Alzheimer s Disease without Dementia

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1 Alzheimer s Disease without Dementia Dr Emer MacSweeney CEO & Consultant Neuroradiologist Re:Cognition Health London Osteopathic Society 13 September 2016

2 Early diagnosis of Alzheimer s Disease How and why? Innovations in Clinical Research for AD Alzheimer s without Dementia

3 Understanding Cognitive Impairment in 2016 Alzheimer s Disease with Dementia Changing the trajectory of Alzheimer's MCI & Alzheimer s Disease without Dementia What is happening in the brain in AD What s new on the horizon in this rapidly developing space Emerging treatments: to slow progression of AD boost memory / cognition

4 Cognitive Impairment: Problems with any aspect of thinking ability Insight Concentration Abstract Thought Planning Judgment Concept formation Working memory Inhibition Problem solving Memory Cognition Executive Function Visuo-spatial skills Speech and language Calculation

5 Cognitive Impairment Why is this a challenge? All ages Multiple causes Coexisting morbidities Symptoms not specific Frequently of gradual onset Often requires multiples specialists working in an integrated team

6 The Challenge Acquired brain injury (ABI) ADHD Stroke /TIA PTSD Stress/ anxiety Encephalitis Chemo Radiotherapy Normal pressure hydrocephalus Traumatic brain injury Vascular disease Brain tumours Drugs/ Alcohol Depression Subdural haematoma Cognitive Impairment Parkinson CAA Frontotemporal Mild and progressive neurodegenerative disease HIV Epilepsy MS MCI Alzheimer s disease Lewy body

7 Dementia and Alzheimer s Disease To meet criteria for dementia, cognitive impairment must be in two domains, progressive, and impact on activities of daily living Diagnostic guidelines refer to Alzheimer s Disease dementia a clinical syndrome where criteria for dementia are also met McKhann et al: Alzheimer s Dementia May ; 7(3):

8 Early diagnosis: in 2016 what s the point? Understanding and choice opens doors Drugs and non-drug interventions Exclude other reversible causes of symptoms, e.g. depression Care-giver education / support Improved access to medical and social services Maintain independence longer / delay care home Planning the future (wills, PoA, care needs) Eligibility for CLINICAL TRIALS AND CHANCE TO CHANGE OUTCOME

9 Changing the Trajectory of Alzheimer s Disease Alzheimer s is the only leading cause of death that is still on the rise Based on USA data, a treatment breakthrough by 2015 that delays age of onset of AD by 5 years would result in: Reduction in the number of age 65+ with SEVERE AD of 54% reduction in those 65+ with severe Alzheimer s by % reduction in those 65+ with severe Alzheimer s by 2050 Alzheimer s Association, 2011 Alzheimer s Disease Facts and Figures, Alzheimer s & Dementia Volume 7, Issue 2 (issued March, 2011)

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11 How has diagnosis advanced - historically

12 How has diagnosis advanced

13 52 year old lawyer

14 52 year old lawyer

15 Diagnostics amyloid imaging 52 year old lawyer 86% of MCI patients with positive amyloid PET amyloid scan develop clinical AD over 3 years

16 Alzheimer s disease without dementia? Mild Cognitive Impairment (MCI) Cognitive decline greater that that expected for age and education level but does not interfere with ADLs Can be seen as an entity with high risk for conversion to dementia High rate of conversion to AD > 60% over 3 yrs

17 Alzheimer s without and with Dementia

18 Symptoms of Early Cognitive Impairment MCI ADLs intact Repeatedly asking same question Trouble remembering recent or past events Losing or misplacing items Depression, anger, anxiety and agitation 18

19 What causes Alzheimer s Disease Can we slow its progression? β Amyloid plaques, extracellular Abnormal Tau protein neurofibrillary tangles = > neuronal and synaptic loss

20 Current and Emerging Mechanisms for Treatment for AD Symptomatic drugs New Disease Modifying Treatments New Symptomatic Treatments New Rx In Phase II/III Clinical Trials for Alzheimer s Disease

21 Symptomatic vs Disease Modifying Treatments The death of brain cells in Alzheimer's is currently unstoppable. Current medications = symptomatic Aricept/Donepezil, Galantamine, Rivastigmine o Managing only the symptoms of dementia by helping the dying brain cells function better. New medications: o Disease modifying drugs aimed to keep the brain cells alive reduce B amyloid & Tau Protein in the brain. o More effective Symptomatic drugs

22 Disease Modifying Drugs To reduce amyloid protein plaque synthesis/deposition/clearance.

23 Disease Modifying Drug To reduce Tau Protein Tau protein normally stabilises axonal microtubules With permission Prof Claude Wischik Microtubules inside axon critical for neurones to communicate with other parts of the brain : cortico-cortical association circuits Abnormal Tau Protein replicates and forms neurofibrillay tangles (Alzheimer s discovery) 23

24 Tau-aggregation cascade is prion-like Initial nucleation of Tau appears to require Amyloid APP fragment Once initiated Tau aggregation cascade is self-propagating and exponential ie turbo-charged leading to cell destruction 24

25 Tau Protein Tau aggregation is highly correlated with clinical dementia in AD Tau aggregation is self-propagating New Tau Aggregation Inhibitor (TAI) in clinical development To dissolve and enhances clearance of pathological Tau from AD brain

26 Spread of pathology and Braak staging Synapse Nerve Axon Toxic Tau oligomer passes to next cell Stages 4-6 Stages 1-3 Stages

27 Symptomatic Treatments

28 New treatments Disease Modifying: Anti Tau Proteinopathy Treatments Anti amyloid treatments: Symtomatic: Enhance neuro transmitters

29 Final Phase Clinical Trials for New Medications All medications prior to international license To confirm results from earlier studies Large number of participants across the world Double blind randomised Open label extension

30 Disease Modifying Drugs To reduce amyloid protein By increasing clearance of amyloid plaques. By reducing production of ab-amyloid

31 Amaranth Astra Zeneca Eli Lilly Amyloid Disease Modifying Treatment currently enrolling The AMARANTH Phase II/III clinical trial AZD3293 1,500 + patients Inhibits production of the abeta amyloid by80-90%

32 Amaranth Global Sites

33 OTHER New Disease Modifying treatment Studies 2016 New Studies 2016/2017 To reduce production and increase clearance of Amyloid Preclinical / Prodromal(MCI) / Mild AD MMSE 20-30

34 AXOVANT Mindset New Enhanced Symptomatic Rx A selective 5-HT6 receptor antagonist. Mild/ Moderate AD MMSE Donepezil 6/12 and 2/12 (stable dose) No Memantine

35 No Drug Axovant Drug + Donepezil / Aricept

36 Overcoming the clinical challenges: new AD paradigm Clinical research Medical care; Differential diagnosis Pathological continuum continuum Normal Preclinical Stage MCI/ Prodromal AD Alzheimer s disease AD is a clinical-biological entity with a clinical phenotype ranging from normal cognition to severe dementia Specific symptoms imply that we are in the clinical spectrum of the continuum Biomarkers, if correlate with pathology, indicate that we are within the continuum AD, Alzheimer s disease; Dubois B, et al. Lancet Neurol 2010;9(11): C-PIB PET is not approved for clinical use.

37 Revised dynamic biomarkers of the hypothetical Alzheimer s disease pathological cascade model Jack CR, Jr. et al. Lancet Neurol 2013;12(2):

38 Management of individuals with MCI/AD How to access clinical Trials? Physical exercise Diet Medical Rx: BP etc Souvenaid Early diagnosis empowers individuals Cognitive interventions Cranial Stimulation Cerebral protective agents Cerebral enhancing agents Non-pharmacological Pharmacological 38 Lin F, et al. J Gerontol Nurs. 2012;38(12):22-35

39 Implications of epidemiological analysis ALZHEIMER S DISEASE IS AN UNACCEPTABLE PROBLEM AD is a self-propagating pathology that spreads through the brain It is extremely widespread and presents a global problem for all aging societies Management should be as for any common chronic condition that begins in middle age 39

40 International message for the public: Run, don t walk if you get a diagnosis. The earlier, the better Clinical research is unlocking answers < 4-5 years before drugs available outside trials International Phase 3 Clinical Trials don t miss the opportunity now

41 Discussion Contact details: Dr Emer MacSweeney

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