CNSforum The Lundbeck Institute

Dementia: Genetics of Alzheimer's disease

Alleles of apolipoprotein

There are 3 isoforms of apolipoprotein (ApoE) designated ε2,ε3 and ε4. ApoE is a constituent of a subclass of high-density lipoproteins involved in cholesterol transport activity. The presence of the ε4 isoform of ApoE4 has been shown to increase the risk of developing Alzheimer’s disease (AD) and to decrease the age of onset for AD and is the major genetic risk factor for the late-onset form of the disease. ApoE4 intensifies all the biological hallmarks of AD including amyloid deposition, neurofibrillary tangle formation, increase neuronal cell death, oxidative stress, synaptic plasicity and cholinergic signalling. In contrast, other ApoE isoforms are protective.

Familial Alzheimer’s disease — established mutations in the amyloid precursor protein

A number of genetic mutations have been identified within the amyloid precursor protein (APP) in various families with Alzheimer's disease. In the 'Swedish' family, there is a double mutation at position 670/671, close to the β-secretase cleavage site. This mutation selectively increases the formation of β-amyloid, the principal component of neuritic plaques. Mutations at position 692 and 693, the Flemish and Dutch mutations, which lie close to the α-secretase cleavage site, result in hereditary cerebral haemorrhage with amyloidosis and/or Alzheimer's disease. Mutations at the δ-secretase cleavage site (716/717) also selectively increase the formation of β-amyloid.

Presenilin gene mutations in familial early-onset Alzheimer’s disease

The highly homologous presenilin-1 (PS1) and -2 (PS2) genes are found on chromosomes 14 and 1, respectively. Both genes encode cellular proteins with at least 7 transmembrane (TM) spanning domains. The PS1 and PS2 genes are predominantly expressed in neurones and glia, and while their exact function is unknown, mutations of these genes are implicated in the development of familial early-onset Alzheimer’s disease (AD). Mutations of the PS1 gene account for about 70% of all early-onset cases. More than 40 causative mutations have been found in the PS1 gene, while only 3 have been identified in PS2. One residue is mutated in both presenilins and this is the N135 (PS1)/N141(PS2) residue. It is unclear how mutations in the presenilins cause AD, but evidence suggests they have a role in amyloid precursor protein (APP) processing and apoptosis.

The role of tau gene mutations in neurodegenerative disease

Mutations in the tau gene lead to the abnormal aggregation of tau protein and the onset/progression of frontotemporal dementia. This finding demonstrates a role for tau production dysregulation in neurodegenerative disease. The six isoforms of tau found in Alzheimer’s disease contain either three (3R) or four (4R) microtubule-binding domains. Mutations in exon 10 result in alternative splicing of the tau gene and an increase in the proportion of 4R tau isoforms. This change is sufficient to produce nerve cell and glial cell dysfunction, leading to tau filament formation and degeneration. Tau mutations are thought to be instrumental in many neurodegenerative disorders, including Alzheimer’s disease.

The isoforms of TAU

There are 6 isoforms of tau expressed in the human central nervous system. These isoforms arise from the differential spicing of a single gene that is located on chromosome 17. The isoforms are differentiated from each other by the number of microtubule domains. Three isoforms (Htau 40, Htau 34 and Htau24) contain 4 microtubule binding domains; where as three isoforms (Htau 39, Htau 37 and Htau 23) contain three. The isoforms can be further differentiated by the presence of 0, 1 or 2 exons in the N-terminus of the molecule. Both the number of microtubule binding domains and the number of N-terminal inserts have an effect on the assembly properties of the tau molecule.

Psychogenetics of Alzheimer's disease

Alzheimer's disease (AD) is a heterogeneous disease. One-third of cases present at an early age (<60 years) and show autosomal dominant inheritance. The majority of these familial cases are due to mutations in the amyloid precursor protein (APP) gene and presenilin (PSEN) 1 and 2, two genes encoding 7-transmembrane domain proteins. The remaining cases present at a later age and display more complex inheritance. Susceptibility loci (AD5–8) have been mapped to chromosomes 10, 12 and 20 Candidate genes have been identified within AD6 and AD8. The gene for insulin-degrading enzyme, a metallopeptidase that can degrade a number of peptides including beta amyloid, is located within AD6 and the CST3 gene, encoding cystatin C, an inhibitor of cysteine proteases that has been shown to co-deposit with APP in AD brains, maps within AD8.   Associations have been demonstrated with the ApoEε4 allele on chromosome 19 and a polymorphism in A2M and LRP1.