Pathophysiology of Alzheimer's disease

Alzheimer's disease is a progressive disorder that causes brain cells to waste away (degenerate) and die. Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently.
Symptoms: Amnesia; Dementia
Diseases or conditions caused: Dementia
Pathophysiology
Pathology
BPharm 2nd Semester
MPharm
Therapeutics
MBBS

1. Maharshi Dayanand University Department of Pharmaceutical Sciences Assignment of: Pathophysiology On topic: Pathophysiology of Alzheimer's Disease विद्यया विन्दतॆऽमृतम् Submitted By: Deepanshu Goyal B.Pharm 2nd Sem Submitted To: Dr. Vineet Mittal Dept. of Pharmaceutical Sciences M.D.U. Rohtak

2. Alzheimer's Disease or Alzheimer or just AD is An irreversible, progressive cerebral disease of lowly know etiology that slowly destroys intellectual and cognitive functions and hence the ability to reason, remember, learn and imagine. This disease lasts at least six months Alzheimer is the most common cause of Dementia, which is not a disease itself, but a symptom. AD leads to a state of confusion, loss or poor memory, decreased learning ability, mood and emotional instability, personality changes and premature death. It affects many parts of Brain, but Neocortex, Amygdala and hippocampus are most affected and severe dysfunction may lead to Aphasia. The first case was studied and described by a German Psychiatrist and Neuropathologist – Dr. Alois Alzheimer in 1906. Introduction Healthy Neuron Diseased Neuron Disintegrating Microtubules β Amyloid Plaques Tau Proteins Microtubules Axon

3. Epidemiology and Statistics A bit more prevalent in Females with 65% of the cases On average, a person with Alzheimer's lives four to eight years after diagnosis, but can live as long as 20 years. Generally it affects more to the people aged more than 65 and around half of the cases being in patients above the age 85. Currently around 4.5 Million people have AD and predictions claim 1 in every 85 people will be suffering from AD globally in 2050. Most of the cases are sporadic while 5-10% are Familial.

4. Features Of Alzheimer’s Disease Cl inical General Body weakness Bed ridden Memory Loss of recent events that progresses to Dementia Loss of methodology of tasks and motor skills of Familiar tasks Loss of Lingual ability i.e. ability to converse. Mood and Personality Disturbances Disorientation to time and place More prone to infections, most common being Rhinitis, Pneumonia Sleeplessness Anxiety Depression

5. Normal Brain Advanced A.D. Brain Macroscopic Examination of Brain shows: Destruction of Neurons and their connections Neuritic -Amyloid Plaques Neurofibrillary Tangles Inflammation Atherosclerosis of Brain Arteries Cortical Atrophy Ridges of Brain called Gyri Shrinks Grooves of Brain called sulci widens Ventricular Enlargement Shrinkage of Hippocampus Pathologic changes In Entorhinal Cortex

6. Stages of Alzheimer’s Disease Mild Person may function independently, drive, work etc. Person feels of having memory lapses Common Difficulties include Remembering word or name Losing or Misplacing objects Increased trouble in Strategy, Planning etc. Can live well with proper health maintenance Moderate Longest Stage – Can last for many years Require greater level of care with the progression More Dementia symptoms Confusion with words, days Frustration and anger Change in sleep pattern Unexpected Acts/delusions/suspicions Difficulty expressing Thoughts Feeling moody or withdrawn Need assistance in performing routine works Trouble controlling Bladder Severe Severe Dementia symptoms Loss of ability to respond to environment Inability to carry on a conversation Expressing pain is difficult Round the clock assistance required More vulnerable to infections Hospice care The symptoms of Alzheimer's disease worsen over time with varying progression rate. Changes in the brain related to Alzheimer's begin years before any signs of the disease. This time period, which can last for years, is referred to as preclinical Alzheimer's disease. It may be difficult to place a person with Alzheimer's in a specific stage as stages may overlap.

7. Pathophysiology of Alzheimer’s Disease Amyloid β Chopped at here by β secretase Chopped at here by α secretase Chopped at here by ɣ secretase Cell membrane of Neuron In the Neuronal cell membrane, there is a protein embedded called Amyloid Precursor Protein [APP] with one end inside and other outside. Its function is related to growth and repair of Neuron, but it gets used up/broken itself and recycled. It is chopped off by α , β and ɣ secretase enzymes with the location of their splice can be seen in the image beside. ɣ always works either with α that leads soluble products or with β that leads insoluble product known as Amyloid β , which is sticky, hence it makes clumps called β Amyloid Plaques just outside the neuron. The clump when comes in synaptic cleft between two neurons, disrupt the communication and signaling, impairing the respective function, especially memory, and can also initiate an immune response.

8. These plaques may deposit in or around the brain’s blood vessels causing Atherosclerosis or Amyloid Angiopathy respectively and later on hemorrhage. Cytoskeleton is a network of microtubules attached together with τ (tau) proteins in the cell that acts like a pathway for internal transport, signaling and structural support.. Without τ proteins, microtubules would detach leading to disruption of Transport and signaling pathway. β Amyloid Plaques may activate kinase which attach phosphate group to τ proteins which help in transport and bridge between two microtubules and this activation cause tangling of these proteins called Neurofibrillary tangles along with disruption of cytoskeletal and microtubular function and further towards Apoptosis. Too much of Apoptosis leads to Atrophy of the various regions of the brain, shrinkage of Gyri and widening of sulci and ventricles. Pathophysiology of Alzheimer’s Disease (continued…)

9. Difference in Sporadic and Familial Alzheimer Disease This image shows the Neurofibrillary Tangle

10. Various Factors… Neurochemical Factors Acetylcholine Somatostatin Substance P Norepinephrine Genetic Factors Apolipoprotein 4 (APOe4) allele – Larger content of β Amyloid Plaque Down’s Syndrome Environmental and Lifestyle Certain Infections that can cross blood Brain barrier Use of statins Heavy Metal and other Toxins Gender – Women are more likely Risk Factors Family History Chronic Hypertension Smoking Alcoholism Age Diabetes Cardiovascular Diseases ApoE3 ApoE2 ApoE ApoE4

11. Etiological Factors Changes in Nerve cell Proteins Accumulation of neurofibrillary Tangles and Plaques Granulo -vascular Degeneration Loss of Cholinergic Nerve Cells Loss of Memory, Function and Cognition Layout Diagram for Alzheimer’s Disease

12. Hypotheses Impaired Proteostasis and Axonal Transport Impaired Presenilin (a component of secretase) Function Ca 2+ Dysregulation Soluble oligomer production Amyloid Plaque Formation Age, Oxidative stress, Amyloid β /Presenilin dysfunction Lysosome Autophagy Dysfunction Amyloid β Mutation Aggregated Hyperphosphorylated τ proteins Due to amyloid β overproduction Neurodegeneration Synaptic Dysfunction Neurotoxicity Synaptic toxicity Neurotoxicity

13. Diagnosis Psychiatric and/or Neuropsychological assessments Advanced Imaging Techniques Patient’s and Collateral History Clinical and Pathological Features Advanced Brain imaging techniques:  Computed tomography (CT)  Magnetic Resonance Imaging (MRI)  Positron Emission tomography (PET) Brain Biopsy CSF Examination Electroencephalography (EEG)

14. Treatment Pharmacological Acetylcholine esterase inhibitors like Donepezil prevent breakdown of Acetylcholine, an important chemical messenger NMDA receptor Antagonist like Memantine to stop overstimulation of NMDA receptors by Glutamate Antidepressants Antipsychotics Anticonvulsants Psychosocial Behavioral and Emotion oriented approach Reminiscence therapy Validation Therapy Supportive Psychotherapy Sensory integration Stimulated presence therapy Cognition oriented approach Stimulation oriented approach Caregiving Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs… Caregiving essentially is the treatment and must be carefully managed over the course of the disease with provided Nursing and Facilities to help the Patients for his or her needs and keeping them away from stress and anxiety. S adly , but as of now there is no cure to Alzheimer’s Disease, but the following interventions can be underwent to help the patient deal with the symptoms

15. Prognosis With Alzheimer’s Disease, comes the increased risk of Infections. Along with this other problems related to age such as Stroke, Cancer, Cardiovascular disease etc. arise which may deteriorate the patient’s physical and metal condition. Prevention Blockage of production of Amyloid in the brain as well as breaking down of the β Amyloid once it is released from your cell before its aggregation and development into insoluble plaques. Research and Studies are under conduction to develop an AD vaccine where immune responses may result in the elimination of formation of Amyloid Plaques.

16. Bibliography: The data was retrieved from various sources as follows: Kumar, Abbas et al – Pathologic Basis of Disease – Elsevier Publishers – 9 th edition – Pg. 1313 to 1317 Grossman S, Carol MP – Porth’s Pathophysiology – Lippincott Publishing – 9 th Ed – Pg. 563 to 566 www.nhs.co.uk – Alzheimer’s Disease Causes Kaushik M - Textbook of PATHOPHYSIOLOGY - PV publishers – 2017 – Pg. 268 to 270 www.cdc.gov – What is Alzheimer’s Disease? www.wikipedia. o rg – Alzheimer’s Disease www.ajc.com – What you need top know about Alzheimer’s Disease www.nia.nih.gov – Alzheimer’s Disease Fact Sheet www.medicalnewstoday.com – What to know about Alzheimer’s Disease?

17. THANK YOU…