2. Neurodegenerative disease resulting in mental and intellectual decline (alz.org).
3. Most common cause of dementia and progressively worsens leading to patient’s death.
a. Memory loss (alz.org).
b. Inability to solve daily tasks and problems
c.Confusion about place and time
d. Depression and social withdrawal
- Causes of AD
- i. Presence of Amyloid peptide oligomers and neurofibrillary tangles that result in damage and death of neurons.(Gravitz, 2011)
ii. Inherent Genetic predisposition. (APOE) allele 4, GSK3 and TREM2 are part of gene clusters associated with AD (Bertram, Lill& Tanzi, 2010).
- The presence of amyloid oligomers and neurofibrillary tangles results in inhibition of communication between neurons causing neuronal death.
- Diagnosis of AD (Ballard, Gauthier, Corbett, Brayne, Aarsland and Jones, 2011)
- Patient history provided by patient and their care giver.
- Neuropsychological analysis
- CSF analysis of the Apeptides and ratio of free to phosphorylated form of tau protein,
- CT scanning and MRI to rule out other brain injuries and presence of tumors or hematoma (Cummings & Cole, 2002)
- MRI is used to detect brain atrophy, another diagnostic marker for AD. (Ballard, Gauthier, Corbett, Brayne, Aarsland and Jones, 2011)
- PET can measure glucose metabolism that is a marker of AD.
- SPECT scanning to measure blood flow to brain and transport of neurotransmitters.
- Treatment of AD (Citron, 2010)
- Acetylcholinesterase inhibitors increase acetylcholine concentration that prevents neuronal damage
- NMDA receptor antagonist prevents overstimulation by glutamate an excitatory neurotransmitter.
- Psychotropic agents to reduce psychosis, depression, delusion associated with AD(Ballard, Gauthier, Corbett, Brayne, Aarsland and Jones, 2011)
- Current Research
- Identification of new gene markers of AD. (http://www.nature.com/ng/journal/v45/n12/full/ng.2802.html)
- Development of novel AD drug targeting H3 histamine receptor. (http://dx.doi.org/10.1016/j.bmcl.2013.09.090)
Ballard, Clive, Serge Gauthier, Anne Corbett, Carol Brayne, Dag Aarsland and Emma Jones. “Alzheimer’s disease”. Lancet. (2011). 377, 1019-1031.
“Basics of Alzheimer’s disease brochure”. Alzheimer’s association. www.alz.org. Retrieved Dec, 5, 2013.
Bertram Lars, Christina M. Lill & Rudolph E. Tanzi. “The genetics of Alzheimer disease: back to the future”. Neuron (2010), 270-281.
Citron, Martin. "Alzheimer's disease: strategies for disease modification." Nature Reviews Drug Discovery 9.5 (2010): 387-398.
Cummings, Jeffrey, Greg Cole. “Alzheimer’s disease”. Journal of the American Medical Association. (2002). 287, 18, 2335-2337.
Gravitz, Lauren. “A tangled Web of targets”. Nature (2011), 475, 59-62.
Lambert, Jean-Charles, Carla Ibrahim-Verbaas, Denis Harold, et al. “Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease”. Nature Genetics (2013). 45, 1452–1458
Wilson David M, James Apps, Nicholas Bailey, Mark J. Bamford, Isabel J. Beresford, et al. “Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists”. Bioorganic and Medicinal Chemistry letters, 2013, 23, 24. 6890-6896.
Alzheimer’s disease (AD) and its symptoms. Alzheimer’s disease (AD) is the most prevalent source of dementia in the elderly. It is a neurodegenerative disease that slowly progresses to complete loss of cognitive ability of the patient. AD accounts for about 60-70% of progressive mental and intellectual decline in the elderly population. The number of patients with AD has been estimated to be approximately 2.3 million based on the Alzheimer’s disease association statistics. The risk associated with AD diagnosis doubles every five years as a person reaches the age of 60. The risk of developing AZ is higher in women as compared to men. Every year almost 360000 new cases of AD are diagnosed. It is the sixth foremost cause of mortality in the US (alz.org). While it is generally a disease associated with old age, 5-8% of AD patients are between the ages of 40-50. A number of symptoms of AD are commonly associated symptoms of aging making the diagnosis complicated. Memory loss is first and foremost important AD symptom. Some of the other symptoms include inability of solve common problems (such as balancing checkbook), difficulty in solving common daily tasks (setting a washer/dryer), confusion about place, time and date, forgetting common words, inability to join a conversation, misplacing things and difficulty locating them, inability to make visual association, change in personality, depression, separating themselves from social surroundings, failure of judgment and loss of ability to care for oneself. The symptoms described above characterize an extensive failure of previously known skills that begin gradually and develop to severe loss.
Principle causes of Alzheimer’s disease. There are two chief hallmarks of AD, amyloid peptide oligomers and neurofibrillary tangles resulting in damage and death of neurons. Amyloid oligomers are formed by Amyloid peptides, which are generated by cleavage of Amyloid precursor protein (APP). Enzymes such as and secretase cleave the APP to peptide fragments that are 40-42 amino acids long. A1-42 demonstrate a greater tendency to aggregate to form oligomers (Gravitz, 2011). These oligomers are now believed to bind to receptors on neurons, modifying the synapses and leading to damage of neuronal communication. The A oligomers are also known as amyloid-derived diffusible ligands (ADDLs). The presence of tau neurofibrillary tangles is another marker of AD. Tau, a soluble microtubule associate protein, undergoes hyper-phosphorylation to form tau threads. The tau threads then form neurofibrillary tangles that lead to disintegration of neuronal microtubule cytoskeleton. This affects the transport system of neurons eventually affecting biochemical communication and causing death (Ballard, Gauthier, Corbett, Brayne, Aarsland and Jones, 2011). Patients who present symptoms of early onset familial AD before the age of 65 inherit autosomal dominant form of three genes, amyloid precursor protein (APP), presenilin 1 and 2. Mutations in these genes increase the concentration of A1-42 and alter ratio of A1-42 to A1-40. However, most cases of AD occur after 65 years (Cummings & Cole 2002). The greatest genetic risk factor of AD, is the presence of Apolipoprotein E (APOE), allele 4. Individuals who carry one copy of the 4 allele have a threefold while those carrying two copies of 4 allele have a 7 fold increased risk for developing AD. Additionally, 13 genes or gene clusters have been identified to have a role in development of neurodegeneration in AD. These include TREM2, CLU, BIN1, CR1, GSK3, PICALM, CD33, CD2AP etc (Bertram, Lill& Tanzi, 2010). Other risk factors associated with AD include head injury, low level of serum vitamin B12 and folate levels, elevated homocysteine level, fewer years of formal education, poor income
Diagnosis of AD. AD is most accurately diagnosed post mortem with the evaluation of brain tissue. However, in order to treat the disease and improve the quality of life of the patient a timely diagnosis of the disease is vital. The diagnosis of AD is made based by combination of diagnostic on evaluation of patient history based on the patient’s and care giver’s or partner’s perspective, clinical observations, presence of neuropsychological features. It is also important to rule out loss of cognitive ability due to other neurological disorders. The National Institute of Neurological and communicative disorders and stroke (NINCDS) and the Alzheimer’s disease and related disorders association (alz.org) have established and updated criteria for diagnosis of AD. These criteria require the manifestation of intellectual impairment and positive identification of one syndrome of dementia that can be tested by testing of neuropsychological sensitivity. CT and MRI scans are performed to rule out the presence of a hematoma, tumor or other disease that can lead to dementia like symptoms. Evaluation of the level of the Apeptides and ratio of free to phosphorylated form of tau proteins in the cerebrospinal fluid (CSF) are also utilized in the diagnosis of AD. Atrophy in the medial temporal lobe of the brain which can be detected by MRI is a useful tool for confirmation of AD (Ballard, Gauthier, Corbett, Brayne, Aarsland and Jones, 2011). Functional methods of neuroimaging such as PET (positron emission tomography), SPECT (single-photon emission computed tomography) to measure blood flow or to observe a neurotransmitter system are also used as part of the diagnosis criteria(Cummings& Cole, 2002). The degree of glucose metabolism in certain parts of brain is also a sensitive marker for early stage of AD and can be detected by PET scan. The presence of a family member with an established AD’s related mutation is also a useful criteria for AD diagnosis.
Treatment of AD. There are currently two class of drugs that are clinically approved for the treatment of Alzheimer’s disease. Cholinesterase inhibitors include tacrine, donepezil, rivastigmine and galantamine. These agents inhibit the breakdown of acetylcholine and as a result increase the concentration of acetyl choline in the brain. These drugs have been shown to improve cognition and reduce behavioral disorders. This NMDA receptor antagonist (Memantine) prevents their overstimulation by glutamate which is an excitatory neurotransmitter. Memantine is approved by the FDA for the management of mild to severe Alzheimer’s disease. In addition to these FDA approved drugs, certain medications such as psychotropic agents such as Risperdione, Aripiprazole, anti-depressants such as Citalopram and anti-convulsants are used off label for management of psychosis, aggression and depression associated with Alzheimer’s disease. In addition to these drugs, a number of other agents that target the aggregation of formation of amyloid peptide oligomers and tau neurofibrillary tangles are undergoing clinical trials. No success was observed after the phase 3 clinical trial of an immunotherapy agent Bapineuzumab for AD treatment (Citron, 2010).
Current research studies involving AD. A recent study published in the journal Nature genetics in 2013 looked at genome wide association studies (GWAS) in patients of European ancestry and performed a meta-analysis to identify 11 novel genomic regions/ gene markers for late onset Alzheimer’s disease. The scientists carried out the meta-analysis in two stages. They looked at accredited genotyped data used in 4 prior published studies on 7,055,881 single nuclear polymorphisms (SNPs) (where a single nucleotide is altered between two chromosomes) on GWAS data collection comprising of 17008 patients with Alzheimer’s disease and 37,154 control subjects. In the next stage 11,632 SNPs were evaluated and analyzed for their association in a separate set of 8572 AD cases and 11312 controls. They identified 19 clusters of gene of which 11 were novel genes associated with AD. CD2AP, EPHA1, CR1 and BIN1 were 4 of the 11 new identified genes from the study. (Wilson, et al. 2013)
The next study looks at the development of a novel potential drug for the AD treatment. The authors are working to develop and modify the structure of putative inhibitors of H3 histamine receptor based on the lead drug benzazepine. H3 histamine receptor works by inhibiting the secretion and release of key neurotransmitters including acetylcholine, histamine and noradrenaline. Inhibition of this receptor stops the inhibitory feedback mechanism resulting in increased neurotransmitter concentration. The authors describe a lead molecule belonging to the benzazepine class of compounds and describe a structure activity relationship to identify potent drug candidates by altering the chemical structure of the lead (Lambert, et al. 2013).