role in identifying biomarkers that may assist in early diagnosis and in monitoring progression and, most importantly, response to therapy.

Blacker D, Lovestone S. · Department of Psychiatry, Mass General Hospital/Harvard Medical School, Boston, MA, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16880361 No free full text.

Abstract: In preparation for the development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed), the American Psychiatric Association convened workshops reviewing scientific evidence relevant to diagnosis of dementia. One of the domains covered was genetics, which is reviewed here. The following areas are reviewed: genetic data on Alzheimer's disease and other dementias; the impact of nosology on genetic research in terms of its potential to improve diagnostic sensitivity and specificity and to decrease heterogeneity; the impact of genetic research findings on nosology, specific diagnostic criteria, and subtypes; and recommendations and future directions. The focus is on Alzheimer's disease, where more genetic data are available, and other dementias are reviewed more briefly. In addition, a separate section reviews the relationship of genetic findings and mild cognitive impairment, a boundary zone between normal aging and dementia, particularly Alzheimer's disease.

Ritchie K, Lovestone S. · Institut National de la Santé et de la Recherche Médicale, EMI 99-30, Hôpital La Colombière, Montpellier, France. · Lancet. · Pubmed #12480441 No free full text.

Abstract: Dementia affects about 5% of the elderly population over age 65 years and has an unexplained predominance in women and a low rate in some cultures. Different forms of dementia are now distinguished-Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and dementia secondary to disease, such as AIDS dementia. However, such nosological boundaries are being re-evaluated because different dementias are believed to have common underlying neuropathology. Neurochemical and neurobiological research has led to advances in understanding causes of dementia, and functional imaging has allowed identification of possible biomarkers; from these, a range of potential treatment approaches have arisen that focus on enhancement of neurotransmitter function, intervention at the level of amyloid production and deposition, and reduction of secondary risk factors such as hypertension, depression, and hypolipidaemia. Molecular diagnostic testing and genetic counselling for families with autosomal dominant early-onset dementia are new developments; however, this approach is not useful for late-onset dementia, in which the identified candidate susceptibility genes have a relatively small effect on risk. While fundamental research works towards new biological treatment strategies, much remains to be done in the area of disease management and the development of appropriate models of long-term care.

Mudher A, Lovestone S. · Depts of Neuroscience and Psychological Medicine, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK. · Trends Neurosci. · Pubmed #11801334 No free full text.

Abstract: The amyloid cascade hypothesis has been the predominant model of molecular pathogenesis in Alzheimer's disease. The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process. However, some observations remain difficult to reconcile with the hypothesis. In transgenic mice, for example, amyloid generation does not induce the predicted cascade and in man, plaques and tangles are separated temporally and spatially. One alternative possibility is that some common factor, loss of wnt signalling for example, might induce both plaques and tangles.

Lovestone S, McLoughlin DM. · Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #11796764 links to  free full text

Abstract: This review considers some of the recent advances made in the understanding of the pathogenic proteins known to aggregate and be implicated in neurodegenerative dementing disorders. It concentrates on the two most obvious candidates for the role of toxic protein in Alzheimer's disease (AD)--beta-amyloid peptide and tau--but also considers other proteins in this disorder and in less common but equally devastating diseases.

Lovestone S, Anderton B, Betts J, Dayanandan R, Gibb G, Ljungberg C, Pearce J. · Department of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, U.K. · Biochem Soc Symp. · Pubmed #11447827 No free full text.

Abstract: The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles. In this chapter we will review the evidence for and against an interaction between ApoE and the neuronal cytoskeleton, in particular with the microtubule-associated protein tau.

Liddell MB, Lovestone S, Owen MJ. · Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK. · Br J Psychiatry. · Pubmed #11136203 links to  free full text

Abstract: BACKGROUND: Clinicians are increasingly asked by relatives of patients with Alzheimer's disease to advise on their genetic risk of developing Alzheimer's disease in later life. Many clinicians find this a difficult question to answer. AIMS: To provide information for old age psychiatrists wishing to advise relatives of their risk of developing Alzheimer's disease. METHOD: A selective review of the key literature on the genetic epidemiology of Alzheimer's disease. RESULTS: Currently a DNA diagnosis is attainable in some 70% of families with autosomal dominant Alzheimer's disease. In first-degree relatives of most cases, risk is increased some three- or four-fold relative to controls, but only one-third of this is realised in the average life span. Apolipoprotein E genotyping cannot be used as a predictive test and confers only minimal diagnostic benefit. CONCLUSIONS: Pedigrees with familial Alzheimer's disease should be referred to a Regional Centre for Medical Genetics. Accurate risk prediction is not possible in the vast majority of pedigrees with Alzheimer's disease, although it is possible for the psychiatrist to give a rough estimate of the risk, which can reasonably the couched in reassuring terms.

Lovestone S. · Institute of Psychiatry, London, UK. · J Neurol. · Pubmed #10195399 No free full text.

Abstract: Alzheimer's disease (AD) has a significant genetic background manifested as autosomal dominant inheritance in some early-onset families and as familial risk in late-onset cases. Three genes responsible for early-onset autosomal dominant AD have been identified, and one gene, apolipoprotein E, has been confirmed as a susceptibility gene for late-onset forms of the disorder. These findings raise the possibility of genetic testing, either for early diagnosis or prediction. For early-onset autosomal dominant AD genetic testing will have a limited but useful role in confirming diagnosis in established cases and in predictive counselling for relatives; a situation analogous to that for Huntington's disease. For late-onset AD significant problems remain to be overcome before the advances in molecular genetics have a direct clinical application

Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. · NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley Foundation NHS Trust and the MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK. · Int J Geriatr Psychiatry. · Pubmed #18181229 No free full text.

Abstract: OBJECTIVE: To assess the safety and feasibility of prescribing long term lithium to elderly people with mild to moderate Alzheimer's disease (AD). METHODS: An open label treatment group with low dose lithium for up to 1 year with the Lithium Side Effects Rating Scale as the primary outcome measure. A comparison group matched for cognition and age not receiving lithium therapy. RESULTS: Twenty-two people with AD initiated lithium. Fourteen participants discontinued therapy after a mean of 16 weeks of treatment compared to the 39 weeks for those continuing to take treatment at the end of the study. Three patients discontinued treatment due to possible side effects that abated on ceasing therapy. The reports of side effects on the primary outcome scale did not differ between those discontinuing therapy and those remaining in the study. Two patients died whilst receiving lithium--in neither case was the treatment felt to be related to cause of death. There was no difference in deaths, drop outs or change in MMSE between those receiving lithium and the comparison group. CONCLUSIONS: Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.

Velayudhan L, Lovestone S. · Institute of Psychiatry, King's College London, London, United Kingdom. · J Clin Psychopharmacol. · Pubmed #19593181 No free full text.

Abstract: BACKGROUND: Olfactory dysfunction, impaired odor identification in particular, is known to occur in Alzheimer disease (AD). The entorhinal cortex and the olfactory bulb, critical areas for olfactory function, are rich in acetylcholine, the neurotransmitter implicated in AD pathology and treatment. In view of the common anatomical substrate, we aimed to determine whether performance on an olfaction test can be used as a clinical marker for monitoring the efficacy of donepezil in elderly people with AD. METHODS: Twenty-five participants with mild to moderate AD, planned for donepezil treatment, were recruited from mental health services for older adults in this open-labeled study. Assessments before commencing donepezil included Mini-Mental State Examination, Neuropsychiatric Inventory, Bristol Activities of Daily Living, and the University of Pennsylvania Smell Identification Test. After 3 months of treatment, the primary outcome measure, the Clinician Interview Based Impression of Change plus caregiver input (CIBIC-plus), was completed, and the baseline assessments were repeated. RESULTS: Eighteen patients continued to receive donepezil at follow-up. The CIBIC-plus outcome correlated with changes in University of Pennsylvania Smell Identification Test and Bristol Activities of Daily Living scores from the baseline (r = 0.7, P < 0.01). In addition, it was the change in smell identification function after treatment that best predicted CIBIC-plus outcome (P < 0.05) on ordinal regression analysis. CONCLUSIONS: Smell identification function could be useful as a clinical measure to assess treatment response with donepezil in AD. This is a nonblind uncontrolled study, and the outcome indicates the need for a controlled study.

Thambisetty M, Hye A, Foy C, Daly E, Glover A, Cooper A, Simmons A, Murphy D, Lovestone S. · King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. · J Neurol. · Pubmed #19156487 No free full text.

Abstract: BACKGROUND AND METHODS: There is an urgent need for peripheral surrogates of Alzheimer's disease (AD) that accurately reflect disease state and severity as well as correlate with key features of its neuropathology. The aim of this study was to identify plasma proteins associated with known in vivo markers of disease activity. In an earlier proteomic study of plasma, we discovered a panel of 15 proteins that were differentially expressed in AD and further validated complement factor-H (CFH) and alpha-2-macroglobulin (A2M) as AD-specific plasma biomarkers. In the present study, we extended these findings by testing the associations of these plasma proteins with neuro-imaging measures of disease progression in AD. We combined (1)H-magnetic resonance spectroscopy of the hippocampus and MRI-based hippocampal volumetry with proteomic analysis of plasma in early AD and mild cognitive impairment (MCI) to achieve this goal. Using (1)H-magnetic resonance spectroscopy, we derived estimates of the hippocampal metabolite ratio N-acetylaspartate/myo-inositol (NAA/mI), a biochemical measure that is associated with cognitive decline in early AD. We also undertook a proteomic analysis of plasma in these individuals using two-dimensional gel electrophoresis (2DGE). RESULTS: We observed that two plasma proteins previously shown to be differentially expressed in AD, complement factor-H (CFH) and alpha-2-macroglobulin (A2M) showed significant positive correlations with hippocampal NAA/mI ratio in AD. CONCLUSIONS: The association of plasma CFH and A2M with hippocampal NAA/mI in this cohort of AD subjects suggests that these proteins may reflect disease progression in early AD. These findings warrant validation in large population-based datasets.

Winblad B, Frisoni GB, Frolich L, Johannsen P, Johansson G, Kehoe P, Lovestone S, Olde-Rikkert M, Reynish E, Visser PJ, Vellas B. · B. Winblad, Karolinska Institute - Alzheimer Disease Research Center, Stockholm, Sweden. · J Nutr Health Aging. · Pubmed #19043641 No free full text.

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Kwok JB, Loy CT, Hamilton G, Lau E, Hallupp M, Williams J, Owen MJ, Broe GA, Tang N, Lam L, Powell JF, Lovestone S, Schofield PR. · Prince of Wales Medical Research Institute, Randwick, Sydney, Australia. · Ann Neurol. · Pubmed #18991351 No free full text.

Abstract: OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.

Archer N, Brown RG, Reeves S, Nicholas H, Boothby H, Lovestone S. · Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, UK. · Psychol Med. · Pubmed #18694539 No free full text.

Abstract: BACKGROUND: There may be important public health implications of increasing our knowledge of factors associated with age of dementia onset. The pre-morbid personality domain of Neuroticism constituted an interesting and theoretically plausible, yet uninvestigated, candidate for such an association. We aimed to examine whether midlife Neuroticism was associated with earlier age of onset of Alzheimer's disease (AD). METHOD: This was a case-comparison study of 213 patients with probable AD. Detailed clinical information was collected for all patients including age of onset of dementia symptoms. One or two knowledgeable informants rated each patient's midlife personality retrospectively using the Neuroticism, Extraversion, Openness Five-Factor Inventory (NEO-FFI) questionnaire. The relationship between midlife Neuroticism and age of dementia onset was evaluated using both correlational analysis and backward linear regression analysis. RESULTS: Midlife Neuroticism predicted younger age of dementia onset in females but not in males. The association found in females was independent of pre-morbid history of affective disorder. CONCLUSIONS: This finding and its potential mechanism warrant further investigation.

Beacher F, Daly E, Simmons A, Prasher V, Morris R, Robinson C, Lovestone S, Murphy K, Murphy DG. · Institute of Psychiatry, King's College, London, UK. · Psychol Med. · Pubmed #18667098 No free full text.

Abstract: BACKGROUND: Individuals with Down's syndrome (DS) are at high risk of developing Alzheimer's disease (AD). However, few studies have investigated brain anatomy in DS individuals with AD. METHOD: We compared whole brain anatomy, as measured by volumetric magnetic resonance imaging (MRI), in DS individuals with and without AD. We also investigated whether volumetric differences could reliably classify DS individuals according to AD status. We used volumetric MRI and manual tracing to examine regional brain anatomy in 19 DS adults with AD and 39 DS adults without AD. RESULTS: DS individuals with AD had significantly smaller corrected volumes bilaterally of the hippocampus and caudate, and right amygdala and putamen, and a significantly larger corrected volume of left peripheral cerebrospinal fluid (CSF), compared to DS individuals without AD. The volume of the hippocampus and caudate nucleus correctly categorized 92% and 92% respectively of DS individuals without AD, and 75% and 80% respectively of DS individuals with AD. CONCLUSIONS: DS individuals with AD have significant medial temporal and striatal volume reductions, and these may provide markers of clinical AD.

Morgan AR, Hollingworth P, Abraham R, Lovestone S, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan MC, Owen MJ, Williams J. · Department of Psychological Medicine, School of Medicine, Cardiff University, UK. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18452187 No free full text.

Abstract: A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE epsilon4 allele [Kuwano et al. (2006); Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.

Al-Shawi R, Hafner A, Olsen J, Olson J, Chun S, Raza S, Thrasivoulou C, Lovestone S, Killick R, Simons P, Cowen T. · Centre for Biomedical Sciences, University College London, Hampstead Campus, Rowland Hill Campus, Rowland Hill Street, London NW3 2PF, UK. · Eur J Neurosci. · Pubmed #18412630 No free full text.

Abstract: The precursor form of the nerve growth factor (proNGF), forms a heterotrimeric complex with the receptors p75 and sortilin; this complex has been implicated in neuron cell death. However, it is not known whether proNGF and the receptors p75 and sortilin contribute to age- and disease-related neurodegeneration. Here we show that proNGF induces cell death in subpopulations of basal forebrain and peripheral sympathetic neurons of old, but not of young, adult rodents. In contrast, proNGF appears to induce neurite outgrowth rather than cell death of young adult sympathetic neurons. We have examined the neurotoxic role of proNGF in old age, and find that proNGF protein is elevated during ageing in the projection areas of some populations of vulnerable central and peripheral neurons; caloric restriction, which has known neuroprotective effects, partially prevents these increases. Sortilin was found to play a significant part in the observed patterns of age-related proNGF-mediated neurotoxicity. In particular, survival of aged neurons was rescued by neurotensin, an alternative sortilin ligand that blocks the sortilin-mediated effects of proNGF. Furthermore, sortilin immunoreactivity increases markedly in ageing rodent basal forebrain and sympathetic neurons; in contrast, p75 levels are either unchanged or reduced. From these data we propose that selective age-related neuronal atrophy and neurodegeneration may be mediated by increased sortilin expression in neurons, together with elevated levels of proNGF expression in some targets.

Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, Hollingworth P, Moskvina V, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan M, Powell J, Lovestone S, Williams J, Owen MJ. · Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18163421 No free full text.

Abstract: Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.

Li Y, Grupe A, Rowland C, Holmans P, Segurado R, Abraham R, Jones L, Catanese J, Ross D, Mayo K, Martinez M, Hollingworth P, Goate A, Cairns NJ, Racette BA, Perlmutter JS, O'Donovan MC, Morris JC, Brayne C, Rubinsztein DC, Lovestone S, Thal LJ, Owen MJ, Williams J. · Celera, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA. · Hum Mol Genet. · Pubmed #18063669 links to  free full text

Abstract: Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD sample sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippocampus of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD.

Hamilton G, Proitsi P, Williams J, O'Donovan M, Owen M, Powell J, Lovestone S. · MRC Centre for Neurodegeneration, Institute for Psychiatry, Kings College London, Denmark Hill, London SE5 8AF, UK. · Neuromolecular Med. · Pubmed #17999207 No free full text.

Abstract: There is evidence to suggest a role for immune dysfunction in the pathogenesis of Alzheimer's disease, and it has previously been shown that blood plasma levels of the protein complement factor H, a member of the alternative complement pathway, was specifically elevated in people with late-onset Alzheimer's disease. We have genotyped the common complement factor H Y402H polymorphism in a large case-control cohort to investigate association with late-onset Alzheimer's disease susceptibility and find no evidence that this SNP is associated with disease risk. However, it remains possible that another variant in this gene may modify susceptibility for late-onset Alzheimer's disease.

Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung GY, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD. · GlaxoSmithKline, Research Triangle Park, North Carolina, USA. · Arch Neurol. · Pubmed #17998437 links to  free full text

Abstract: OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. DESIGN: Case-control study with replication. SETTING: Memory referral clinics in Canada and the United Kingdom. PARTICIPANTS: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. RESULTS: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). CONCLUSIONS: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.