Targeted Therapeutics and the new genomic medicine

Alzheimers diseaseTargeted Therapeutics and the new genomic medicine1Most common form of dementiaAccounts for 60-80% of cases in the elderlyAs yet, no effective treatment to reverse memory loss

SymptomsImpairment of recent memory, function and attentionFailure of language skills, visual-spatial orientation, abstract thinking, and judgmentAlterations of personality

Histopathological changes consist of: neurofibrillary tangles, senile plaques and a diffuse loss of neurones.Definition and symptomsDementia is a syndrome characterised by failure of recent memory and other intellectual functions, tends to progress steadily.

Current treatment can improve memory and concentration by preserving acetylcholine levels in the brain by inhibiting acetylcholinesterase but doesnt slow down damage and only works for a few months. Another treatment type blocks glutamate, which is released in excessive amounts when brain cells are damaged by AD causing them to be further damaged

Diagnosis can only be confirmed by post mortem examination and the presence of tangles (collections of intraneuronal cytoskeletal filaments), plaques (extracellular deposits of abnormal amyloid protein) and loss of neurones.2

Tau proteins stabilise microtubules, abundant in neurones of the CNS. Their presence, distribution and density are used to define the six stages of Alzheimers disease, Braak stages. Hyperphosphorylation leads to tangles, also prone to misfolding (tau hypothesis, abnormal proteins lead to a disease cascade) has similarities to prion diseases. Destruction of the cell cytoskeleton.3

Alzheimers isnt usually inheritedIn a small number of cases, it is a dominant genetic disorderMutations of gene that codes for APP (amyloid precursor protein), and presenilins 1 and 2Result in increased amounts of A42, a toxic form of the beta amyloid peptideThe GeneticsAPP gene on chromosome 21, found by Goldgaber. APP expressed in many tissues, concentrated in neurone synapses, function unknown but thought to be implicated in the regulation of synapse formation, neural plasticity and iron export. . Presenilins are transmembrane proteins, part of gamma secretase enzymes, which cut APP.

Beta amyloid formed by enzymes cutting APP, aggregate to form different ogliomers. Misfolded ogliomers thought to induce misfolding of tau protein. Function of beta amyloid is also unknown4

ApoE binds with high affinity to A protein3 main alleles: e2, e3 and e4Inheritance of e4 allele is a risk factor for late onset Alzheimer's diseaseBut inheriting e4 is insufficient to cause Alzheimers diseaseCellular/molecular mechanisms by which e4 allele increases the susceptibility are not understoodThe GeneticsApoE (apolipoprotein E) gene isoform found on chromosome 19, same region as genetic markers associated with late onset form of AD. As a result, scientists began to explore the the relationship of the different alleles of ApoE with individuals with that specific type of AD. ApoE normally chaperones cholesterol through the bloodstream.

E3 normally has the highest frequency (0.78) but in AD patients, e4 frequency rose to 0.52. Almost 8 times more likely to develop AD compared to those homozygous for e3. Individuals with no copies of e4, only 20% develop AD by age of 75 compared to 90% with two copies of e4. 5Develop therapies aimed at inhibiting formation or facilitating clearance of the toxic A42 peptideAmyloid imaging for screening of A depositsCreation of AD animal modelsGenetic testing for patients already with symptoms for early onset familial ADDIAN research into treatment for dominantly inherited ADTherapeutic options

CNS amyloid imaging useful for testing the effectiveness of Alzheimers drugs developed effectiveness of reducing plaque formation.

Often transgenic mouse models over-expressing human APP for development of therapeutic programs, not ideal as not full models of AD and so conclusions not fully transferable to humans, however gene therapy has been used to reverse memory loss in early stages of AD in mice. Current drug trials development of drug by TauRx company, development of inflammation/neurotransmitter modulators, other approaches, no success yet.

Genetic testing not helpful in terms of actual treatment but can relieve psychological burdens of patients believing their difficulties are their own fault. DIAN dominantly inherited Alzheimer network, they assess & quantify the clinical, biological and imaging markers to predict/track the progression of AD6