6/19/18. Update on Research in the Prevention, Diagnosis and Treatment of Alzheimer s and Other Dementias. Objectives. Disclosures

Transcription

1 Update on Research in the Prevention, Diagnosis and Treatment of Alzheimer s and Other Dementias Dana Saffel, PharmD, BCGP, CPh President, CEO PharmaCare Strategies, Inc Objectives Differentiate common dementias Describe new research in the prevention, diagnosis, and treatment of dementias Discuss the role of the consultant pharmacist in implementing new research into the care of dementia patients. 2 Disclosures Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO PharmaCare Strategies Acadia Pharmaceuticals Consultant, speaker Astellas Pharmaceuticals Consultant Axovant Pharmaceuticals Consultant Mylan Pharmaceuticals Consultant Sunovion Pharmaceuticals Consultant, speaker 3 1

2 6/19/18 Question 1 The two most common types of dementia are: a. Alzheimer s and Vascular b. Alzheimer s and Lewy Body c. Alzheimer s and Mixed d. Alzheimer s and Frontotemporal Lobe 4 We Are All Going to Die But Let s Put It Off As Long As We Can Leading Causes of Death, US Suicide Nephritis Inflenza/Pneumonia Diabetes Alzheimer's Stroke Accidents COPD Cancer Heart disease 0 100, , , , , , ,000 5 Centers for Disease Control and Prevention. Accessed April 18,

3 Types of Dementias 1 Alzheimer s 2 Vascular 3 Lewy Body 4 7 Frontotemporal Lobe Alzheimer s Dementia Most common type of dementia; Accounts for an estimated 50% - 80% of cases Slowly progressive brain disease that begins well before symptoms emerge. Symptoms: Early: Difficulty remembering recent conversations, names or events is often an early clinical symptom; Apathy and depression are also often early symptoms. Later Impaired communication Poor judgment Disorientation Confusion Behavior changes Difficulty speaking, swallowing, walking Brain changes: Plaque Normal Deposits of the protein fragment beta-amyloid (plaques) and twisted strands of the protein tau (tangles) Nerve cell damage and death in the brain. Alzheimer s Association. Accessed April 23, Vascular Dementia Previously known as multi-infarct or post-stroke dementia Accounts for about 10% of dementia cases Occurs from blood vessel blockage or damage leading to infarcts (strokes) or bleeding in the brain. The location, number and size of the brain injuries determine whether dementia will result and how the individual s thinking and physical functioning will be affected. Symptoms: Early Impaired judgment or ability to make decisions, plan or organize Brain changes: Blood vessel problems 9 3

4 6/19/18 Lewy-body Dementia Accounts for 10% of dementia cases Symptoms: Early Sleep disturbances Visual hallucinations Slowness, gait imbalance and other parkinsonism movements Later Memory loss and thinking problems similar to Alzheimer s Brain changes: Lewy bodies are abnormal aggregations (or clumps) of the protein alpha-synuclein. Alpha-synuclein also aggregates in the brains of people with Parkinson's disease. Initiates in basal ganglia substantia nigra Dementia is similar to Lewy-body dementia 10 Frontotemporal Lobe Dementia Accounts for about 10% of dementia cases Includes dementias such as: Behavioral-variant frontotemporal lobar degeneration (FTLD) Primary progressive aphasia Pick's disease Corticobasal degeneration Progressive supranuclear palsy Symptoms: Changes in personality and behavior Difficulty with language Nerve cells in the front and side regions of the brain are especially affected Brain changes: No distinguishing microscopic abnormality is linked to all cases. The symptoms of FTLD may occur in those age 65 years and older, similar to Alzheimer s, but most people with FTLD develop symptoms at a younger age. About 60 percent of people with FTLD are ages 45 to Rare Dementias Crutzfield Jacob Dementia Believed to be caused by consumption of products from cattle affected by mad cow disease. Symptoms: Rapidly fatal disorder that impairs memory and coordination and causes behavior changes. Brain changes: Results from misfolded prion protein that causes a "domino effect" in which prion protein throughout the brain misfolds and thus malfunctions. Normopressive Hydrocephalus Symptoms: Symptoms include difficulty walking, memory loss and inability to control urination. Brain changes: Caused by the buildup of fluid in the brain. Can sometimes be corrected with surgical installation of a shunt in the brain to drain excess fluid. 12 Alzheimer s Association. Accessed April 23,

5 Rare Dementias (Con t) Huntington s disease Progressive brain disorder caused by a single defective gene on chromosome 4 Symptoms: Include abnormal involuntary movements, a severe decline in thinking and reasoning skills, and irritability, depression and other mood changes. Brain changes: The gene defect causes abnormalities in a brain protein that, over time, lead to worsening symptoms. 13 Alzheimer s Association. Accessed April 23, Mixed Dementia Abnormalities linked to more than one cause of dementia occur simultaneously in the brain. Occurs in 50% of people with dementia Incidence increases with age Highest in the oldest-old (people age 85 or older). Brain changes: Most common: Alzheimer s combined with vascular dementia, Common: Alzheimer s with dementia with Lewy bodies & Alzheimer s with vascular dementia and dementia with Lewy bodies. Less common: Vascular dementia with dementia with Lewy bodies 14 Alzheimer s Dementia is Most Common In 2017, 6 million Americans are living with Alzheimer's or dementia New diagnosis in almost 500,000 Americans a year More deaths than both breast cancer and prostate cancer combined By 2060, 15 million Americans will have Alzheimer s 15 5

6 Age Is the Best Predictor of Alzheimer s Beginning at age 65: Nearly 10% of people will have Alzheimer s or dementia Probability of developing Alzheimer's doubles every 5 years. By the age of 85: > 30% of people will have developed the disease. 16 Risk Factors Family History (Genetics) Lifestyle Medical Conditions Gender Alzheimer s probably develops as a result of complex interactions among multiple factors, including age, genetics, environment, lifestyle, and coexisting medical conditions. 17 Alzheimer s Association. Alz.Org Research Center. Accessed April 17, Genetics Risk genes increase likelihood but not a guarantee APOE-ε4 1 copy = increased risk of developing Alzheimer s 2 copies = even higher risk May correlate with developing Alzheimer s at a younger age Deterministic genes directly cause the disease Genes coding three proteins: Amyloid Precursor Protein (APP) Presenilin-1 (PS-1) Presenilin-2 (PS-2) Usually develop symptoms in 4 th or 5 th decade Accounts for only 1% of Alzheimer s cases 18 Alzheimer s Association. Alz.Org Research Center. Accessed April 17,

7 Medical Conditions Heart and brain health are closely intertwined Studies have shown that individuals with certain medical conditions are at a 30% - 50% percent higher risk of developing Alzheimer s or vascular dementia High blood pressure Heart disease Atrial Fibrillation Diabetes High cholesterol History of stroke 19 Alzheimer s Association. Alz.Org Research Center. Accessed April 17, Medical Conditions (con t) Seizure Medications (AED) Associated with a significantly greater risk of developing: Dementia (adjusted OR 1.28) Alzheimer s (adjusted OR 1.15) Higher AED exposure = greater risk of dementia and AD AEDs with known cognitive adverse events (CAE) were tied to a higher risk of dementia (dementia OR 1.59; AD OR 1.19) Head Trauma There is a strong link between future risk of Alzheimer's and serious head trauma Especially when injury involves loss of consciousness Managed Healthcare Connect. Accessed April 18, Gender & Ethnicity Gender Women are at greater risk: Cause is unknown Potential that sex hormones testosterone and may influence the progression of Alzheimer s Disease progresses almost 2x as fast as in men estrogen Ethnicity Latinos are about 1.5x as likely as whites to have Alzheimer s and other dementias as they age African-Americans are about 2x as likely to have Alzheimer s and other dementias as whites as they age Alcohol Use Heavy alcohol ingestion and binge drinking have a 3x increase in risk for dementia 21 Alzheimer s Association. Alz.Org Research Center. Accessed April 17,

8 6/19/18 PREVENTION 22 Nutrition Heart-healthy eating may also help protect the brain Heart-healthy eating includes: Limiting the intake of sugar and saturated fats Eating plenty of fruits, vegetables, and whole grains DASH diet (Dietary Approaches to Stop Hypertension) Emphasizes vegetables, fruits and fat-free or low-fat dairy products; includes whole grains, fish, poultry, beans, seeds, nuts, and vegetable oils Limits sodium, sweets, sugary beverages, and red meats Mediterranean diet Emphasizes whole grains, fruits and and shellfish, and nuts, fats Limits red meat vegetables, fish olive oil and other healthy Alzheimer s Association. Alz.Org Research Center Accessed April 18, Calorie Restriction Diets low in calories benefit cognitive function in old age. A small study of 50 healthy, normal-weight to overweight elderly patients underwent 3 months of calorie restriction (30% reduction) Results found a significant increase in verbal memory scores, correlated with decreases in fasting plasma levels of insulin and high sensitive Creactive protein 24 Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19,

9 Question 2 Supplementation with Vitamin B6, B12, D and E have been shown to reduce the likelihood of developing Alzheimer s dementia. a. True b. False 25 Vitamin D Adults who were moderately deficient in vitamin D had a 53% increased chance of developing dementia Adults who were severely deficient were at a 125% increased risk of developing dementia. A vitamin D supplement is important, especially in individuals above the age of 60. Supplement: 2000iu 5000iu capsule daily Aim for blood levels > 30ng/ml Taking vitamin D may not treat or prevent Alzheimer s 1. J Neurol Neurosurg Psychiatry Jul;80(7): doi: /jnnp Epub 2009 May J Geriatr Psychiatry Neurol Sep; 22(3): Vitamin B6, B12, and Folic Acid Vitamin B1 (thiamine) Vitamin B12 (cyancobalamine) Helps maintain healthy nerve cells and red blood cells. Vitamin B12 deficiency most common in older adults and vegetarians Can cause various signs and symptoms, including memory loss In these cases, vitamin B-12 supplements can help improve memory Vitamin B6 (pyridoxine), Vitamin B9 (folic acid) and B12 lower homocysteine levels High levels of homocysteine are associated with Alzheimer s disease While B6, B9 and B12 can lower homocysteine levels, they are not effective in preventing or treating Alzheimer s disease There is no clear evidence that B vitamin supplements prevent the development of or improve memory for people with Alzheimer's disease. Mayo Clinkc. Accessed April 18,

10 Other Vitamins Vitamins C and E are essential nutrients for humans People who consume high levels of vitamins C & E through their diets have a lower risk of dementia It is unclear whether the key factor is a healthy diet or the specific vitamins Supplements do not appear to offer the same protection 28 Alcohol Use Light to moderate alcohol consumption has been linked to reduced risk of development of AD Abstainers, heavy drinkers, and binge drinkers had an increased risk of cognitive impairment when compared to light to moderate drinkers in a Finish study. Among abstainers, increased risk was limited to subjects who did not carry the APOE E4 allele. Heavy drinking is the strongest potentially modifiable risk factor for dementia Those with a history of alcohol use disorders had 3x increased risk for dementia Over half those with early-onset dementia had a history of alcohol problems. Of 57,000 patients who had developed dementia under the age of 65 years 57% had a history of alcohol use disorders (66% of men and 37% of women) 29 Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19, Reduce or Avoid Anticholinergic Drug Use Robust association between come anticholinergic drug and increased risk of developing dementia Link goes back up to 20 years before diagnosis of dementia Increased Risk of Dementia Antidepressants Overactive bladder Anti-parkinson s Anticholinergic Drugs No Change in Risk of Dementia Antispasmodics Antipsychotics Antihistamines Effect could be caused by a class specific effect or by drugs being used for very early symptoms of dementia Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure Richardson K, et al. BMJ 2018;361:k

11 Physical Exercise Regular physical exercise may be a beneficial strategy to lower the risk of Alzheimer's and vascular dementia. Exercise may directly benefit brain cells by Increasing blood and oxygen flow in the brain Aim for going for a walk each day, but at least a minimum of 3 times a week Attending social gathering Play sports Become active in your community Attending an event once a week may be enough to prevent the onset of dementia or Alzheimer's. Alzheimer s Association. Alz.Org Research Center Accessed April 18, Mentally Stimulating Exercise Engage in mentally-challenging activities (puzzles, games, reading) Join a book club Be socially active, spend time with friends or family at least once a week. Social activity is some of the best mental stimulation Alzheimer s Association. Alz.Org Research Center Accessed April 18, Prevent Head Trauma/ Avoid Smoking Protect the head Wear a seat belt Use a helmet when participating in sports "Fall-proof the home Avoid smoking, smoking has shown to increase the chance of developing Alzheimer's by 80% Alzheimer s Association. Alz.Org Research Center Accessed April 18,

12 Proposed Risk and Protective Factors for Dementia Risk Factors Age Genetic Familial aggregation APOE e4 CR1, PICALM, CLU, TREM2, TOMM40 Vascular and Metabolic Cerebrovascular lesions Cardiovascular diseases Diabetes mellitus and pre-diabetes Hypertension High BMI (overweight & obesity) High serum cholesterol Lifestyle Smoking High alcohol intake Diet Saturated fats Homocysteine J Intern Med Mar; 275(3) Protective Factors Genetic Psychosocial Factors High levels of education and High level of complexity of work Rich social network and social engagement Mentally stimulating activity Lifestyle Physical activity Moderate alcohol intake Diet Mediterranean diet PUFAs and fish-related fats Vitamins B6, B12 and folate Antioxidant vitamins (A, C, and E) Vitamin D 34 Proposed Risk and Protective Factors for Dementia (con t) Risk Factors Others Depression Traumatic brain injury Occupational exposure (heavy metals, ELF-EMFs) Infective agents (herpes simplex virus type 1, Chlamydophila pneumoniae, spirochetes) Increased Risk Genetic and environmental factors in midlife APOE e4 magnifies the effect of high alcohol intake, smoking, physical inactivity and high intake of saturate fat Vascular and metabolic factors in midlife Co-occurrence of hypertension, obesity, hypercholesterolemia and/or physical inactivity has an additive effect Vascular and metabolic factors/diseases in late-life Higher risk in individuals with brain hypoperfusion profile: chronic heart failure, low pulse pressure, low diastolic pressure Higher risk in individuals with atherosclerosis profile: high systolic pressure, diabetes mellitus or prediabetes, stroke J Intern Med Mar; 275(3) Protective Factors Drugs Antihypertensive drugs Statins HRT NSAIDs Decreased Risk Genetic and environmental factors in midlife High education level reduces the negative effect of APOE e4 Physical activity counteracts the risk due to APOE e4 Environmental factors in midlife High level of complexity of work modulates the increased dementia risk due to low level of education Genetic and environmental factors in late life Active leisure activities or absence of vascular risk factors reduces the risk due to APOE e4 35 Risk Factors and Protective Factors Sindi, Shireen & Mangialasche, Francesca & Kivipelto, Miia. (2015). Advances in the prevention of Alzheimer's Disease. F1000Prime Reports /P7-50)

13 6/19/18 Changing Lifestyle Can Make a Difference Up to 33% of worldwide AD cases are attributable to 7 risk factors Diabetes mellitus Midlife hypertension Midlife obesity Physical inactivity Depression Smoking Low education A 10-20% reduction of all these risk factors might decrease AD prevalence by 8 15% by 2050 NortonS, et al. Potential for primary prevention of Alzheimer s disease: an analysis of population-based data. The Lancet. Neurology 2014,13: DIAGNOSIS

14 Question 3 The detection of beta-amyloid in the brain is an example of which type of neurological imaging: a. Structural imaging b. Functional imaging c. Molecular imaging 40 Research in Early Diagnosis - Biomarkers Neuroimaging Structural Imaging Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) Provides information about the shape, position or volume of brain tissue Currently used chiefly to rule out other conditions that may cause symptoms similar to Alzheimer s Chronic subdural hematoma Normal-pressure hydrocephalus Tumors Functional Imaging Positron Emission Tomography (PET) and Functional MRI (fmri). Reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen May be useful in atypical cases or when Frontotemporal lobe dementia is likely Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19, Early Diagnosis - Biomarkers Molecular Imaging Pittsburgh compound B (PIB) was the first radiotracer capable of highlighting deposits of beta-amyloid Florbetaben (Neuraceq ), Florbetapir (Amyvid ) and Flutemetamol (Vizamyl ) have been recently approved for detection of beta-amyloid in the brain B-amyloid imaging is appropriate for patients with persistent or progressive unexplained MCI, progressive dementia, or atypical early age of onset. 42 Alzheimer s Association. Accessed April 18,

15 Research in Early Diagnosis (con t) Cerebral Spinal Fluid (CSF) proteins Alzheimer's disease in early stages may cause changes in CSF levels: Tau (usually elevated) Beta amyloid (usually low) Genetic risk profiling As more effective treatments are developed, genetic profiling may become a valuable risk assessment tool for wider use APOE-ε4 Amyloid Precursor Protein (APP) Presenilin-1 (PS-1) Presenilin-2 (PS-2) Measuring both proteins can achieve specificity of 80% - 90% Alzheimer s Association. Accessed April 18, Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19, Genetics Prevention Trial Dominantly Inherited Alzheimer Network (DIAN-TU), Testing whether antibodies to beta-amyloid can reduce the accumulation of betaamyloid plaque in the brains of people with such genetic mutations Hypothesis: delay or prevent symptoms Participants in the trial are receiving antibodies (or placebo) before they develop symptoms, and the development of beta-amyloid plaques is being monitored by brain scans and other tests Anti-Amyloid Treatment in Asymptomatic Alzheimer s (A4 Study) Testing whether antibodies to beta-amyloid can reduce the risk of Alzheimer s disease in older people (ages 65 to 85) at high risk for the disease Autosomal Dominant Alzheimer's Disease (ADAD) Studying the effects of crenezumab that delivers antibodies against beta-amyloid in an effort to reduce the negative cognitive effects of excess beta-amyloid 44 Alzheimer s Organization. Accessed April 18, Importance of Early Diagnosis A better chance of benefiting from treatment More time to plan for the future Lessened anxieties about unknown problems Increased chances of participating in clinical drug trials, helping advance research An opportunity to participate in decisions about care, transportation, living options, financial and legal matters Time to develop a relationship with doctors and care partners Benefit from care and support services, making it easier for them and their family to manage the disease. 45 Alzheimer s Association. Accessed April 18,

16 TREATMENT 46 Currently Approved Drugs for Dementia Drug Name Brand Name Target Approved For Stage Donepezil Aricept Acetylcholinesterase Mild, Moderate & Severe Rivastigmine Galantamine Exelon (oral & patch) Razadyne Acetylcholinesterase Acetylcholinesterase Mild, Moderate & Severe Mild to Moderate Memantine Namenda Glutamate NMDA Moderate Severe Donepezil & Memantine Namzaric Acetylcholinesterase & Glutamate Moderate to Severe Side Effects Nausea, vomiting, diarrhea, dizziness, headache, and confusion Cholinesterase inhibitors work by slowing down the process that breaks down acetylcholine needed for decision making Memantine, is an NMDA (N-methyl-D-aspartate) receptor antagonist, which works by regulating the activity of glutamate involved in learning and memory Current therapies show modest benefit on measures of cognitive function and activities of daily living but do not address the underlying cause of disease Alzheimer s Association. Accessed April 19, Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19, Nutritional Supplement Caprylidene (Axona) Medical food Metabolized into ketone bodies Brain can use for energy when ability to process glucose is impaired Indicated for clinical dietary management of metabolic processes associated with mild to moderate Alzheimer s dementia 48 Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19,

17 Experimental Therapies in the Past 10 Years Have Yielded Disappointing Results Free-radical scavenger therapy Oxidative stress (high-dose Vitamin E 2000iu) Demonstrates delayed dementia clinical progression Increases cardiovascular complications Supplementation not recommended Anti-amyloid therapy: Vaccination with amyloid species Administration of monoclonal antiamyloid antibodies Administration of intravenous immune globulin that may contain amyloid-binding antibodies Selective amyloid-lowering agents Chelating agents to prevent amyloid polymerization Brain shunting to improve removal of amyloid Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment To date, no phase III study of anti-amyloid therapies has shown a combination of acceptable efficacy and adverse effects. 49 Sheheen EL, et al. Alzheimer Disease. Medscape. Accessed April 19, Question 4 Current research is targeting which of the following pathways? a. Beta-amyloid b. Tau protein c. Inflammation d. Infection e. All of the above 50 Highlights of Current Research Targeting Beta Amyloid Tramiprosate has been shown to block the formation of toxic amyloid oligomers associated with the development and progression of AD. FDA has designated ALZ-801 Fast Track status drug to slow the progression of Alzheimer s disease in patients with APOE-ε4 Aducanumab - a recombinant monoclonal antibody targeting aggregated forms of beta-amyloid, such as oligomers and fibrils, that can develop into amyloid plaque in the brains of people with Alzheimer s disease. Early studies showed decreased levels of beta-amyloid in the brains of study volunteers. Two phase 3 studies are underway to test whether monthly doses of Aducanumab can slow cognitive and functional decline in people with early Alzheimer s disease. The studies are expected to be completed in late (Drug is still in research; not available to the public.) Beta-secretase (BACE) an enzyme that clips APP and makes it possible for beta-amyloid to form. Therapies that interrupt this process may reduce the amount of beta-amyloid in the brain and ultimately intervene in the development of Alzheimer s disease. JNJ inhibits the ability of the beta-secretase enzyme to make beta-amyloid. It is currently in a phase 3 study to determine if it slows cognitive decline in people who do not have Alzheimer s symptoms but do have elevated levels of beta-amyloid in the brain. The study is expected to be completed in JNJ is administered in pill form. (Drug is still in research; not available to the public.) Posiphen - a selective inhibitor of the production of amyloid precursor protein (APP)

18 Highlights of Other Current Research Tau Protein AADvac1 - a vaccine that stimulates the body s immune system to attack an abnormal form of tau protein that destabilizes the structure of neurons. If successful, it has the potential to help stop the progression of Alzheimer s disease. Current in Phase II studies. Inflammation Sargramostim - Approved by the FDA for bone marrow stimulation in people with leukemia, Sargramostim stimulates the innate immune system. Being tested in Alzheimer s because it may stimulate immune processes that could protect neurons in the brain from toxic proteins. Currently in Phase II studies. Infection COR388 Bacterial protease inhibitor that targets a pathogen identified in brain tissue and cerebral spinal fluid of people with Alzheimer s disease. Synapse Dysfunction Neflamapimod Small molecule drug designed to inhibit processes that lead to dysfunction of synapses in the brain. 52 Phase III Therapeutic Agents in Clinical Trials for Alzheimer s (Registration Trials) Aducanumab: amyloid antibody Biogen Albumin + Immunoglobulin: treats primary immunodeficiency Grifols Biologicals ALZT-OP1: Mast cell stabilizer + antiinflammatory AZTherapies Azeliragon: Inhibits receptor for advanced glycation endproducts vtv Therapeutics CAD-106: amyloid vaccine Novartis CNP520: BACE inhibitor Novartis Crenezumab: amyloid antibody Hoffmann-La Roche Elenbecestat (E2609): BACE inhibitor Eisai, Biogen Gantenerumab: amyloid antibody Hoffmann-La Roche JNJ : BACE inhibitor Janssen Research & Development Lanabecestat (LY , AZD3293): BACE inhibitor Eli Lilly, AstraZeneca MB2 (TRx0237, Methylene Blue): tau aggregation inhibitor TauRx Therapeutics Ltd Sodium oligo-mannurarate (GV-971): inhibits beta-amyloid aggregation Shanghai Greenvalley Pharmaceuticals Solanezumab: amyloid antibody Eli Lilly For related symptoms: AVP-786 (agitation): NMDA receptor antagonist Avanir Pharmaceuticals AXS-05 (agitation): combination of bupropion (NDRI) and dextromethorphan (NMDA receptor antagonist Axsome Therapeutics Bupriopion (agitation): norepinephrine and dopamine reuptake inhibitor Axsome Therapeutics ITI-007 (agitation): 5-HT2A receptor antagonist Intra-Cellular Therapies Pimavanserin (psychosis): selective inverse agonist of serotonin 5- HT2A receptor Acadia Pharmaceuticals Suvorexant (Belsomra ) (sleep): orexin receptor antagonist Merck Sharp & Dohme 53 Phase III Therapeutic Agents in Clinical Trials for Alzheimer s (Academic Trials) Candesartan: Angiotensin receptor Insulin (intranasal): Hormone controlling blocker blood sugar Ihab M. Hajjar, Emory University University of Southern California Curcumin: nutritional supplement Lisinopril: Angiotensin receptor blocker University of Florida Ihab M. Hajjar, Emory University Exenetide (Exendin-4): improves insulin Losartan, Amlodipine & Atorvastatin sensitivity combination therapy: blood pressure Azienda Ospedaliero-Universitaria reducers di Parma University of Texas Southwestern Gantenerumab: amyloid antibody Medical Center Washington University School of Octohydroaminoacridine Succinate: Medicine, Hoffmann-La Roche acetylcholinesterase inhibitor Ginkgo biloba (with or without donepezil): Shanghai Mental Health Center nutritional supplement Vitamin D: nutritional supplement First Affiliated Hospital with Nanjing University Hospital, Tours Medical University Guanfacine: α2a receptor agonist For related symptoms: Imperial College London Carbamazepine (agitation): voltage-gated Human neural stem cells: pluripotent cell sodium channel blocker line University of Sussex Second Affiliated Hospital of Escitalopram (agitation): selective Soochow University serotonin reuptake inhibitor (SSRI) Icosapent Ethyl/ Omega-3 fatty acid: Johns Hopkins School of Public nutritional Health Center for Clinical Trials VA Office of Research and Development Escitalopram (alone or with Memantine): selective serotonin reuptake inhibitor (SSRI) (Depression) University of California, Los Angeles Methylphenidate: norepinephrine dopamine reuptake inhibitor (NDRI) (Apathy) Johns Hopkins Bloomberg School of Public Health Mirtazapine (agitation): atypical antidepressant University of Sussex Nabilone/ Dronabinol (agitation): synthetic cannabinoid Sunnybrook Health Sciences Centre Zolpidem (sleep): Short-acting nonbenzodiazepine Brasilia University Hospital Zoplicone (sleep): Nonhypnotic sleep aid Brasilia University Hospital 54 18

19 Phase II Therapeutic Agents in Clinical Trials for Alzheimer s Disease AADvac1 Deferiprone LM11A-31-BHS ABBV-8E12 (C2N8E12) Albumin + Immunoglobulin ANAVEX2-73 AstroStem (stem cells) Atomoxetine AZD0530 (Saracatanib) BAC BAN2401 Benfotiamine BI BIIB092 Boost A (dietary supplement) Brainport (berry extract) Bryostatin 1 CAD106 Candesartan CB-AC-02 (stem cells) CERE-110 Cilostazol CNP520 CPC-201 Crenezumab CT1812 Curcumin DAOIB As of 04/2018 DHP1401 Losartan, Amlodipine & Atorvastatin Elderberry Juice combination therapy Elenbecestat (E2609) L-serine Fesoterodine LY Formoterol LY Freshly-pressed extra virgin olive oil MB2 (TRx0237, methylene Blue) Gantenerumab MLC901 Ginkgo biloba (with or without Montelukast buccal film donepezil) Neflamapimod Grape powder NeuroStem (stem cells) Grape Seed Extract Nicotinamide GV1001 Nicotine Human mesenchymal stem cells Nilotinib Human neural stem cells Octagam Icosapent ethyl / Omega-3 fatty acid Omega-3 fatty acid ID1201 ORM Insulin (nasal) Oxybutynin Insulin detemir Perindopril Insulin glulisine Pirometaline IONIS MAPTRx Polyamine dietary supplement JNJ Pomegranate Juice Lanabecestat (LY , Posiphen AZD3293) Probucol Levetiracetam Rasagiline Liraglutide (Victoza ) Riluzole Lithium RO Rotigotine transdermal patch add-on to AChEI therapy S47445 Sargramostim (Leukine ) S-Equol Simvastatin (Zocor ) Simvastatin + L-Arginine + Tetrahydrobiopterin (SLAT) STA-1 (plus donepezil) SUVN-502 T3D-959 Thiethylperazine UB 311 UCMSC (stem cells) Valaciclovir Xanamem For related symptoms: AXS-05 (agitation) Bupropion (agitation) Cannabis oil (agitation) Lemborexant (sleep) MP-101 (psychosis) Nabilone/ Dronabinol (agitation) Pimavanserin (agitation, psychosis) 55 Phase I Therapeutic Agents in Clinical Trials for Alzheimer s Disease Aducanumab AGN (+ Donepezil and/or Memantine) Allopregnanolone AstroStem (stem cells) BIIB076 Bisnorcymserine (BNC) Bosutinib CB-AC-02 (stem cells) COR388 Crenezumab CT1812 Deferiprone Elderberry Juice Escitalopram Gemfibrozil Growth hormone releasing hormone Huperzine A Idalopirdine Insulin aspart IONIS MAPTRx JNJ Ketogenic medium chain triglyceride drink KHK6640 LM11A-31-BHS LMSC (stem cells) Lu AF20513 LY LY NDX-1017 NeuroStem (stem cells) NP001 NPT088 Oxaloacetate (OAA) Posiphen Probucol Resveratrol RGN1016 Salsalate S-Equol T3D-959 TAK-071 Telmisartan TPI 287 UCMSC (stem cells) Venlafaxine Vorinostat VU319 As of 04/