Alzheimers Disease 2023 PDF

Alzheimer’s Disease José O. Colón Sáez, PhD. FARM-7225 Objectives • Understand the basic pathophysiology of Alzheimer’s disease. ✓b-Amyloid: plaques ✓Tau: tangles ✓Cholinergic Hypothesis • Alzheimer’s disease treatment: ✓Memantine AChEIs ✓Rivastigmine ✓Tacrine ✓Galantamine ✓Donepezil ✓Aducanumab...

Alzheimer’s Disease José O. Colón Sáez, PhD. FARM-7225 Objectives • Understand the basic pathophysiology of Alzheimer’s disease. ✓b-Amyloid: plaques ✓Tau: tangles ✓Cholinergic Hypothesis • Alzheimer’s disease treatment: ✓Memantine AChEIs ✓Rivastigmine ✓Tacrine ✓Galantamine ✓Donepezil ✓Aducanumab ✓Lecanemab Cause of Alzheimer’s • There is no clear cause. ✓More likely the result of a combination of inter-related factors, including genetics and environmental factors; range from previous head trauma to educational level to one’s experiences early in life. • A growing body of research is also helping to identify various “lifestyle factors,” such as dietary habits, high blood pressure and high cholesterol, which may influence risk. • Develops as a result of a complex cascade of biological processes that take place over many years inside the brain. Brief History • In 1906, Dr. Alzheimer observed a patient, Auguste Deter, in a local asylum who exhibited strange behaviors. He followed her care and noted her memory loss, language difficulty and confusion. Alois Alzheimer • After her death at the age of 51 he examined her brain tissue. The slides showed what are now known as plaques and tangles that are recognized as Alzheimer’s disease. • In 1911, Doctors were using Dr. Alzheimer’s research to base diagnosis. • In the 1960’s British pathologists determined that AD was not a rare disease of the young but rather what had been termed “senility.” Auguste Deter • In the 1990’s researchers identified that the b-amyloid protein was a factor in AD. Impact http://www.alz.org/documents_custom/2017-facts2017_infographic.pdf Alzheimer’s Prevalence Dementia cases in U.S. Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128. Year Patients (millions) 2010 5.8 2020 6.8 2030 8.7 2040 11.8 2050 14.3 Symptom for Alzheimer’s • Difficulty performing familiar tasks. ✓Preparing a meal, using household appliances… • Memory loss that affects job skills. ✓Confused that and unable to concentrate. • Problems using language ✓Less fluent, difficulty writing coherently. • Disorientation to time and place. ✓Forget what year it is and can become lost on familiar streets and not be able to find their way home. • Loss of good judgment. ✓Wearing inappropriate clothing or suddenly giving away large amounts of money. Symptom for Alzheimer’s • Problems with abstract thinking. ✓Forget the meaning of numbers. • Misplacing things. ✓Putting things in unusual places. • Rapid mood swings. ✓Unexplained anger or going from apparent calm to sudden crying. • Personality changes. ✓Changes in personality are often sudden and dramatic. • Loss of initiative, sleeping longer than usual, and loss of interest. ✓In the usual activities can be signs of depression but are also warning signs of Alzheimer’s disease. Stages of Alzheimer’s Stage 1: Normal Mentally healthy person Stage 2: Normal aged forgetfulness >65 cognitive and/or functional difficulties. Stage 3: Mild cognitive impairment Executive functioning becomes compromised. Stage 4: Mild Alzheimer’s disease ↓ ability to manage instrumental (complex) activities of daily life Stage 5: Moderate Alzheimer’s disease ↓ ability to choose proper clothing to wear for the weather conditions and/or for the daily circumstances (occasions). Stage 6: Moderately severe Alzheimer’s disease The ability to perform basic activities of daily life becomes compromised. Stage 7: Severe Alzheimer’s disease Patients require continuous assistance with basic activities of daily life for survival. Neuropathology of Alzheimer’s Disease Inside the Brain Cortex Ventricles Hippocampus The Alzheimer brain: • The cortex shrivels up, areas involved in thinking, planning and remembering are damaged. • Shrinkage is especially severe in the hippocampus, an area of the cortex that plays a key role in formation of new memories. • Ventricles (cerebrospinal fluidfilled spaces within the brain) grow large. Source: Alzheimer’s Association: http://alz.org/alzheimers_disease_4719.asp Brain Tour Neuropathology of Alzheimer’s Disease • AD is characterized by loss of neurons and synapses. Alzheimer’s Normal ✓Cerebral and frontal cortex, temporal and parietal lobe, and cingulate gyrus. • Amyloid plaques and tangles are clearly visible . Source: Image from the Alzheimer’s Society of Saskatchewan ✓Many older individuals develop some plaques and tangles as part of normal aging; AD patients have a greater number of them in specific brain regions such as the temporal lobe. Neuropathology of Alzheimer’s Disease • Plaques: dense, mostly insoluble deposits of β-Amyloid peptides and cellular material outside and around neurons. • Tangles: tau deposits. ✓Microtubule-associated protein, that becomes, hyper phosphorylated and accumulates inside of nerve cells. Neuropathology of Alzheimer’s Disease Exactly how disturbances of production and aggregation of the bamyloid peptide gives rise to the pathology of AD is not known. • b-amyloid hypothesis: their accumulation is the central event triggering neuron degeneration. ✓Believed to induce apoptosis. ✓Builds up in the mitochondria inhibiting certain enzymes and the utilization of glucose by neurons. • Various inflammatory processes may also have a role in the pathology of Alzheimer's disease. ✓Inflammation may be secondary to tissue damage or a marker of an immunological response. Cholinergic Hypothesis • Role: ✓Acetylcholine (ACh) is an important in brain regions involved in memory. neurotransmitter • Impact: ✓ Loss of ACh in AD correlates with impairment of memory. • Treatment approach: ✓Enhancement of cholinergic function may stabilize or improve et al. N Engl J Med. 1999;341:1670-1679. cognitive function and may Mayeux affect Rbehavior and daily functioning. Cholinergic Hypothesis Nucleus basalis: group of neurons in the forebrain rich in choline acetyltransferase. ✓In AD undergoes degeneration. • ↓ ACh production → abnormal brain function (↓ mental capacity and learning). • Atrophy of the nucleus basalis of Meynert, the source of choline acetyltransferase, causes a cholinergic deficit. ✓Cholinergic therapy partially improve behavioral symptoms of AD. • Cholinergic therapy does not interrupt the disease process. • It may contribute to behavioral symptoms of AD ✓ Psychosis-agitation ✓ Dis-inhibition ✓ Apathy-indifference ✓ Aberrant motor behavior Treatment of Alzheimer’s Disease There is no way to stop the progression or cure AD. • Researchers are making advances in treatment, including medications and non-drug approaches to improve symptom management. Drugs used to treat people with Alzheimer’s fall into two broad categories: ✓Drugs to treat cognitive symptoms, such as memory problems and other mental deficits of Alzheimer’s. ✓Drugs to treat behavioral symptoms that do not respond to nonpharmacological behavioral-management approaches. • These drugs might include a variety of types of drugs broadly categorized as anti-agitation drugs. Oda et al, 2014 FDA Approved drugs for Alzeihemer’s • Namenda® Memantine *Paxil 3% *Zyprexa 3% • Razadyne, Reminyl® Galantamine • Exelon® Rivastigmine • Aricept® Donepezil • Cognex®* Tacrine Other 25% *Zoloft 3% Vitamin E 3% *Ativan 4% *Haldol 6% Aricept 44% *Risperdal 9% *These uses are investigational. Source: National Disease and Therapeutic Index, 1998. Alzheimer’s Disease Treatments AChE inhibitors (Jeger 2013) First FDA-approved therapies to treat the cognitive symptoms of early AD and remain the first line of therapy today. Although effective at improving the memory and cognitive function the beneficial effects are typically short lived (desensitization). • Donepezil (Aricept) • Rivastigmine (Exelon) • Galantamine (Razadyne) • Tacrine (Cognex) Hypothesized Treatment Effect in Alzheimer’s Disease Untreated Cholinesterase Inhibitor (CI) 6– Cognitive Function (ADAS –Cog) 4– 2– 0– -2 – -4 – -6 – -8 – -10 – -12 – -14 – -16 – 1 year 2 years FDA Approved drugs for Alzeihemer’s • Moderate/Severe AD: Namenda (memantine): regulates glutamate in the brain. ✓Delay the worsening of symptoms in some people. ✓Allow patients to maintain certain daily functions a little longer than they would without the medication. • Mild/Moderate AD Cholinesterase inhibitors ↑ the levels of ACh in the brain, which plays a key role in memory and learning. ✓Postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it. ✓Most prescribed for AD include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine). Tacrine (Cognex) • First drug with anti-AChE and other cholinomimetic actions used for the treatment of mild to moderate AD. • Efficacy is modest, and hepatic toxicity is significant. ✓Half-life of 3–5 hours (variable, affected by food intake). • 4-times-daily dosing of 10 to 40 mg (40 to 160 mg/day). ✓Associated with hepatotoxicity (monthly liver testing suggested). • Metabolize by hepatic Cytochrome p450. ✓Adverse gastrointestinal effects (somewhat alleviated by concomitant food intake). Tacrine has been discontinued in the US in 2013, due to concerns over safety. Second generation AChE Inhibitors • Donepezil, Galantamine, and Rivastigmine are newer, more selective AChE inhibitors that appear to have the same modest clinical benefit as Tacrine but with less toxicity. • Donepezil may be given once daily because of its long halflife (70 hrs), and it lacks the hepatotoxic effect of tacrine. ✓No trials comparing these newer drugs with tacrine have been reported. Donepezil (Aricept) • Most widely used drug to treat the symptoms of AD. ✓t 1/2 ~ 70 hours (Once-a-day dosing of 5 to 10 mg). ✓Long-term efficacy is maintained for up to 50 weeks. • Metabolize by hepatic CYP450. • Higher doses associated with cholinergic side effects, but generally well tolerated. ✓ Nausea (17%) ✓ Fatigue (8%) ✓ Diarrhea (17%) ✓ Muscle cramps (8%) ✓ Vomiting (10%) Rivastigmine (Exelon) • Available as capsule, liquid, and patch. ✓Low oral bioavailability (about 40%). ✓t 1/2 ~ 1.5 hours (multiple doses a day). ✓3-times-daily dosing of 2-4 mg (6-12 mg/day). • Metabolism independent of hepatic CYP450. • Gastrointestinal adverse events are common, including weight loss. • Inhibits Acetylcholinesterase and butyrylcholinesterase. • Rivastigmine is generally safe and well tolerated, although cholinergic side effects occur at high doses. Exelon package insert. ® Galantamine (Razadyne) • Dual mechanism of action. ✓Competitive inhibition of AChE. ✓Allosteric modulation of pre and postsynaptic nicotinic receptors. • May increase release of ACh (and other neurotransmitters). • May have a neuroprotective effect. • Delays the worsening of Alzheimer's symptoms for 6 to 12 months in about half of the people who take it. • Between 80 and 100% oral bioavailability. ✓t 1/2 ~ 7 hours (4 mg twice a day). ✓Comes in extended release, once-a-day tablet. • Metabolized hepatically by Cytochrome P450. Dual Mechanism of Action N = nicotinic Presynaptic nerve terminal ACh = acetylcholine N receptor Galantamine ACh Postsynaptic nerve terminal • Choline • Acetic acid Galantamine  ACh and other neurotransmitters N receptor Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170. Tariot PN et al. Neurology. 2000;54:2269-2276. Cholinesterase Inhibitors • Side-effect profiles are similar: ✓Tacrine: liver toxicity, nausea, vomiting, diarrhea ✓Donepezil: nausea, vomiting, diarrhea, muscle cramps ✓Rivastigmine: nausea, vomiting, diarrhea, headache, dizziness ✓Galantamine: nausea, vomiting, agitation, sleep disturbances The transdermal rivastigmine patch is associated with less frequent gastrointestinal effects. Aducanumab Amyloid beta-directed antibody approved under the accelerated approval pathway. https://www.cnbc.com/2022/01/04/why-biogens-alzheimers-drug-aduhelm-is-so-controversial-.html