Molecular genetic studies in AD have come a long way from the early linkage studies, which aimed at describing a few loci and subsequently finding one or a few genes of major effect relevant for all cases of AD. It has now become clear, that AD are heterogeneous disorders, caused by several rare—most likely—monogenetic disorders (as fragile X syndrome, mutations in TSC1/TSC2, LAMB1, CNTNAP2, PTEN, DHCR7, SHANK3, NLGN3/4, or RPL10). In addition, “contiguous gene syndromes” are likely causes of AD, as the overall rate of CNVs and large chromosomal deletions, duplications, and translocations is increased in individuals with AD compared to controls.
Common variants, on the other hand, may shape the phenotype or eventually may lead to the disorder by interacting with rare mutations or CNVs. A mechanism like this has been shown for PTEN
haploinsufficient individuals. The serotonin-transporter gene SLC6A4
has been discussed as both an AD susceptibility gene and a second-site modifier in AD [7
]. A study in PTEN
haploinsufficient mice [57
] demonstrated that the phenotypes of these mice were modified in an additive fashion by SLC6A4
haploinsufficiency. In addition, the role of PTEN
in the maintenance of genomic stability [65
] makes it likely that PTEN
haploinsufficiency may increase the probability of a secondary modifying event, such as a copy number variation in a chromosomal region relevant to AD. Common variants also might increase the risk for autistic traits in the general population as well as for less severe autistic disorders as Asperger Syndrome or PDD-NOS.
From results of current genetic findings in AD, it is likely that mutations or common variants in genes coding for gene products involved in (1) cell–cell interaction and synaptic function, including development of dendritic spines, (2) neuronal migration and growth, or (3) excitatory and inhibitory neurotransmission are causes of AD. The pathway influencing cell–cell interaction and synaptic function includes NRXN
. In addition, the FMR protein, which is missing in fragile X syndrome, modulates dendritic spine formation and synaptic plasticity by inhibiting mGluR1/5 mediated dendritic protein synthesis [33
]. Neuronal migration and growth are influenced by gene products of LAMB1
or the MET receptor tyrosine kinase gene. The mTor/PI3-kinase (PI3K) pathway involves PTEN
, and several other genes, which were observed in CNVs in individuals with AD [19
]. It strongly influences (neuronal) cell growth. Gene products influencing the regulation of excitatory and inhibitory neurotransmission are GABA and glutamate receptors. In addition, dysbalance of excitatory and inhibitory neurotransmission was also observed in fragile X syndrome. Clearly, this list of possibly involved pathways is not exhaustive, and other mechanisms or pathways may emerge as results of further studies will be published.