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Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD − P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6(rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p= 1.26 × 10−8) and one spanning the 3′-UTR of an alternatively spliced transcript of SUMF1(rs201109606, O.R. 0.65 (0.56–0.76), p= 3.24 × 10−8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOErisk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented opportunity to perform high-throughput screening of novel drugs for neurological and neurodegenerative diseases. Such screenings require a robust and scalable method for generating large numbers of mature, differentiated neuronal cells. Currently available methods based on differentiation of embryoid bodies (EBs) or directed differentiation of adherent culture systems are either expensive or are not scalable. We developed a protocol for large-scale generation of neuronal stem cells (NSCs)/early neural progenitor cells (eNPCs) and their differentiation into neurons. Our scalable protocol allows robust and cost-effective generation of NSCs/eNPCs from iPSCs. Following culture in neurobasal medium supplemented with B27 and BDNF, NSCs/eNPCs differentiate predominantly into vesicular glutamate transporter 1 (VGLUT1) positive neurons. Targeted mass spectrometry analysis demonstrates that iPSC-derived neurons express ligand-gated channels and other synaptic proteins and whole-cell patch-clamp experiments indicate that these channels are functional. The robust and cost-effective differentiation protocol described here for large-scale generation of NSCs/eNPCs and their differentiation into neurons paves the way for automated high-throughput screening of drugs for neurological and neurodegenerative diseases.

Recessive mutations in the phenylalanine hydroxylase PAH gene predispose to phenylketonuria PKU in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAHvariations could confer risk for schizophrenia, but comprehensive followup has not been reported. We analyzed 15 common PAH“tag” SNPs and three exonic variations that are rare in Caucasians but common in AfricanAmericans among four independent samples total n  5,414. The samples included two US Caucasian cohorts 260 trios, 230 independent cases, 474 controls, Bulgarian families 659 trios, and an AfricanAmerican sample 464 families, 401 controls. Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele G of rs1522305 from case–control analyses z  2.99, P  0.006. This SNP was independently replicated in the Bulgarian cohort z  2.39, P  0.015. A nonsignificant trend was also observed among AfricanAmerican families z  1.39, P  0.165, and combined analyses of all four samples were significant rs1522305: χ2  23.28, 8 d.f., P  0.003. Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case–control results in AfricanAmericans detected an association with L321L P  0.047, OR  1.46. Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted. © 2008 WileyLiss, Inc.