Alzheimer's disease

Definition
Statistics of AD
A brief introduction
Signs and symptoms of AD
NMDA receptors
Classification
Causes
Risk Factors
Pathophysiology
AD… The great unknown
Treatment Options
Future Trends

1. ALZHEIMER’s DISEASE Assigned By: Sir Muhammad Nadeem Presented By: Ahsan SAQI Pharm-D Department of Pharmacy IUB

2. Contents Definition Statistics of AD A brief introduction Signs and symptoms of AD NMDA receptors Classification Causes Risk Factors Pathophysiology AD… The great unknown Treatment Options Future Trends

3. Definition “A progressively degenerative neurological disorder leading to dementia with increasing mental confusion, emotional instability, and premature death.”

4. Statistics of Alzheimer’s disease : Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early onset of Alzheimer’s can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050 .

5. A Brief Introduction Alzheimer’s is the most common cause of dementia in adult life and is associated with the selective damage of brain regions and neural circuits critical for memory and cognition The pathogenesis of this disease is complex, and involves many molecular, cellular, and physiological pathologies The neurons in the neocortex, hippocampus, amygdala, and the basal forebrain cholinergic system are the most affected brain regions.

6. Signs & Symptoms : Memory loss for recent events Progresses into dementia  almost total memory loss Inability to converse, loss of language ability Affective/personality disturbance Death from opportunistic infections, etc.

7. Alzheimer’s Disease: Postmortem Analysis normal advanced Alzheimer’s

8. Stages:

9. NMDA receptors Definition “The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR ) A glutamate receptor P redominant molecular device for controlling synaptic plasticity and memory function .”

10. NMDA receptors Introduction The NMDAR is a specific type of ionotropic glutamate receptor. NMDA ( N -methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other 'glutamate' receptors. Activation on the opening of an ion channel that is nonselective to cations with an equilibrium potential near 0 mV. A property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg 2+ & Zn 2+ ions.

11. This allows the flow of Na + and small amounts of Ca 2+ ions into the cell and K + out of the cell to be voltage dependent. Calcium flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in two ways: First, it is both ligand-gated and voltage-dependent; Second, it requires co-activation by two ligands: glutamate and either d-serine or glycine .

12. NMDA receptors

13. Classification : FAD v SAD: Familial AD versus Sporadic AD ( 2) Early v Late Onset : Early onset = usually before 65 Early onset correlated with FAD LOAD = late onset AD

14. Causes of AD M ultiple causes for Alzheimer's disease S ome causes may not have been discovered yet. In fact, the causes for any given person vary greatly and are difficult to determine. However , researchers have come up with a list of risk factors that may make a person more likely to develop Alzheimer's disease.

15. Similarly, researchers have identified factors that decrease the risk of developing Alzheimer's disease. And finally, researchers have ruled out certain popular myths about what causes the disease. Genetic and environmental factors are the major contributors .

16. Risk Factors Age P rimary risk factor for Alzheimer's disease. The number of cases of Alzheimer's disease doubles every 5 years beyond age 65. According to the U.S. Alzheimer’s Association, 1 in 8 people age 65 and older have Alzheimer’s disease. About 6% of people age 65 to 74 have Alzheimer’s and nearly half (45%) of people age 85 years and older have the disease. While less common, Alzheimer’s can also affect younger people. About 200,000 Americans younger than age 65 have early-onset Alzheimer’s disease.

17. Gender More women than men develop Alzheimer’s disease but this is most likely because women tend to live longer than men . Race and Ethnicity African Americans and Hispanics are at greater risk for developing Alzheimer’s disease than whites. This may be in part because they have a higher prevalence of medical conditions such as high blood pressure and diabetes, which are associated with increased risk for Alzheimer’s .

18. Family History People with a family history of Alzheimer's are at higher than average risk for the disease. Heart and Vascular Diseases Risk Factors

19. Pathophysiology of AD There are 3 consistent neuropathological hallmarks : Amyloid-rich senile plaques Neurofibrillary tangles Neuronal degeneration

20. Amyloid Plaque Formation Alzheimer’s patients show numerous plaques which are composed of 4 kD Amyloid-beta (A-beta) peptides, which are derived from beta amyloid precursor proteins (APPs) APP is a membrane associated glycoprotein of 110-135 kDa that is proposed to normally behave in the brain as a cell surface signaling molecule A-beta peptides are generated in the endosomal compartment and in the endoplasmic reticulum or Golgi complex by endoproteolytic cleavage of APP by Beta, alpha, and gamma secretases

21. Neuronal Plaques in Alzheimer’s Disease

22. Presenilins Presenilin 1 (PS1) and presenilin 2 (PS2) are highly homologous 43-50 kD proteins with eight transmembrane domains Presenilin’s make crucial contributions to neurodegeneration in AD Presenilin’s are crucial components of the enzymes that work to cleave APP, and mutations in presenilins cause the production of A-beta42 and A-beta43 peptides (insoluble forms of A-beta)

23. Neurofibrillary pathology Intracellularly, alzheimer’s patients show neurofibrillary pathology Affected neurons accumulate tau and ubiquitin immunoreactivities within neurofibrillary tangles, in cell bodies and dendrites, and in dystrophic neuritis

24. Neurofibrillary Tangles in Alzheimer’s Disease

25. Plasmin In the brain, plasminogen and its proteolytic fragment are abundant in the hippocampus It has been hypothesized that brains of patients with AD may have lower levels of plasmin The higher production of amyloid peptide together with less efficient degradation would to A-beta accumulation and aggregation

26. Brain Atrophy in AD

27. Amyloid Hypothesis The trigger for Alzheimer's disease is the A-beta peptide, and the accumulation of this peptide in the form of plaques is the initiating molecular event The plaques trigger an inflammatory response, neuronal cell death, and gradual cognitive decline The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is caused by an imbalance between A-beta production and A-beta clearance

28. Calcium Hypothesis Calcium modulates many neural processes, including synaptic plasticity and apoptosis Dysregulation of intracellular calcium signaling has been implicated in the pathogenesis of alzheimer’s disease Increased intracellular calcium elicits the characteristic lesions of this disorder, including the accumulation of amyloid-beta, the hyperphosphorylation of TAU and neuronal death Every gene that is known to increase susceptibility to Alzheimer’s disease also modulates some aspect of calcium signaling

29. Calcium Hypothesis The disruption of calcium homeostasis might be one of the principal mechanisms by which A-beta manifests its neurotoxicity A-beta has been shown to destabilize neuronal calcium homeostasis, generally leading to an increase in cytosolic calcium which can then trigger neuronal apoptosis

30. Acetylcholine Hypothesis Acetylcholine (ACh) is an important neurotransmitter in areas of the brain involved in memory formation Loss of Ach activity correlates with the severity of AD

31. AD: The Great Unknown What is causing the majority of AD cases?

32. Cases with no known etiology: (theoretical extremes) Mendelian / Phenocopy Disease (Genetic) Heterogeneity Multifactorial/ Threshold CDCV Common disease/ common variant

33. Treatment Options Pharmacological Non- pharmacological Specific symptom management Resources

34. Future Trends Alzheimer’s as a multifactorial syndrome Pendulum of history Vaccine Gene therapy

35. THANKS…