Alzheimers Disease Rachelle S. Doody, MD, PhD Effie Marie Cain - PowerPoint PPT Presentation

Alzheimer’s Disease Rachelle S. Doody, MD, PhD Effie Marie Cain Chair in Alzheimer’s Disease Research Director Alzheimer’s Disease and Memory Disorders Center Baylor College of Medicine

Key Questions  What causes AD?  How do you know when someone has AD?  When do you have to intervene in order to prevent or effectively treat AD?  What are current treatments?  What is the status of treatments under development?

Classic Elements of Alzheimer Neuropathology Neuritic (Senile) Plaques Neurofibrillary Central element: Central element: β -amyloid hyperphosphorylated tau From: http:/ / www.neuropat.dote.hu/ alzheim.htm

What causes AD?  Plaques and tangles?  Loss of reserve?  Biochemistry of aging?  “Weak” genetic background?  Bad habits?  Chronic inflammation?  All of the above? Doody Alzheimer’s Dementia Ed Doody RS Carma Publishing, 2008

Risk factors for AD  Age, menopause  Genetics: Apo E 4, TOMM 40, CR1, CLU, PI CALM, SORL1 , TREM 2 Genetic risk is probably cumulative  Elevated glucose or diabetes  Elevated cholesterol  Elevated homocysteine  Major head injury with LOC  Chronic inflammation?

What do we know about preventing AD?

Large (N> 2K) AD Prevention Trials Study Population Treatment Study Design Results GuidAge SML Ginkgo Randomized, PC, Primary NS Biloba 5 years incidence Those on >4 years 50% decrease ≥ Age 75 GEMS Ginkgo Randomized, PC, NS Normal or Biloba 5 years incidence MCI WHIMS PM Estrogen ± Randomized, PC, Worse in treated Women ≥ Progesterone 3 arm, 5 year groups. Early 65 Incidence MCI or termination dementia and cognitive change ≥Age 70 ADAPT NSAIDs, Randomized, PC, Worse in Naproxen +FHx in Naproxen 3 arm cognitive group. Early first and change termination (1.5/7 degree Celecoxib years) relative

Possible Preventive Measures  Weight control/ Dietary factors  Exercise (mental & physical)  Normalizing  Blood pressure  Blood sugar  Cholesterol  Vitamin B12 and Homocysteine levels  Preventing immune over-activation?

Planned AD Prevention Trials Study Population Treatment Study Design Alz Prevention FAD esp Crenezumab Delay AAO, reduce Initiative Colombian incidence of AD DIAN FAD Solanezumab, Delay AAO, reduce Gantanerubab, Lilly cognitive loss BACE inhibitor NC with A β , ADCS A4 Trial Solanezumab Prevent worsening stratified by of cognition on APO E composite Sargramostim MCI Sargramostim Prevent progression Prevention of AD (GM CSF) to AD TOMM 40 NC with high Pioglitazone (low Qualify biomarker /Pioglitazone and low risk dose) algorithm. Prevent MCI due to AD. ADCS Exercise Study MCI Structured exercise Prevent progression program to AD

Speculation Regarding Prevention of AD  Public health measures may reduce the number of cases but will not prevent disease  I ndividuals with pre-symptomatic disease will already be biologically conditioned to respond differently to different treatments (endophenotype theory)

How do we know when someone has AD?

Markers of Asymptomatic AD?  Strong  AD genetic mutations  Multiple biological markers of AD neuropathology  Multiple neuroimaging markers C/W AD  Variable  Biomarkers of AD neurodegeneration  Neuroimaging (metabolic, functional, structural)  Weak  One or more AD risk factors (genetic and non- genetic)

Clinical, Cognitive Structural, Metabolic, and Biochemical Changes as a Function of Estimated Years from Expected Symptom Onset 2 Standardized Difference A β deposition 1 CSF tau 0 CDR - SOB CSF A β42 -1 Hippocampal Volume Glucose Metabolism -2 -35 -30 -25 -20 -15 -10 -5 0 5 10 15 Estimated Yr From Expected Symptom Onset Modified from Bateman et al NEJM 2012;367(9):795-804

Role of Biomarkers in Diagnosis  For deposition of beta amyloid (A β ) • Low CSF A β 1-42 • Positive PET amyloid imaging  For downstream neuronal degeneration and injury • Elevated CSF tau (total and phosphorylated) • Decreased FDG uptake on PET in temporoparietal cortex and post. cingulate • Disproportionate atrophy on structural MR images in medial, basal, lateral temporal lobe, and medial parietal cortex • 14

Amyloid imaging slides Positive Scan Negative Scan

New Research Criteria for Preclinical AD A β PET or Stage Description Neuronal Subtle CSF I njury Cognitive Tau, FDG Change PET sMRI 1 Asx cerebral Positive Negative Negative amyloid 2 1 + downstream Positive Positive Negative neurodegeneration 3 2 + subtle Positive Positive Positive cognitive/behavior al decline Sperling etal Alz & Dem 2011;7:280-292

Developing Treatments for Early Preclinical AD  Amyloid accumulation in the brain is not the same thing as AD  Have to use biomarkers to select patients and as the outcome since there are no clinical symptoms  Very high screen failure rates ie > 80%  Risk factors are uncontrolled

Early Symptomatic AD: Mild Cognitive I mpairment  A set of mild cognitive disorders  Amnestic MCI likely a transitional state between normal and clinical AD  Non-amnestic MCI may also evolve to AD  “Diagnosing” MCI takes skill and objective test measures

MCI Subtypes Peterson RC. Continuum . 2004;10:9-28 . Cognitive Complaint Not normal for age Not demented Cognitive decline Essentially normal functional activities MCI Yes No Memory impaired? Non-Amnestic MCI Amnestic MCI Single nonmemory Yes No Yes No Memory Cognitive domain I mpairment only ? I mpaired? Non-Amnestic MCI Amnestic MCI Amnestic MCI Non-Amnestic MCI Multiple Domain Single Domain Multiple Domain Single Domain

How is aMCI determined?  Patient and/ or informant notices a change  Demonstrable problem with delayed verbal recall on testing (-1.5 SD)  Originally, no second domain  Normal activities of daily living Petersen etal Arch Neurol 1999; Petersen and Doody et al Arch Neurol 2001, Rountree et al Dementia 2007

New Research Criteria for MCI due to AD A β (PET or CSF) Neuronal injury Diagnosis/ Biomarker Liklihood Probability of (tau, FDG, AD sMRI ) MCI core Uninformative Conflicting/Undete Conflicting/Undete rmined/Untested rmined/Untested MCI due to AD Intermediate Positive Untested Intermediate Untested Positive MCI due to AD Highest Positive Positive High MCI due to AD Lowest Negative Negative Unlikely Albert etal Alz & Dem 2011;7:270-279

MCI is Different From Early AD  Neuropathology is not as widespread  Compensatory mechanisms, including cholinergic sprouting, may play a role  Data show that response to AD therapies and probably safety profiles differ and did not support FDA approval for routine treatment of MCI with AD drugs

Pharmacologic I nterventions for aMCI Donepezil Galantamine Rivastigmine ADCS Long-term I nDDEx Gal 11 and Gal 18 ‘conversion’ trials (3-4 years) (2 years) (3 years ) 401 (24 weeks) ‘Symptomatic’ - - trials 412 (52 weeks) Co-Primary Negative Negative Negative outcomes Significant short-term delay in conversion in ADCS Other - - + ve outcomes on modified ADAS-cog in 401 & 412 Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88 Feldman HH, et al. Lancet Neurol. 2007;6:501-12 ; Winblad etal Neurology 2008;70:202402035 Doody R, et al.Neurology 2009;72:1555-61

Developing Therapies for MCI  No clear regulatory pathway and no FDA approved drugs  High screen failure rates ,ie > 70%  No strong biomarkers of progression or surrogate markers of treatment effect  Cognitive measures more challenging than for AD (so effect sizes small)  Large, long studies required

Former AD Research Criteria  Core clinical criteria for Dementia and AD  I nsidious onset and clear progression – Amnestic: most common; should include impairments in learning and recall – Nonamnestic » Language—eg, word-finding difficulties » Visuospatial—eg, object agnosia, impaired face recognition » Executive function—eg, impaired reasoning, judgment  Exclusions—eg, significant vascular disease, other dementias • 25

New Research Criteria for AD A β (PET or CSF) Diagnosis Biomarker Neuronal I njury Probability of AD (tau, FDG-PET, sMRI Probale AD Dementia Clinical Uninformative Unavail, Confl, Indet Unavail, Confl, Indet Pathophysiol Evid Intermediate Unavail, Indet. Positive Intermediate Positive Unavail, Indet. High Positive Positive Possible AD (Atypical Clinical) Clinical Uninformative Unavail, Confl, Indet Unavail, Confl, Indet Pathophysiol Evid High, could be Positive Positive secondary Dementia—Unlikely AD Lowest Negative Negative McKhann etal Alz & Dem 2011;7:263-269

Current Approved AD Therapies  Cholinesterase I nhibitors (donepezil/ Aricept; rivastigmine/ Exelon; galantamine/ Reminyl)  NMDA Receptor Antagonist (memantine/ Namenda)  Anti-oxidant Vitamins? (Vitamin E 1000 I U; Vitamin C 1000 mg)  Medications for Behavioral and Psychological Symptoms of Dementia