10. Future Trends
The globalization of the present economic crisis will negatively affect future investments in CNS research and drug development; however, for the first half of the coming decade, after an initial period with some programmes put on standby, it is expected that progress in the pathogenesis of CNS disorders, molecular diagnosis, and therapeutics will evolve favorably. Genome-wide family-based association studies, using single SNPs or haplotypes, will help to identify associations with genome-wide significance [47,48,199,200]; similarly, genome-wide expression analysis will be useful for the discovery of new drug targets. Some studies will try to elucidate the weight of genome-environment interactions in the pathogenesis and clinical course of CNS disorders, and also the emerging role of epigenetics. The validation of protocols for genomic screening will contribute to introducing structural genomics (genotyping, genome-wide analysis), functional genomics (genotype-phenotype correlations), and proteomics as diagnostic aids and therapeutic targets [201]. New initiatives for the prevention of dementia will also emerge [202], together with new insights into the role of nutrition and nutrigenomics in brain function and neurodegeneration [203].
Priority areas for pharmacogenetic research are to predict serious adverse reactions (ADRs) and to establish variation in efficacy [204]. Both requirements are necessary in psychotic disorders and dementia to cope with efficacy and safety issues associated with current antipsychotics and anti-dementia drugs, and new CNS drugs as well. Since drug response is a complex trait, genome-wide approaches (oligonucleotide microarrays, proteomic profiling) may provide new insights into drug metabolism and drug response. Of paramount importance is the identification of polymorphisms affecting gene regulation and mRNA processing in genes encoding cytochrome P450s and other drug-metabolizing enzymes, drug transporters, and drug targets and receptors, with broad implication in pharmacogenetics since functional polymorphisms which alter gene expression and mRNA processing appear to play a critical role in shaping human phenotypic variability [205]. It is also most relevant, from a practical point of view, to understand the pharmacogenomics of drug transporters, especially ABCB1 (P-glycoprotein/MDR1) variants, due to the pleiotropic activity of this gene on a large number of drugs [206]. There are over 170 human solute carrier transporters which transport a variety of substrates, including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, toxic xenobiotics, chemical compounds, and proteins [207].
In approximately 3–5 years novel data on clinical trials with anti-amyloid vaccines will be delivered and AD immunotherapy will face new vaccine models (active and passive immunization) and new therapeutic challenges regarding the amyloid burden in AD [208]. Other expected developments in AD therapeutics include γ-secretase inhibitors, β-secretase inhibitors, β-sheet breakers and chaperone inhibitors, regulators of the ubiquitin-proteasome system, small molecule activators (non-peptide neurotrophic factors) of the Trk receptors, p38α mitogen-activated protein kinase (MAPK) regulators, ADNP (activity-dependent neuroprotective protein) derivatives (NAP peptides), GSK-3β modulators, phospholipase A2 inhibitors, the medium-chain triglyceride AC-1202, inhibitors of insulin-regulated aminopeptidase, amphiphilic pyridinium salts, and some other novel compounds, still in a preclinical stage, most of which are intended to be Aβ lowering agents. There will be some initiatives for nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS, as well as for new transdermal and intranasal delivery systems. 
Another important issue in the pathogenesis and therapeutics of CNS disorders and dementia is the role of microRNAs (miRNAs), RNA interference (RNAi) and gene silencing. Double-stranded RNA-mediated interference (RNAi) is a simple and rapid method of silencing gene expression in different organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. Genetic and biochemical studies revealed a two-step mechanism of RNAi-induced gene silencing: (i) degradation of dsRNA into small interfering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase III-like activity; (ii) the siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it. Key components such as Dicer, RNA-dependent RNA polymerase, helicases, and dsRNA endonucleases play important roles in RNAi. Some of these components also control the development of many organisms by processing many noncoding RNAs, called micro-RNAs. In the context of RNAi, the genome also undergoes alterations in the form of DNA methylation, heterochromatin formation, and programmed DNA elimination. RNAi is being considered as an important tool for functional genomics and for gene-specific therapeutic activities that target the mRNAs of disease-related genes [209,210,211].
Nearly 97% of the human genome is non-coding DNA, and introns occupy most of it around the gene-coding regions. Numerous intronic sequences have been found to encode microRNAs, which are responsible for RNA-mediated gene silencing through RNA interference (RNAi)-like pathways. microRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies. miRNAs were firstly discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development. Intronic microRNA is a new class of miRNAs derived from the processing of gene introns. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of type II RNA polymerases (Pol-II) and spliceosomal components for their biogenesis. There is an evolutionary preservation of the intron-mediated gene silencing through miRNA functionality in cell and in vivo, suggesting the existence of an intracellular miRNA-mediated gene regulatory system, fine-tuning the degradation of protein-coding messenger RNAs [212]. New inventories of miRNA expression profiles from CNS regions will be reported in the near future. These inventories of CNS miRNA profiles will provide an important step toward further elucidation of miRNA function and miRNA-related gene regulatory networks in the mammalian CNS. RNAi has led in recent years to powerful approaches to silencing targeted genes in a sequence-specific manner with potential therapeutic applications in neurodegenerative diseases. RNAi procedures for gene-selective inhibition must improve (i) cytoplasmic delivery of short sdRNA oligonucleotides (siRNA), which mimics an active intermediate of an endogenous RNAi mechanism; and (ii) nuclear delivery of gene expression cassettes which express a short hairpin RNA (shRNA), which mimics the micro interfering RNA (miRNA) active intermediate of a different endogenous RNAi mechanism. 
These technologies, complemented by non-viral gene delivery systems and ligand-targeted plasmid-based nanoparticles for RNAi agents, will bring new hopes for the treatment of different complex disorders [213,214]. We need more information about the feasibility of targeting AD genes (e.g., APP-London mutation, APP-Swedish mutation, PS1, APLP1, APLP2, PEN-2, APH-1a, Nicastrin, BACE, MAPT-V337M) with RNAi and making sure that gene silence in CNS disorders does not affect proteomic and/or metabolomic networks which are fundamental for a correct brain function [215]. 
Another area of growing interest is the role of adult neurogenesis and stem cells in AD. Stem cell therapy has been suggested as a possible strategy for replacing damaged circuitry and restoring learning and memory abilities in patients with AD and other neurodegenerative disorders; however, there is a long path ahead from the promising investigations which are raising hopes, and the challenges behind translating underlying stem cell biology into an effective therapy for CNS disorders and dementia [216].