National Press Foundation

1. National Press Foundation R. Scott Turner, MD, PhD Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu rst36@georgetown.edu

2. Case 1 • A 64 year old judge was referred by her PCP for evaluation of memory loss. Her husband reports memory loss and repeating questions for about 18 months. Her colleagues and law clerks have expressed concerns due to several small mistakes. She reports that she has “fallen a little behind at work”, and is planning to retire in 1 month because she has lost the “trust and confidence” of her colleagues…

3. Case 1 • She has a history of well-controlled hypertension and takes only an anti-hypertensive medication. She has no other medical or psychiatric history. There is no history of stroke, TIA, alcohol abuse, gait disorder, falls, or head trauma. Her parents died in their 60’s of “old age”. She works as a judge and lives with her husband. She states that at one time her IQ was “170”.

4. Risk factors for AD • Age • Family history/genetics • ApoE polymorphism • Minority • Downs syndrome • Head injury with LOC • Smoking • Hypertension • Diabetes • Stroke • Low education, occupational level

5. NIH conference April 2010 Factors that may affect risk of both AD & cognitive decline with aging (ARHQ publication 10-E005; Plassman et al., Annals of Internal Medicine; Archives of Neurology, 2011) • Increase risk • ApoE4, diabetes, current smoking, depression • Decrease risk • Physical activity, Mediterranean diet/vegetable intake, cognitive training/cognitively engaging activities

6. ADLs • Complex • Working, living alone, driving, keeping appointments, handling finances, daily medications… • Basic • Dressing, bathing, grooming, toileting, walking, transfers, eating…

8. Case 1 • Pleasant, cooperative, and well-appearing elderly woman. Vital signs normal, as is the general medical examination. Mental status examination reveals good attention with deficits in memory, orientation, language, and visuospatial skills. The MMSE score is 25/30, with points off for orientation and memory, consistent with a mild dementia.

9. MMSE is Alzheimer’s disease-centric

10. Case 1 • The remainder of the neurological examination reveals normal eye movements, strength, tone, sensation and coordination. There are no signs of parkinsonism. Reflexes are 2+ and symmetric. Gait is normal. There are no asymmetric features.

11. Case 1 • A CBC, chemistry panel, thyroid function tests, and B12 were all normal. A test for syphilis was negative. • A head MRI revealed cortical atrophy and periventricular white matter changes (“small vessel ischemic changes”). No tumor, hemorrhage, subdural hematoma, or large cerebral infarct. • Neuropsychologic evaluation confirmed mild dementia, with deficits in memory, language, visuospatial skills, and frontal/executive function, and a lower than expected IQ.

12. Case 1 • …has multiple cognitive deficits which impair her functional abilities and represent a cognitive decline. • There is no evidence for delirium or depression by history, examination, or laboratory evaluation. • Diagnosed with mild dementia due to probable Alzheimer’s disease.

14. Case 1 • prescribed a cholinesterase inhibitor; effects and side-effects of the drug were discussed. • advised to continue treatment for hypertension with her primary care physician. • discussed prognosis, advance directives, and limitations concerning complex ADLs, including driving, handling finances, taking medications... • recommended ad libitum physical activity, social activity, and mental activity. • Qualified and interested, thus offered enrollment in a 12 month clinical trial of drug x (add-on to current drug therapy).

15. > 65 years old SS established 1935

17. 21 September 2009 World Alzheimer Day; World Alzheimer Report released www.actionalz.org/about_wad.asp

18. Clinical Criteria for AD • Probable AD (NINCDS-ADRDA) • Dementia on clinical examination and neuropsychologic testing • Deficits in two or more areas of cognition • Progressive worsening • No disturbance of consciousness • Onset 40-90, usually > 65 • All else ruled out McKhann et al, Neurol 1984

19. Clinical Criteria for AD • Possible AD • Dementia with atypical presentation or course for AD • With a second disorder which may cause dementia • Definite AD • Probable AD diagnosed clinically • Brain tissue diagnostic for AD McKhann et al, Neurol 1984

20. Diagnostic criteria • A. Dementia • Interferes with ability to function at work or at usual activities • A decline from a previous level of functioning • Not delirium or psychiatric disorder • Diagnosed by history, examination • Involves at least 2 cognitive domains: • Memory • Reasoning and judgment • Visuospatial • Language • Personality, behavior, comportment Alzheimer’s and Dementia, April 2011

21. Diagnostic criteria • A. Probable AD • Dementia • Insidious onset • Worsening of cognition over time • Amnestic vs. non-amnestic presentation • Not due to another dementia diagnosis • B. Probable AD with evidence of AD pathophysiology • Ab (CSF or amyloid PET) • Neuronal injury (CSF tau, FDG-PET, structural MRI) Alzheimer’s and Dementia, April 2011

22. Neuropathology of AD Cruz et al, PNAS 1997

23. Kretzschmar, 2009

24. Reagan Pathologic Criteria for AD Neurobiology of Aging 18, S1-S2, 1997

25. NH2 COOH Ab b-secretase (BACE-1) a-secretase g-secretase g-secretase (presenilin) p3 Ab Amyloid Precursor Protein (APP) catabolism

26. Genetics of sporadic AD Apolipoprotein E (ApoE) Strittmatter et al, Science 1993

27. The amyloid cascade Downs APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss-->dementia-->death (mild, moderate, severe) APP, PS-1, and PS-2 mutations ApoE4 ? Age Turner, Seminars in Neurology 2006

28. The amyloid cascade Ab immunization? APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe) b- or g-secretase inhibitors? Turner, Seminars in Neurology 2006

29. The amyloid cascade APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters inflammatory responses excitotoxicity apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe) cholinesterase inhibitors memantine Turner, Seminars in Neurology 2006

30. FDA-approved drugs for dementia due to AD • Donepezil (Aricept) tablet, orally-disintegrating tablet • 5 mg daily, increase to 10 mg daily after 4-6 weeks; then 23 mg daily after 3 months (optional) • Rivastagmine (Exelon) capsule, transdermal patch, liquid • 1.5 mg twice daily, increase to 3, 4.5, and 6 mg twice daily in 2 week intervals • 1 patch daily (4.6 mg daily, increase to 9.5 mg daily after 4 weeks) • Galantamine (Razadyne, Razadyne ER) tablet, ER capsule, liquid • 4 mg twice daily, increase to 8 and 12 mg twice daily in 4 week intervals • for ER, 8 mg daily, increase to 16 and 24 mg daily in 4 week intervals • Memantine (Namenda, Ebixa) tablet, liquid • Start 5 mg daily, increasing in 1 week intervals up to 10 mg twice daily

31. Donepezil (Aricept) Rogers et al, Neurology 1998

32. Donepezil (Aricept) Rogers et al, Eur Neuropsychopharmacology 1998

33. Avid 18F-PET Aß-Amyloid Imaging 18F-AV45 Distinguishes Patients with AD from Cognitively Normal Controls AD 77 F MMSE 24 Healthy 74 F MMSE 30

34. CSF biomarkers Shaw et al, Annals Neurology 2009 Tau AD Normal Ab42

35. FDG-PET: AD MCI Langbaum et al, Neuroimage2009

36. AD brains reveal atrophy -- particularly in regions mediating higher cognitive functions

37. MRI atrophy in MCI & ADMcDonald et al, Neurology 2009

38. FDG-PET CSF Aβ42 MRI hipp Cog CSF tau Fxn

39. Prevalence of MCI Petersen et al, Archives of Neurology 2009

40. MCI: Rates of Progression to Dementia Petersen et al, Archives of Neurology 2009

41. MCI Progression Petersen et al, Archives Neurology 2009

42. Cure Arrest Progression Symptomatic Therapy (NOW) Goals of AD therapy Cognition Natural Course Time

43. Phase II Bapinezumab with PIB-PET Rinee et al, Lancet Neurology, March 2010

44. Summary • We are witnessing a growing epidemic of dementia in the US and the world, most of which is AD • The amyloid hypothesis is alive and well, and does not exclude other important and essential pathologic processes • The genetics of familial AD provides the strongest evidence for the amyloid hypothesis • Despite recent high-profile failures, many active trials target Ab/amyloid generation or clearance • Other AD trials target other essential pathologic processes, with the probable result of a therapeutic cocktail (as now…)

45. Summary • Current (FDA-approved) therapies for AD provide consistent yet modest, temporary, and palliative benefits • We are searching for disease-modifying treatments to halt dementia progression, or prevent dementia onset • We are in need of validated biomarkers for: screening, diagnostic accuracy, evidence of efficacy, reduction of the cost of clinical trials (decreased numbers of participants) • Treatments and prevention will increasingly target subjects with MCI, then healthy high-risk individuals • Future treatments will be tailored to ApoE genotype (pharmacogenomics, personalized medicine)

46. memory.georgetown.edu