Review: The Genetics of Alzheimer’s Disease and Frontotemporal Dementia

The paper reviewed here is ‘Recent Insights into the Molecular Genetics of Dementia’ by Rademakers and Rovelet-Lecrut and freely available here. In the introduction, the authors briefly discuss Frontotemporal Lobar Degeneration associated Tau aggregates and TAR DNA-binding protein 43.

Rendering of Tar DNA-Binding Protein 43

In the section on genetic aspects of AD and FTLD, the authors cover five important genes: Presenilin 1 (see also this video which mentions the gene briefly), Presenilin 2, APOE, MAPT and GRN along the way explaining how an understanding of the Presenilin genes led to the generation of the Amyloid cascade hypothesis. They also comment on late-onset Alzheimer’s Disease thus:

Aggregation of late-onset AD also occurs in families, though 75-85% of late-onset AD is sporadic

The authors then go on to discuss PGRN and TDP43 in more detail in the next section. At this stage a number of candidate roles for these two genes have been proposed and the authors note that there are a large number of mutations that have been examined and associated with cases. In the next section, the authors consider copy number variants and point out the importance of these in Down Syndrome, which led to the identification of an association of extra copies of Amyloid Precursor Protein with Alzheimer’s Disease and also Alzheimer’s Disease in association with Cerebral Amyloid Angiopathy. Next up in the discussion are the miRNA’s which are involved in post-transciption regulation and the authors discuss some promising avenues of research including the regulation of BACE1. They then look at novel associations but the article was published before the very interesting GWAS studies (see resources below) identifying three gene associations CLU, PICALM and CR1.

In conclusion, this is a brief but informative paper on the genetics of Alzheimer’s Disease and FTLD which includes some interesting narratives about the discoveries that led to some of the central pathophysiological models. The article is necessarily theoretical but it will be interesting to see how genetic data will be translated into clinical practice in due course.

Acknowledgements

Tar DNA-Binding Protein 43. Author: EMW. License: Creative Commons Attribution-Share Alike 3.0 Unported. Web Reference: http://en.wikipedia.org/wiki/File:Protein_TARDBP_PDB_1wf0.png.

Resources

  • The Alzforum has a very useful gene database in which they have catalogued the relevant studies for each gene.
  • For a previous review of a paper on the genetics of Alzheimer’s Disease see here.
  • Excerpt from News Round-Up 2009 ‘Three genes associated with Alzheimer’s Disease were identified in 2  studies published in Nature Genetics. Amouyel and colleagues conducted a two-part study (Amouyel et al, 2009). In the first part of the study they undertook a Genome-Wide Association Study involving 537,029 single nucleotide polymorphism’s (SNP’s) in a French sample of 2032 people with Alzheimer’s Disease and 5328 controls.As there were multiple comparisons, they needed to control for this (with a Bonferroni correction) and a marker in the CLU gene on chromosome 8 (8p21-p12) showed a statistically significant correlation just above the threshold. They then attempted a replication in the second stage which involved 3978 probable cases of Alzheimer’s Disease and 3297 controls. This second stage involved subjects from Spain, Belgium and France. They confirmed a statistically significant association of CLU with the probable Alzheimer’s Disease subjects and additionally found a significant correlation with CR1 on chromosome 1 (1q32). The researchers then estimated the contribution of each gene to the risk of Alzheimer’s Disease and estimated that the attributable risk for APOE (a well established risk factor for Alzheimer’s Disease) was 25.5%, for CLU it was 8.9% and for CR1 it was 3.8%. Nevertheless the CR1 did not show up in the first stage of the study.In the second study, Professor Julie Williams and colleagues (including Professor Michael Owen) undertook another two part study. This involved ‘up to 19,000 subjects’ in the initial stages of the study, these subjects being recruited from Europe and the United States. Again, this was a Genome Wide Association Study. After quality control measures, they looked at 529,205 autosomal single nucleotide polymorphisms in 3,941 people with Alzheimer’s Disease and 7,848 controls. They identified one marker in CLU (the same gene identified in the study above) and a second in the PICALM gene on chromosome 11. Importantly both of these findings were replicated in the second stage of the study which involved 2,023 people with Alzheimer’s Disease and 2,340 age-matched controls.They then looked further to see if they could identify which areas within the gene were significantly correlated and produces some candidate regions. The team point out that there are other significant genes which wouldn’t have been identified in this analysis.Thus the three identified genes were CLU, PICALM and CR1.The CLU gene (Clusterin) which was identified in both studies encodes an apolipoprotein which together with APOE is found in the central nervous system as well as other tissues. There are many suggested pathways for the involvement of CLU in the pathology of Alzheimer’s Disease. Thus CLU is found in the amyloid plaques found in Alzheimer’s Disease and there is evidence also suggesting that it may be involved in the removal of Beta Amyloid from the brain (by forming soluble complexes which can cross the blood brain barrier) and may play a role in inflammation in the brain.The PICALM gene which was significantly associated with Alzheimer’s Disease in the second study encodes a protein that is involved in endocytosis. Mutations in PICALM (phosphatidylinositol-binding clathrin assembly protein) may therefore interfere with the transport of materials into the neurons and the team suggest that synaptic vesicle cycling may affected (for another study looking at vesicle cycling see the study below which involved a newly discovered protein – the Flower protein which may be involved in Calcium regulation within the neuron emphasising the importance of endocytosis in neuronal functioning).The CR1 gene which was significantly associated with Alzheimer’s Disease in the second stage of the first study, encodes a receptor for C3b protein. The C3b protein forms part of the complement cascade and again there is some evidence suggesting that it may be involved in the removal of Beta Amyloid. The CR1 receptor may be involved in the process of phagocytosis  – when material is ingested by the immune cells.

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