We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10−157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10−9) and rs3851179, a SNP 5′ to the PICALM gene (p= 1.9×10−8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10−10, odds ratio= 0.86; rs3851179: p= 1.3×10−9, odds ratio= 0.86). We also observed more variants associated at p< 1×10−5 than expected by chance (p=7.5×10−6), including polymorphisms at the BIN1, DAB1 and CR1 loci.

We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.

Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations. Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years. Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions. © 2004 American Association for Clinical ChemistryIncreased plasma total homocysteine (tHcy) 7 is a sensitive marker of folate and cobalamin (vitamin B 12 ) deficiency (1, 2 ) and an independent risk factor for cardiovascular disease (CVD) (3,4 ). Plasma tHcy concentrations are also related to birth defects (5 ), pregnancy complications (6 ), psychiatric disorders (7 ), and cognitive impairment in the elderly (8 ). The measurement of tHcy in the clinical setting is thus potentially of great importance (9 ).The introduction of tHcy assays in the mid-1980s (10, 11 ) started a new era of research on Hcy. However, it was the advent of immunoassays in the latter half of the 1990s (12, 13 ) that changed tHcy determinations from research tools to widely used clinical chemistry tests. As a result, interest in this field has increased exponentially in both routine diagnostics and research.Although several reviews on tHcy determinations have been published (14 -18 ), few have provided recommendations for their use in clinical practice (19 -23 ). Our aim was to review the practical aspects of tHcy determinations in clinical practice as well as in the research setting and to survey the data on tHcy in diagnostics or as screening tests in several target populations.Ideally, guidelines should be established by a multidisciplinary team including all relevant stakeholders, and the recommendations should be according to evidence-based medicine (24 ). There are not sufficient data in the Hcy field, however, to use such an approach. In particular, -32 (2004) Review 3 data from controlled clinical trials are sparse. Neverth...

A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia, using evidence from postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the septohippocampal system and the motor functions of the basal ganglia. Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum, and the amygdala to nucleus accumbens, and their interaction with the ascending dopaminergic projection to the accumbens. Psychologically, the model emphasises a failure in acute schizophrenia to integrate stored memories of past regularities of perceptual input with ongoing motor programs in the control of current perception. A number of recent experiments that offer support for the model are briefly described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections, and of the effects of amphetamine and neuroleptics, on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect; and studies of the latter two phenomena in acute and chronic schizophrenics.

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In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.