DR.M.ISHAQUE SARHANDI. M.B.B.S,M.C.P.S.(Psych),F.C.P.S (Psych).

1. Dementias: DR.M.ISHAQUE SARHANDI. M.B.B.S,M.C.P.S.(Psych),F.C.P.S (Psych). Coordinator Psychiatry, Neurology and Head Students’ Counseling Unit. Sulaiman Al-Rajhi Colleges, Bukayria, Qaseem, KSA.

2. DEMENTIA • It is an acquired, chronic brain disorder, characterized by generalized impairment of intellect, personality, and memory with no impairment of consciousness. • Prevalence of Moderate to severe dementia • in age 65 -80 years 5 % • in age 80+ 20 % Ferri et al. Lancet 2005; 366: 2112–2117

10. According to experts, without the introduction of disease-modifying treatments, • Alzheimer’s disease is poised for an exponential increase throughout the world with projections that it will quadruple over the next 40 years • To affect 1 in every 85 people on earth.

11. What they expect is Over 100 Million people by 2050.

12. Prognosis • There is currently no cure for Alzheimer’s disease. There is variation in the time it takes from diagnosis to death. The estimated median survival for Alzheimer’s disease from onset has been calculated as 7.1 years (95% CI 6.7-7.5 years) in the USA¹. • And is reported in about 10 years in the UK². • Although, survival figures are varied and depend on whether they are from time of reported onset to time of actual diagnosis, in general a diagnosis of Alzheimer’s disease halves life-expectancy. 1. Fitzpatirick and colleagues. 2.Warrell and colleagues .

15. Fortunately, major progress is being made in understanding the cause of Alzheimer's disease and new treatments are being designed to interfere with the known pathological processes in an attempt • To halt them, • Stop disease progression, • And potentially to reverse the disease before neurons are irretrievably lost.

16. The events leading to Alzheimer’s Disease.

17. To understand Alzheimer’s disease, it is necessary to understand current concepts about the two hallmarks of this disorder, that How • Amyloid plaques • and Neuro-fibrillary tangles, are formed in the brain?

18. FOR MANY YEARS, SCIENTISTS HAVE DEBATED WHICH OF THESE TWO ARE MORE IMPORTANT, • The Beta Amyloid Plaques (BAPs) thought to be caused by abnormal processing of Amyloid proteins, • Secondly the Tangles, which are thought to be caused by abnormal phosphorylation of Tau proteins in neuronal microtubules.

19. Although sometimes taking on the tone of religious fervor between these two schools( i.e., the BAP-tists versus the Tau-ists), the consensus now is known as the: AMYLOID CASCADE HYPOTHESIS.

20. This theory posits that Alzheimer’s disease starts with the abnormal processing of Amyloid , which then leads to abnormal phosphorylation of tau proteins as a down stream consequences.

21. AMYLOID CASCADE HYPOTHESIS • This leading contemporary theory for the biological basis of Alzheimer’s disease centers around the formation of toxic Amyloid plaques due to the abnormal processing of Amyloid peptides from Amyloid precursor protein(APP).

22. ONE IDEA IS THAT NEURONS IN SOME PATIENTS DESTINED TO HAVE ALZHEIMER'S DISEASE HAVE ABNORMALITIES EITHER IN: • 1. The enzymes that cut this Amyloid precursor protein (APP) into smaller peptides. • 2.Genes that code for APP.

23. 1. THE ENZYMES THAT CUT THIS APP INTO SMALLER PEPTIDES • There are two pathways that cut the APP into smaller Peptides: • PATHWAY ONE • One pathway for Amyloid Precursor Protiens(APP) processing is the process which does not produce toxic peptides and involves the enzymes alpha secretase.

24. Alpha secretase cuts APP close to the area where the protein comes out of the membrane, forming two peptides: • a soluble fragment known as alpha APP, • and a smaller 83 amino acid peptide. Which remains embedded in the membrane until it is further cleaved by a second enzymes acting within the neuronal membrane, called gamma secretase.

25. Gamma secretase produces two smaller peptides, P7 and P3 from smaller 83 amino acid peptide. Which remain embedded in the neuron, and are apparently not “amyloidogenic” and therefore not toxic.

26. Gama secretase produces P7 and P3

27. PATHWAY TWO • Another pathway for APP processing can produce toxic peptides that form Amyloid Plaques (i.e. “Amyloidogenic” peptides).

28. In this case a different enzyme, Beta secretase, cuts APP a little bit further away from the area where APP comes out of the membrane, forming two peptides: • A soluble fragment known as Beta APP • And a smaller 91 amino acid peptide that remains embedded in the membrane until it is further cleaved by Gamma secretase within the membrane.

29. This release A-Beta peptides of 40-42-43 amino acids, that are “amyloidogenic,” especially A-Beta-42.

30. Gama secretase produces A-Beta peptides of 40,42 and 43 from Smaller amino acid 91.

31. In Alzheimer's disease, genetic abnormalities may produce an altered APP that, when processed by this second pathway involving Beta secretase, produces smaller peptides that are especially toxic. • Individual who do not get Alzheimer's disease may produce peptides that are not very toxic or may have highly efficient removal mechanisms that prevent neuronal toxicity from developing.

32. The amyloid cascade hypothesis of Alzheimer's disease therefore begin with an APP that is hypothetically genetically abnormal; • therefore, when it is processed into smaller peptides, those peptides are toxic, or Amyloidogenic. • HYPOTHETICALLY, THIS TRIGGERS A LETHAL CHEMICAL CASCADE THAT ULTIMATELY RESULTS IN ALZHEIMER'S DISEASE.

33. So, • Specifically , abnormal genes cause the formation of an altered Amyloid Precursor Protein(APP), which is first processed into toxic A-beta-42 peptides.

34. What Next,

35. The A-beta-42 form oligomers (a collection of a few copies of A-beta-42 assembled together.) • These oligomers can interfere with synaptic functioning and neurotransmitter actions such as those of acetylcholine, but they are not necessarily lethal to the neurons.

36. Eventually, A-beta-42 oligomer form amyloid plaques, which are even larger clumps of A-beta-42 peptides stuck together with a number of other molecules.

37. FUTHER MORE:

38. A NUMBER OF NASTY BIOCHEMICAL EVENTS THEN OCCUR: • including inflammatory responses, • activation of microglia and astrocytes, • With release of toxic chemical including cytokines and free radical.

39. These chemical events then hypothetically trigger the formation of tangles within neurons by altering the activities of various kinases and phosphates, • Thus causing hyper-phosphorylation of Tau- proteins, • and converting neuronal microtubules into tangles.

40. Finally wide spread synaptic dysfunction from A-beta-42 oligomers , and neuronal dysfunction and death from formation of amyloid plaques outside of neurons and neuro-fibrillary tangles within neurons.

41. Lead to diffuse neuronal death in the cortex in and the relentless progression of Alzheimer symptoms of : • AMENSIA, • APHASIA, • AGNOSIA, • APRAXIA, • AND EXECUTIVE DYSFUNCTION.

42. :THE ONSET OF ALZHIEMERS: • Early onset Alzheimer occurs due to mutation on chromosome 21 codes for a defect in APP, leading to increased deposition of beta amyloid. • Recall that down’s syndrome is also a disorder of this same chromosome (i.e. trisomy21) and virtually all such persons develop Alzheimer’s disease if they time past age 50 years.

43. A different mutations on chromosome 14 and 1 by presinlin 1 and presenilin 2, the component of Gama secretase have been hypothesized, • leading to the pathophysiology of usual sporadic, non familial and late onset case of Alzheimer’s disease.

44. Apo-E AND THE RISK OF ALZHEIMER’S DISEASE • A deduction from already proven proposition of the amyloid cascade hypothesis, is the possibility that something may be wrong with a protein that binds to amyloid in order to remove it. • THAT PROTEIN IS CALLED APO-E.

45. In the case of “good” Apo-E, it binds to Beta Amyloid and removes it, preventing the development of Alzheimer’s disease and dementia.

46. In the case of “Bad” Apo-E, a genetic abnormality in the formation of Apo-E causes it to be ineffective in how it binds to Beta Amyloid. • This causes Beta Amyloid to be deposited in neurons ,which then goes on to damage the neurons and cause Alzheimer’s disease.

47. Genes coding for Apo-E are associated with different risks for Alzhimer’s disease. There are three alleles (or copies) of this gene coding for this Apo-lipoprotien called E2, E3, and E4.

48. Having one or two copies of E4 increases the risk of getting Alzheimer’s disease, and Alzheimer patients with E4 have more Amyloid deposits.

49. GLUTAMATE HYPOTHESIS OF COGNITIVE DEFICIENCY IN ALZHEIMER’S DISEASE: