Joseph D. Buxbaum

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

OBJECTIVESnTo determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.nnnDESIGNnAssociation study of AD and CLU, PICALM, CR1, and APOE genotypes.nnnSETTINGnAcademic research institutions in the United States, Canada, and Israel.nnnPARTICIPANTSnSeven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals.nnnRESULTSnUnadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 and PICALM.nnnCONCLUSIONSnWe confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Alzheimers disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimers disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimers disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E−09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E−23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E−04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Association of TREM2 variants with Alzheimer's disease in African-Americans: For the Alzheimer's Disease Genetics Consortium (ADGC)

P1-063 ASSOCIATION OF TREM2 VARIANTS WITH ALZHEIMER’S DISEASE IN AFRICANAMERICANS: FOR THE ALZHEIMER’S DISEASE GENETICS CONSORTIUM (ADGC) Christiane Reitz, Gyungah Jun, Adam Naj, Badri Vardarajan, Li-SanWang, Eric Larson, Neill Graff-Radford, Denis Evans, Philip De Jager, Paul Crane, Joseph Buxbaum, Nilufer Ertekin-Taner, Mark Logue, Robert Green, Laura Cantwell, Danielle Fallin, Jennifer Manly, Kathryn Lunetta, Ilyas Kamboh, Oscar Lopez, David Bennett, Kathleen Steele Hall, Alison Goate, Goldie Byrd, Walter Kukull, Tatiana Foroud, Jonathan Haines, Lindsay Farrer, Margaret Pericak-Vance, Gerard Schellenberg, Richard Mayeux, Columbia University, New York, New York, United States; Boston University School of Medicine, Boston, Massachusetts, United States; University of Miami Hussman Institute for Human Genomics, Miami, Florida, United States; Columbia University, Boston, Massachusetts, United States; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; Group Health Research Institute, Seattle, Washington, United States; Mayo Clinic Jacksonville, Jacksonville, Florida, United States; Rush University Medical Center, Chicago, Illinois, United States; Brigham & Women’s Hospital, Boston, Massachusetts, United States; Mt. Sinai Hospital, New York, New York, United States; Mayo, Jacksonville, Florida, United States; Boston University School of Medicine/Biomedical Genetics, Boston, Massachusetts, United States; University of Pittsburgh Schools of Nursing and Medicine, Pittsburgh, Pennsylvania, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States; Johns Hopkins University, Baltimore, Maryland, United States; Columbia University Medical Center, New York, New York, United States; Boston University School of Public Health, Boston,Massachusetts, United States; University of Pittsburgh, Pittsburgh, Pennsylvania, United States; University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Rush University Medical Center, Chicago, Illinois, United States; Indiana University, Indianapolis, Indiana, United States; Washington University, St. Louis, Saint Louis, Missouri, United States; North Carolina AT National Alzheimer’s Coordinating Center, Seattle, Washington, United States; Indiana University School of Medicine, Indianapolis, Indiana, United States; Vanderbilt University, Nashville, Tennessee, United States; Boston University, Boston, Massachusetts, United States; Vanderbilt University, Nashville, Tennessee, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States. Contact e-mail: cr2101@columbia.edu