1. Introduction Alzheimer’s disease (AD) is a neurodegenerative disease associated with brain shrinkage and the loss of neurons, particularly cholinergic neurons. This mainly occurs in the hippocampus and basal forebrain (as seen in figure 1). There are two features of AD which are characteristic in sufferers; the formation of extracellular amyloid plaques comprising of the β- amyloid protein (Aβ) and the formation of intraneuronal neurofibrillary tangles consisting of the Tau protein in an abnormal phosphorylated form, which causes it to dissociate from microtubules and be deposited as intracellular paired helical filaments (as seen in figure 2). Both of these characteristics arise from the misfolding of native proteins in the brain and can result in neuronal death. Genetics Familial Alzheimer’s (FAD), also referred as Early-Onset Alzheimer’s is an autosomal dominant condition. Mutations in beta-amyloid precursor protein The beta amyloid peptide (A  40) is obtained from the proteolytic processing of the beta-amyloid precursor protein. Different versions can be obtained from alternatively spliced mRNA. These mutations lead to an amyloidogenic form of beta amyloid peptide (A  42/43), which is longer in length. The most severe mutations cause large a decrease in A  40, and a large increase in A  42. A  40 doesn’t bind to more than 3 other A  40 proteins, whereas A  42 is able to bind to 11 other A  42 proteins, these form beta-sheets, which lead to the large fibrils that form the plaques. Presenilin mutations These mutations were responsible for most genetically-linked FAD. More mutations identified in PS1 (approx. 107 point mutations vs 8 in PS2). Mutations lead to a protein that cant undergo proteolysis. This leads to increased production of A  42. Not fully understood why, one theory is that the mutations alter the gamma-secretase activity so more amyloidogenic form of the A  peptide (A  42/43) is produced. Sporadic Alzheimer’s (SAD) refers to Alzheimer’s cases where the disease has not been present in close family members. SAD tends to be late-onset (after 65) and has a higher prevalence than FAD. SAD occurs as a result of several genetic mutations, ageing and environmental factors. Only a single gene has evidently been associated with SAD- the ε4 allele of the apolipoprotein E gene (APOE4) located on chromosome 19. APOE4 is a lipoprotein; it is thought that mutations in this gene increase the risk of AD by interfering with β-amyloid protein (Aβ) clearance. However the presence of the ε4 allele does not always increase the risk of SAD. First degree relatives of someone with SAD may inherit the mutant APOE4 gene which will result in an increased risk of developing SAD themselves. Pathology Loss of cholinergic neurons It was discovered in 1976 that the loss of cholinergic neurons in the basal forebrain nuclei is a main characteristic in AD patients. The activity of choline acetyltransferase (the enzyme responsible for the formation of the neurotransmitter acetylcholine) is dramatically reduced in the cortex and hippocampus. Nicotinic receptors have also been found in reduced numbers in AD. Cholinesterase inhibitors are widely used to treat AD. References : http://phys.org/news165687229.html Encyclopedia of molecular cell biology and molecular medicine Flesh and Bones of Medical Cell Biology, Norman. Robert. I, Pages 29 & 89 Rang and Dale's Pharmacology, Rang, H.P, Page 476 GeneProteinLocationType of AD APPBeta-amyloid precursor protein Chromosome 21Familial PS1Presenilin 1Chromosome 14Familial PS2Presenilin 2Chromosome 1Familial APOE4ApolioproteinChromosome 19Sporadic Alzheimer's Figure 1 Figure 2 Bhavian Patel Proteasome mechanism, that should degrade inactive proteins, fails Large quantity of protein aggregation Hydrophobic residues exposed at surface of protein increases tendency that the protein will become bound to the membrane Build up of beta amyloid in the neurons Tau protein becomes heavily phosphorylated and causes the formation of helical filaments Beta amyloid plaques and neurofibrillary tangles are formed Transport of action potentials along the axon is impaired Reduced release of neurotransmitter The cognitive ability of an Alzheimer’s sufferer is decreased Figure 1