Pathology and Treatment By Fiona Nicholson

Alzheimer’s Disease Overview History of AD Diagnosis of AD Stages Risk Factors Physiology Treatment

History of AD Auguste D. Alzheimer’s disease was characterized by Dr. Alois Alzheimer in 1906 after performing an autopsy on his patient, Mrs. Auguste D. who was thought to have “amnesiac writing disorder.” Dr. Alzheimer noted “peculiar formations” (amyloid plaques) and “dense bundles” (neurofibrillary tangles). During the autopsy, a substance was noted that was later characterized as the beta-amyloid protein. Dr. Alois Alzheimer

How common is Alzheimer’s? Out of all the neurogenerative diseases, Alzheimer’s has the highest prevalence at 1.450/100,000 The incidence and prevalence of this disease increases with age; between the ages of 65-69, the prevalence is 1.53%, and between the ages of 80-85, the prevalence increases to 25-30% of the population

Diagnosis of AD No direct confirmatory test exists Diagnosis of AD is based on careful clinical assessment which can include medical interviews Laboratory tests are conducted to eliminate the possibility of other diseases that can mimic the AD Neuropsychological tests are conducted to assess the cognitive symptoms Brain scans can show the progression of AD and how the disease influences brain activity

Stages of Alzheimer’s Disease Stage 1: No impairment No memory problems are evident to a health care professional during an interview Stage 2: Very mild cognitive decline Patients may feel they have memory lapses (such as forgetting keys), but these are not evident during a medical interview Stage 3: Mild cognitive decline Friends, family, and coworkers notice memory decline, and the decline is measurable in a clinical setting. Examples are decreased ability to remember names when introduced to new people, losing or misplacing a valuable object, and reading a passage and retaining little information Stage 4: Moderate cognitive decline (early to mid stage AD) AD is able to be diagnosed at this stage, and decreased cognitive ability is very evident in the following areas: decreased ability to recall information about recent occasion, decreased ability to perform mental arithmetic, impaired ability to pay pills and manage finances, reduced memory of personal history. Patients may seem withdrawn in complex situations

Stages of Alzheimer’s Disease Stage 5: Moderately severe cognitive decline (moderate or mid-stage AD) Major deficits in memory and difficulty in cognitive function; AD patients require some assistance with daily activities. Patients may not be able to recall their phone number or current address and can be confused about what day or the week or what season it is. Patients maintain knowledge about themselves, such as their name and the names of close family members. Stage 6: Severe cognitive decline (moderately severe AD) Memory deficits worsen and personality changes are evident. Patients tend to lose awareness of recent events, cannot recollect personality history accurately, need help with everyday activities, and can wander and become lost. Stage 7: Very severe cognitive decline (severe or late-stage AD) Patients lose the ability to respond to the environment, lose the ability to speak, and lose control over their movement.

Risk Factors for AD Age Genetics Lifestyle Head trauma Clinical depression Down’s syndrome Environmental toxins

What causes AD? According to Goodman and Gilman, AD is “characterized by marked atrophy of the cerebral cortex and loss of cortical and subcortical neurons.” (p. 538) Areas of the brain affected:

Physiology of AD 2 Hallmarks of Alzheimer’s Disease 1. Amyloid Plaques 2. Neurofibrillary tangles

Amyloid Plaques Found in the spaces between nerve cells Composed of an insoluble protein peptide called beta-amyloid, other proteins, and remnants of other brain cells (neurons, non-nerve cells, and glial cells) Plaques develop in the brain in many people as they age, but in AD patients, plaques develop in the cognitive areas.

Neurofibrillary Tangles Tangles develop inside nerve cells Abnormal collections of twisted protein fibers Protein threads are composed of the hyperphosphorylated tau protein

Healthy Neuron Neuron with AD

Shrinkage of cerebral cortex Enlarged ventricles Shrinkage of hippocampus

Three Hypotheses Concerning AD Development Amyloid Cascade Hypothesis Tau Hypothesis Cholinergic Hypothesis

Amyloid Cascade Hypothesis The initiating event that leads to the formation of plaques is an excess of Αβ peptides. Patients with missense mutations in the APP, Presenilin 1, and Presenilin 2 genes (“Alzheimer’s genes”) are prone to overproduction. Patients without AD genes start to overproduce Αβ peptides from a failure of metabolism. The response to the excess of Αβ peptides involves an inflammatory response and free radical formation. This toxic cascade, induced by amyloid accumulation, eventually leads to the organization into plaques.

Tau Hypothesis In healthy neurons, Tau normally has a certain amount of phosphate molecules attached, and binds to microtubules and stabilizes them. In an AD neuron, tau is hyperphosphorylated which disengages the protein from the microtubules. The resulting detached tau proteins group together and form tangles. The microtubules disintegrate, which leads to the collapse of the neuron’s transport system.

Cholinergic Hypothesis Acetylcholine biosynthesis is reduced in the presence of plaques and tangles. Because less of a neurotransmitter (acetylcholine) is synthesized, this leads to a loss of neurons. Thus, even more brain cells are lost than usual, which can lead to AD.

There is no cure for Alzheimer’s disease! The following treatments can alleviate symptoms or slow the progression of the disease.

Treatment 1. Symptomatic Treatments: a) Acetylcholinesterase Inhibitors b) NMDA-receptor Antagonists 2. Disease-modifying Treatments: a) Inhibition of amyloid formation b) Inhibition of abeta aggregation c) Tau phosphorylation inhibitors 3. Other Therapies: a) Gingko biloba b) Estrogen therapy for women c) Anti-inflammatory drugs: aspirin 4. Life Style Changes a) Stress control b) Monitor Diet c) Cognitive Stimulation 5. Psychotic Treatments: a) Antidepressants b) Anti-anxiety medicine c) Antipsychotics

1a) Acetylcholinesterase Inhibitors Disadvantages: With long term use, these drugs increase the overall level of Ach in the body which causes gastrointestinal side effects bradycardia, hypotension, hypersecretion, bronchoconstriction, GIT hypermotility, and decrease intraocular pressure. “Smart drugs” Decrease the rate that Ach is broken down, therefore increasing Ach concentration Treatment with these drugs does not cure Alzheimer’s, but they do help to alleviate symptoms These drugs have to be able to cross the blood brain barrier sufficiently More beneficial in early stages of Alzheimer’s versus later stages

Acetylcholinesterase Inhibitor Examples Tacrine 1st drug to be approved for treatment of Alzheimer’s in 1993 No longer clinically used because of its extremely toxicity Donepezil (Aricept) No definitive proof exists that this drug slows down the progression of Alzheimer’s, but studies show benefits in behavior and cognition

Acetylcholinesterase Inhibitor Examples Rivastigmine (Exelon) significant treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioral problems have been observed Treatment for mild to moderate dementia Galantamine (Razadyne) Treatment for mild to moderate Alzheimer’s Extracted from daffodils or snow-drop bulbs

1b) NMDA Receptor Antagonists Hypofunction of the NMDA receptor is thought to contribute to memory deficits associated with old age. Memantine (Axura) Targets the cholinergic system Acts as an noncompetitive antagonist at the 5HT3 receptor

2) Disease-modifying Treatments: Used to treat moderate to severe forms of AD a) Inhibition of amyloid formation to inhibit the toxic cascade that leads to amyloid formation b) Inhibition of abeta aggregation to inhibit the overproduction of the abeta peptide c) Tau phosphorylation inhibitors to prevent hyperphosphorylation of Tau proteins and maintain microtubules

3a) Other Therapies: Ginkgo Biloba Ginkgo biloba is thought to improve thinking, learning, and memory in AD patients Ginkgo has antioxidant properties and increases Ginkgo is used preventively because it is thought to delay the onset of AD in patients that are at higher risk

4. Life Style Changes a) Stress control b) Monitor Diet c) Cognitive Stimulation d) Social and Visual Stimulation

Applicable in later stages of AD a) Antidepressants 5. Psychotic Treatments Applicable in later stages of AD a) Antidepressants b) Anti-anxiety medicine c) Antipsychotics

Noteworthy Cases of AD Ronald Reagan Rita Hayworth Charlton Heston