Disclosures. In the Beginning RECENT ADVANCES IN ALZHEIMERS S DISEASE RESEARCH AND TREATMENT 2/27/2015

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1 RECENT ADVANCES IN ALZHEIMERS S DISEASE RESEARCH AND TREATMENT Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Alzheimer s Disease Research Center Mayo Clinic College of Medicine Rochester, Minnesota Disclosures Consultant: Astellas Advisory Board: Genentech Data Safety and Monitoring Board: Lilly Chair, P&T Committee: Omnicare Wife owns stock in Pfizer, J&J, P&G In the Beginning Alos Alzheimer Used silver stains and linked senile plaques and neurofibrillary tangles as part of the same disease process for the first time From Latin dement, demens (mad) A condition of deteriorated mentality that is characterized by marked decline from the individual s former intellectual level and often by emotional apathy Webster s Third New International Dictionary 1

2 Amyloid fragments are abnormal, accumulate and form insoluable plaques Neurofibrillary tangles consist of twisted fibers that are broken down microtubules once held together by the protein tau Plaques and Tangles Cholinergic Basis of Alzheimer s Disease Progressive loss of cholinergic neurons in the basal forebrain Progressive cortical cholinergic denervation Depletion of acetylcholine Declines in cognition, function, and behavior Sulcus Gyrus Language BF = basal forebrain; FC = frontal cortex; PC = parietal cortex; OC = occipital cortex; H = hippocampus. Coyle et al: Science 219: , 1983 FC Normal PC BF Brain cross section Ventricle Memory H Alzheimer s OC Sulcus Gyrus Language Episodic Memory Decline Episodic memory performance Compensatory mechanisms invoked Plaques and tangles, neuron and synapse losses accruing Mild and relatively stable memory decline in earlier preclinical period Severe and rapid memory decline in late preclinical period Preclinical phase Year Clinical phase 2

3 Spectrum of Dementia Diagnoses Other dementias (eg frontotemporal dementia Creutzfeldt-Jakob disease) Vascular dementias Multi-infarct dementia Vascular dementias and AD AD Dementia with Lewy bodies Parkinson s dementia Diffuse Lewy body disease Lewy body variant of AD AD and dementia with Lewy bodies 5% 10% 64% 6% 9% 6% Am Psychiatric Association, 1997; Lobo et al: Neurology 54(5):S4, 2000; Morris: Clin Geriatr Med. 10:257, 1994; Small et al: JAMA 278:1363, 1997 Living Arrangements for Persons With Dementia Intermittent supervision living at home Near-constant supervision living at home May benefit from day care Personal care Assisted living Special care unit for AD or intermediate care nursing home Skilled care nursing home MMSE score 5 0 Proposed Pathological Sequence Abnormal amyloid deposition Microglial activation NFT Neuronal loss/ neurochemical changes Dementia Normal Time (~20 yr) NFT, neurofibrillary tangles Hardy: Selkoe DJ.Science 297:353,

4 Amyloid Cascade Hypothesis Aberrant APP Processing APP -secretase A 42 monomers Synaptic dysfunction Toxic A oligomer Amyloid plaque Tau pathology Inflammation Neuronal loss -secretase Clearance mechanisms A = amyloid; APP = amyloid precursor protein. Citron: Nat Rev Drug Discov 9:387, 2010; Hardy and Selkoe: Science. 297:353, 2002 Biomarkers for AD Progression Pathophysiology of AD Multiple genetic and environmental factors Biomarkers PS1/PS2/APP mutations, APOE Increase in A production and/or failure of A clearance CSF A 42 or A 40 Gradual deposition of A as amyloid plaques Amyloid PET Tau hyperphosphorylation and NFT Excitotoxicity and inflammation CSF tau protein Inflammatory cytokines Synaptic dysfunction FDG PET (SPECT, MRS, fmri) Neuronal death Structural MRI Cognitive decline Neuropsychologic assessment Wu et al. Mol Diagn Ther 15:313, 2011 Evolving Definition of Alzheimer s Disease THEN AD pathology and clinical symptoms were synonymous Clinical diagnosis of probable AD made when individuals had dementia Definitive diagnosis was only possible postmortem Dementia McKhann et al: Neurology. 34:939,

5 Evolving Definition of Alzheimer s Disease NOW Disease related pathophysiological processes occur years before onset of b amyloid deposition clinically observable symptoms Three stages of AD Preclinical AD MCI due to AD Dementia due to AD Incorporate biomarkers to detect neuropathologic changes in vivo Preclinical MCI Dementia Aisen et al: Alzheimers Dement 6:239, 2010; Jack et al: Alzheimers Diement 7:257,02011 Abnormal Temporal Order of Biomarker Abnormalities Preclinical CSF Aβ42 Amyloid imaging Amyloidosis ~20 yr MCI Dementia Normal Time Aisen et al Neurology , 2011; Bateman et al: NEJM 367:795, 2012; Jack et al:lancet Neurol 9:119, 2010 Abnormal Temporal Order of Biomarker Abnormalities Preclinical Neurodegeneration ~20 yr CSF Aβ42 Amyloid imaging FDG PET MRI hippocampal volume CSF Tau MCI Dementia Normal Time Aisen et al Neurology , 2011; Bateman et al: NEJM 367:795, 2012; Jack et al:lancet Neurol 9:119,

6 Abnormal Temporal Order of Biomarker Abnormalities Preclinical Clinical Decline ~20 yr CSF Aβ42 Amyloid imaging FDG PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL) MCI Dementia Normal Time Aisen et al Neurology , 2011; Bateman et al: NEJM 367:795, 2012; Jack et al:lancet Neurol 9:119, 2010 Abnormal Normal Pre Clinical Preclinical AD Diagnostic criteria for preclinical AD recommended for research purposes only Individuals with preclinical AD may not develop clinical features of AD during their lifetime Provides tools to identify factors which may best predict the risk of progression from normal cognition to MCI and AD Provides critical opportunity for therapeutic interventions at earliest stages of disease Sperling et al: Alzheimers Dement 7:280, 2011 Preclinical Staging Framework Abnormal Pathophysiological Cascade Asymptomatic amyloidosis 1 Amyloidosis + Neurodegeneration 2 Subtle cognitive decline 3 Not enough for MCI criteria Clinical use of biomarkers requires validation and standardization of values that define cutpoints Normal Pre Clinical Sperling et al: Alzheimers Dement 7:280,

7 Diagnostic Criteria for Early Stage Disease MCI (NIA AA criteria) Concern regarding a change in cognition Impairment in one or more cognitive domains Preservation of independence in functional abilities Not demented Prodromal AD (IWG criteria) Clinical symptoms Episodic memory loss of the hippocampal type No significant impact on instrumental activities of daily living Biomarker evidence from CSF or imaging supportive of the presence of AD pathologic changes MCI NIA AA, National Institute of Aging Alzheimer s Association; IWG, International Working Group: Albert et al: Alzheimers Dement. 7:270, 2011; Dubois et al: Lancet Neurol 9:1118, 2010 Dementia Due to AD Reflects advances in Neuropsychological testing Advanced imaging Cerebrospinal fluid measures Still retain probable and possible categories Criteria still includes Inability to function normally Decline from previous level of function Cognitive or behavioral decline in 2 domains McKhann et al: Alzheimers Dement 7:263, 2011 Dementia HC Imaging Biomarkers for Neurodegeneration MCI Mild AD Synaptic Dysfunction Hypometabolism of FDG on PET in temporal-parietal cortex Cell Death Disproportionate brain atrophy by volumetric MRI FDG, 18F fluordeoxyglucose; HC, healthy control; MRI, magnetic resonance imaging; PET, positron emission tomography; Wu et al: Mol Diagn Ther 15:313,

8 11 C PiB PET for Amyloid Imaging HC AD SUVR C PiB, Pittsburgh compound B; HC, healthy control, PET, positron emission tomography; SUVR: Standardized Uptake Value Ratio; Villemagne and Rowe: Int Psychogeriatr. 23(2):S41, 2011 Radioligands for Amyloid Imaging HC AD Half-life 11 C-PiB 11 C ~20 min 18 F-florbetaben 18 F ~110 min 18 F-florbetapir 18 F ~110 min 18 F-flumetamol 18 F ~110 min HC, healthy control Rowe and Villemagne: J Nucl Med 52:1, 2011 Predicting Disease Progression Brains of asymptomatic elderly with high A deposition have faster rates of atrophy Low A burden Annual rate of atrophy High A burden Chételat et al: Neurology 78:477,

9 Predicting Clinical Decline Individuals diagnosed with MCI and positive for A deposition convert to dementia at higher rates than A negative subjects Doraiswamy et al: Neurology, 2012; Kingwell: Nat Rev Neurology 8:471, 2012 Proposed A and Tau interactions Early Alzheimer s Disease Disease Progression Late Alzheimer s Disease Axon Phosphorylated tau Endogenous tau Dendritic tau levels High tau levels Low tau levels amyloid amyloid induced toxicity Cerebrospinal Fluid Biomarkers A 4 2 Tau P (tau) Dementia MCI or N or N or N Control N N N Pg/mL 1,200 1, CSF A 42 Controls AD Pg/mL 1,600 1,400 1,200 1, Controls CSF tau AD Proportion remaining normal CSF tau/ A 42 < Years since baseline clinical adjustment 9

10 Too Little Too Late? Abnormal ~20 yr BACEI inhibitors secretase inhibitors secretase modulators amyloid deposition A antiobodies Dementia Normal Time (~20 yr) Potential Clearance Mechanisms Microglia mediated Direct resolution Peripheral clearance Blockade of toxic oligomers Amyloid Deposit Antibody Microglia -Amyloid Targeted Interventions Amyloid plaque A 42 monomers Toxic A oligomer A antibodies Clearance mechanisms 10

11 Genetic Risk Factors for AD Aberrant APP Processing APP -secretase -secretase X X X X A 42 monomers Synaptic dysfunction Toxic A oligomer Amyloid plaque Tau pathology Inflammation?? Neuronal loss FAD mutations Clearance mechanisms APOE Hypothetical Treatment Response in Alzheimer s Disease 30 Early diagnosis Mild moderate Severe MMSE Onset of treatment Years Feldman and Gracon: Alzheimer s disease: symptomatic drugs under development; Gauthier S: Clinical Diagnosis and Management of Alzheimer s Disease 239, 1996 FDA Approved AD Specific Medications Characteristic Donepezil Rivastigmine Galantamine Memantine Approved for Mild to severe Mild to severe Mild to moderate Dosage available 5 mg, 10 mg, 23 mg Patch 4.6 mg, 9.5 mg and 13.3 mg 4 mg, 8 mg, 12 mg; 4 mg/ml oral solution Doses/day (ER); 2 (RR) 2 Initial dose (mg/d) Dose escalation 4 6 wk 4 wk 4 wk 1 wk Clinically effective dose (mg/d) Moderate to severe 5 mg, 10 mg; 2 mg/ml oral solution 11

12 Choosing Wisely American Geriatrics Society Five Things Physicians and Patients Should Question Don t use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia People with dementia often exhibit aggression, resistance to care and other challenging or disruptive behaviors. In such instances, antipsychotic medicines are often prescribed, but they provide limited benefit and can cause serious harm, including stroke and premature death. Use of these drugs should be limited to cases where non pharmacologic measures have failed and patients pose an imminent threat to themselves or others. Identifying and addressing causes of behavior change can make drug treatment unnecessary Therapeutic Environment Standard of Care Where person can function with minimal failure and maximal use of retained abilities HABIT Healthy Action to Benefit Independence & Thinking Sherrie Hanna M.A., Angela Lunde, Glenn Smith PhD, Mayo Clinic Department of Psychiatry and Psychology and Mayo Alzheimer s Disease Research Center 12

13 Cognitive Rehabilitation Methodology Aims Creation Learning application, Compliance Life Improvement Feedback Outcomes Establishment of a memory support system Progression through acquisition, and adaptation training phases Compliance assessment at baseline during test phase and at end of intervention Functional status and caregiver burden assessment Participant interview for feedback Reducing AD Risk Hallmarks of disease remain memory loss and inability to problem solve Environment must change Caregiver must change Pt with dementia has very little opportunity to improve Pt and their families can still improve their odds Lower cholesterol and homocysteine levels Lower high blood pressure Control diabetes Exercise regularly Engage in social and intellectually stimulating activities Limit Your Risks 13

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16 Importance of Diagnostic Disclosure Provide appropriate patient diagnosis Provide information on disease process, staging, and healthcare needs Initiate and maintain appropriate pharmacotherapy Communicate realistic treatment expectations Encourage planning for financial, legal, and medical issues Summary Practitioners, pt and their families should run toward diagnosis of Alzheimer s disease rather than away from it New criteria establish a framework to evaluate disease earlier in its evolution Biomarkers are not required for clinical diagnosis, but are important emerging tools for early detection and disease progression Beta amyloid remains an important concept to understand Alzheimer s disease, diagnose the disease, and perhaps treat the disease Patients and their families benefit from an environment that allows them to function with MINIMAL failure and MAXIMAL use of retained abilities 16

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