Alzheimer's Disease Past Paper PDF

Alzheimer’s Disease Osama Badary Arwa Mohamed 11/26/2024 1  Alzheimer’s Disease (AD): Overview AD was first recognized in 1906 by the German neuropathologist and psychiatrist , Dr. Alois Alzheimer (1864-1915). Irreversible Progr...

Alzheimer’s Disease Osama Badary Arwa Mohamed 11/26/2024 1  Alzheimer’s Disease (AD): Overview AD was first recognized in 1906 by the German neuropathologist and psychiatrist , Dr. Alois Alzheimer (1864-1915). Irreversible Progressive Neurodegenerative disease Characterized by Memory Impairment plus one or more additional cognitive disturbances Gradual decline in three key symptom domains – Activities of daily living – Behavior and personality – Cognition Most common cause of dementia in people aged 65 and over 11/26/2024 2  Epidemiology of AD AD affects an estimated 1 in 14 people aged over 65 years and 1 in 6people aged over 80 years. Globally, AD is estimated to affect at least 50 million people By 2050, prevalence of AD is expected to reach nearly 100 million globally The prevalence of AD doubles every five years beyond the age of 65. The fifth-leading cause of death among those aged 65 and older and a leading cause of disability and poor health. 11/26/2024 Typical life expectancy after an AD’s diagnosis is four to 3 eight years.  Alois Alzheimer’ first case Auguste Deter In 1901, a German psychiatrist named Alois Alzheimer observed a patient at the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old woman suffered from a loss of short-term memory, among other behavioral symptoms that puzzled Dr. Alzheimer. Five years later, in April 1906, the patient died, and Dr. Alzheimer sent her brain and her medical records to Munich, where he was working in the lab of Dr. Emil Kraeplin. By staining sections of her brain in the laboratory, he was able to identify amyloid plaques and neurofibrillary tangles On Nov 4th, 1906, during a lecture at the 37th Conference of South-West German Psychiatrists in Tubingen, Alois Alzheimer described a peculiar disease of the 11/26/2024 4 cerebral cortex. Pathophysiology (Hallmarks) 1) Amyloid plaques ; 2) Neurofibrillary tangles (NFTs, tau); 3) Synaptic and neuronal cell death. brain atrophy Inflammation. The hippocampus and medial temporal lobe are the initial sites. 11/26/2024 5  Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1. APP sticks through the neuron membrane. 2. Enzymes cut the APP into fragments of protein, including beta-amyloid. 3. Beta-amyloid fragments come together in clumps to form plaques. 11/26/2024 6  AD Neuropathology Multifactorial (difficult treatment). The accumulation of Aβ is thought to be the initial insult, which is the basis for the amyloid cascade hypothesis and abnormal phosphorylation of tau protein, creating the formation of NFTs within neurons. Defect in microglial activation (deficient clearing Aβ in the normal brain). Acetylcholinesterase may promote Aβ assembly by forming stable complexes with Aβ fibrils. (cholinergic neurons are damaged).. Hyperphosphorylated tau and disassembly of microtubules damaging the cytoskeleton and signal transduction in neuronal cells. It is hypothesized that this degeneration contributes to the explanation for memory decline and neuroinflammation (Neuronal damage and death). 11/26/2024 7 11/26/2024 8 Progression of AD 9  Characteristics of Alzheimer Dementia Cognitive or intellectual symptoms - Acalculia (inability to perform simple math calculations), - Aphasia (inability to communicate effectively), - Apraxia (inability to perform ADL such as brushing teeth or combing hair) - Amnesia - Agnosia (loss of the ability to interpret sensory stimuli) Behavioral signs and symptoms — Depression, apathy, and anxiety—( early stages). _ Delusions, hallucinations, and psychosis (latter stages). individuals also may present with extrapyramidal symptoms, such as gait disturbance, myoclonus, tremor, and urinary incontinence. 11/26/2024 10  Types of AD (1) Familial AD (Early-onset AD, 5% ): very rare and typically occurs before the age of 60. gene mutations on chromosomes 1 (Presenilin 2), Rita Hayworth 14 (Presenilin 1), and 21 (APP, amyloid precursor protein). (2) Sporadic (late-onset AD, most). The apo E4 gene, (on chromosome 19Q). APOE2 is neuroprotective 11/26/2024 Ronald Reagan 11  Diagnosis A thorough medical history review, physical examinations, and laboratory tests. Brain imaging techniques, such as MRI or CT scans, help detect structural brain changes associated with AD, while PET scans with specific tracers can identify abnormal protein accumulation linked to the disease. In some cases, CSF analysis or genetic testing might be considered for a more accurate diagnosis, especially in cases of early-onset or familial AD. 11/26/2024 12  Risk factors of AD 11/26/2024 The most significant risk factor 13 for developing the disease is age  Identifying Warning Signs of AD 11/26/2024 14  Mental status assessment Folstein MMSE (range from 0-30 the higher score is better mental function). Heavily relies on verbal and language skills St. Louis University Mental state examination (SLUMS) (range from 0-30 the higher score is better mental function) adjustment for poor education Montreal Cognitive Assessment (MOCA) Mini-Cog Assessment (30 point scale) 5 point scale 11/26/2024 15 11/26/2024 16  Interpretation of MMSE Scores 27-30: Normal cognitive, no dementia 24-26: Possible cognitive impairment 19-23: Mild dementia 10-18: Moderate dementia 0-9: Severe dementia 11/26/2024 17  Mini-Cog 11/26/2024 18  MoCA The MoCA is effective in non-AD dementias and Parkinson's disease. The MoCA is available as a free download from www.mocatest.org. 11/26/2024 19  Family Questionnaire A 5-question family/caregiver assessment of patient status from the Alzheimer’s Association and National Chronic Care Consortium 11/26/2024 20  SLUMSTM – The 11-question St. Louis University Mental Status test used by the Department of Veteran’s Affairs 11/26/2024 21  Reasonable Treatment Goals (1) maintaining QoL, (2) maximizing function and ADLs (activities of daily living ) (3) stabilizing cognition. (4) manage behavioral problems. (5) reduce caregiver distress and burden. 11/26/2024 22  Drugs to Improve AD Symptoms 11/26/2024 23  Drugs (FDA-approved) Improve Symptoms Disease Modifiers 1) acetylcholinesterase (AChE) inhibitors These drugs are used for all Biologicals stages of AD, but inhibition of cholinesterase enzymes works best at the early stage of AD Aducanumab (Aduhelm) Tacrine (1993) (hepatotoxicity) 2021 Donepezil (Aricept 1996: mild- Lecanemab(Leqembi) July to-moderate, 2006:severe) 2023 Rivastigmine (Exelon 2000) Donanemab-azbt (Kisunla) Eli Lily Galantamine (Razadyne 2001) FDA July 2, 2024 2) N-methyl-D-aspartate (NMDA) antagonists Remove beta-amyloid from the Memantine (Namenda) (2003) brain and slow cognitive and 3) (NMDA) antagonist + ACHE functional decline in people living inhibitor with early AD. Namzaric 11/26/2024 24  FDA approved DMT Anti-Aβ antibodies, Aducanumab (Aduhelm) 2021 lecanemab (Leqembi) July 2023 They cannot be prescribed for patients with two copies of that gene 11/26/2024 25 (ApoE4homozygous patients), Donanemab-azbt (Kisunla) Eli Lily FDA July 2, 2024 The first and only amyloid plaque-targeting therapy using a limited-duration treatment regimen based on amyloid plaque removal. In the clinical trial, donanemab reduced amyloid plaques by an average of 61% at 6 months of treatment, 80% at 12 months, and 84% at 17 months compared with the start of the study. Donanemab is administered IVI every 4 weeks, with 700 mg for the first 3 doses followed by 1400 mg thereafter. 11/26/2024 26  Donanemab-azbt Adverse Effects Like lecanemab, amyloid-related imaging abnormalities (ARIA), can occur. ARIA may present as temporary swelling in areas of the brain, which typically resolves with time, or as small spots of bleeding in or on the surface of the brain. ARIA can be serious and life-threatening events may occur. Individuals with ApoE ε4 homozygotes are at higher risk for ARIA; and testing should be performed before treatment initiation In addition to ARIA, the most common adverse effect was headache. There is also a risk for infusion-related reactions, including nausea, vomiting, anaphylaxis, and angioedema. These reactions typically occur during infusion or within 30 minutes post-infusion. 11/26/2024 27  Questions and Controversy With Aducanumab The controversial approval and lack of Medicare funding has resulted in the recent announcement that it will be discontinued in November 2024. “The approval process for aducanumab specifically was very strange,”. The FDA went against the advisory committee recommendation in its approval.” As a result of this decision, 2 members of the advisory board resigned The FDA approved aducanumab in June 2021, the first therapy targeting the underlying pathophysiology of AD. Three separate studies with 3482 participants evaluated the efficacy of aducanumab, but 2 of the studies (EMERGE and ENGAGE ) quickly came under fire for their contradictory results. Although they had identical study designs and the same primary end point, differing study protocols and premature termination of both trials may have led to their contradictory results, in which the high- dose treatment arm in the EMERGE study was the only arm among both trials to demonstrate cognitive improvement. 11/26/2024 28  Aducanumab Controversy Biogen performed extensive subgroup analyses to try and explain these different results, with 2 potential reasons. Firstly, it was noted that there were more individuals who had a rapid decline in the ENGAGE trial than in the EMERGE trial, and removing these outliers from the data set made the results of the 2 trials more compatible. Second, a smaller number of participants in the ENGAGE trial had received the higher doses of the drug. When the label was first released, it did not specify in which stage of the disease the drug should be initiated. In earlier stages of its development, investigators were using anti-amyloid antibodies in patients with more severe moderate stages of disease before learning that these drugs work best in earlier stages. The original label had no requirement for the drug to be used in patients with confirmed amyloid pathology. Medicare officials announced that they would only cover aducanumab for individuals who receive it as part of a clinical trial. Physicians and entire medical centers also announced that they would not be administering the drug due to concerns about its safety and adverse effects, including ARIA. 11/26/2024 29  Aducanumab Discontinuation Nov 2024 Although there was excitement for the phase 4 confirmatory trials to prove aducanumab’s clinical benefit, Biogen decided in January 2024 to terminate the trials and to discontinue the drug’s development and commercialization. The company stated that this decision was due to a reprioritization of funds toward Biogen’s Alzheimer disease pipeline, such as the continued advancement of lecanemab, and not based on investigators’ safety or efficacy concerns. Biogen announced in January 2024 that Aduhelm would be discontinued in November 2024, allowing clinical trial participants access until May 1, 2024, and those receiving it by prescription until Nov. 1, 2024. 11/26/2024 30  Shared Decision Making 11/26/2024 31  Pharmacist roles in AD From the Community to the Clinic 1. Counsel on risk and prevention Anticholinergics, benzodiazepines, proton pump inhibitors, and certain pain medications are associated with an increased risk for Alzheimer disease,as are some chronic conditions. Lifestyle education, diabetes prevention, and all of those things that we know to be potentially reversible causes of dementia.” Due to the high frequency of interactions that a pharmacist has with their patients, they might be one of the first providers to recognizesigns of cognitive decline, especially for cases in which the pharmacist-patient relationship is longstanding. In such instances, a pharmacist can first review medication lists and identify drugs that may be inducing dementia-like symptoms. 2. Enhance medication compliance. To assist with this, pharmacists can makemedication packaging more user-friendly by using easy- open caps, blister packs, and pill organizers. Additionally, as AD progresses,dysphagia is common, which leads to issues with not only swallowing, but also medication adherence. For example, donepezil comes as an oral disintegrating tablet, and rivastigmine is available as a transdermal patch and an oral solution.Other medications taken by the patient may also be inducing esophageal irritation. 32 11/26/2024  Pharmacist roles in AD From the Community to the Clinic 3. Educate on available drugs As disease-modifying agents, the newest drugs for Alzheimer disease target aggregated forms of amyloid, which experts believe underlies the progress of the disease. Aducanumab targets soluble oligomers and fibrils. Lecanemab targets oligomers and protofibrils. A pharmacist can offer up to date knowledge on the clinical evidence behind new drugs, serving as a source of guidance for patientsamongst the controversy with DMT and other new medications. On the other side of the coin, mainstays such as cholinesterase inhibitors and memantine lessen some of the symptoms of the disease but do not interfere with its progress. Pharmacists can help patients and their caregivers have more reasonable expectations of these therapies. Given that older drugs address symptoms only and new drugs are not yet readily accessible, pharmacists might call patients’ and caregivers’ attention to clinical trials and point them toward channels for enrollment. 4. Eliminate dangerous drugs Pharmacists from the community pharmacy to the clinic can make a major impact in this area by identifying and potentially eliminating drugs that may exacerbate dementia symptoms. 5. See signs, recommend resources, make referrals They can take note of whether patients of concern are getting their prescriptions filled regularly and their demeanor when they do so. Pharmacists also have the opportunity to gauge caregivers’ concerns about changes in their loved one’s condition. “We can think about drug formulations, adherence devices, and offering referrals to a geriatrician or a neurologist.” A pharmacist can be a key source in providing information onsupport services and referrals to appropriate providers, alleviating the hardship on the caregiver. 33 6. Become a dementia-friendly pharmacy 11/26/2024