Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical ␥-aminobutyric acid-ergic interneurons are downregulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this downregulation. Protracted L-methionine (6.6 mmol͞kg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD 67 mRNAs in both WT and heterozygous reeler mice. This effect of L-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of L-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulse͞startle interval increased in mice receiving L-methionine. Valproic acid (2 mmol͞kg for 15 days, twice a day) reverted L-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk. S tudies of heterozygous reeler mice (HRM) have provided preliminary evidence of a relationship between reelin haploinsufficiency, the decrease of dendritic spine expression density in frontal cortex (FC) pyramidal neurons and associated neuropil hypoplasticity, the down-regulation of glutamic acid decarboxylase (GAD) 67 expression, and the decrease in ␥-aminobutyric acid (GABA) turnover (1-3). Similar neurochemical and structural abnormalities were detected in the FC of schizophrenia postmortem brains (4-9). Hence, HRM may be a model to evaluate the efficacy of novel treatments for schizophrenia by monitoring drug actions on (i) reelin and GAD 67 mRNA expression, (ii) GABA turnover, and (iii) cortical neuropil plasticity including dendritic spine expression.The HRM model several aspects of the molecular neuropathology expressed in schizophrenia, although the mechanisms operative in these pathologies may be different. In fact, demographic studies of schizophrenia inheritance in identical twins show a concordance of Ϸ50%, which supports an epigenetic model but not gene haploinsufficiency of Mendelian origin. Investigation of a putative epigenetic mechanism attending schizophrenia vulnerability may therefore be in order (10). Along this line of thinking we have hypothesiz...

No abstract