Advisory Council October 2015 Meeting Presentation: ADRD

Monday, October 26, 2015

Overview of Alzheimer’s Disease and Related Dementias

Ronald C. Petersen, Ph.D., M.D.
Mayo Clinic College of Medicine
Rochester, MN

Dementia

AD Related Dementias

• Frontotemporal lobar degeneration
• Dementia with Lewy bodies
• Vascular cognitive impairment-dementia

ALZHEIMER’S DISEASE

• Degenerative etiology
• Gradual progression
• Basic neurological exam normal early
• Clinical-pathology correlation 80-90%

Criteria for AD

• National Institute on AgingAlzheimer’s
• Association
• Alzheimers and Dementia, May, 2011

Introduction to the Recommendations from the National Institute onAging-Alzheimer’s Association Workgroups on Diagnostic Guidelinesfor Alzheimer’s Disease

Clifford R. Jack, Jr, Marilyn S. Albert, David S. Knopman,Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo,Bill Thies, Creighton H. Phelps

Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade

Jack et al: Lancet Neurol 2010

Prevalence of PiB PET in Normals

Rowe et al: 2010

Biomarkers for AD

• Early biomarkers
  • Amyloid deposition
    • PET imaging
    • CSF amyloid
• Later biomarkers
  • Neurodegeneration
    • Structural MRI
    • FDG PET
    • Tau PET
    • CSF tau

 

Neuroimaging in AD

Neuroimaging in AD

• Structural MRI
• Functional imaging
  • FDG PET
• Molecular imaging
  • Amyloid PET imaging

 

Structural Imaging in AD

Structural MRI: Atrophy and AD Stage

Control, 70, F	MCI, 72, F	AD, 74, F

 

Functional Imaging in AD

 

Molecular Neuroimaging

PIB Idealized

CN	aMCI	AD

PIB Examples – Full Spectrum

 

Tau PET Imaging

Alzheimer’s Disease Spectrum

• Preclinical AD
• MCI Due to AD
• Dementia Due to AD

 

Alzheimer’s Disease Treatments2015

Theoretical Drug Responses

Alzheimer’s Disease
Course, Prevention, Treatment Strategies

Intervention Primary prevention Secondary prevention Treatment
Clinical state	Normal	Pre-Clinical AD	Mild cognitive impairment	AD Dementia
Brain pathologic state	No disease No symptoms	Early AD brain changes No symptoms	AD brain changes Mild symptoms	Mild, moderate or severe impairment
Strategies	Identify at-risk Prevent AD	Prevent or delay emergence of symptoms	Stimulate memory Slow progression	Treat cognition Treat behaviors Slow progression
Disease progression

 

SYMPTOM MODIFYING AGENTS

AD TREATMENTS

• CHOLINESTERASE DRUGS
  • DONEPEZIL (ARICEPT)
  • RIVASTIGMINE (EXELON)
  • GALANTAMINE (RAZADYNE)
• NMDA ANTAGONIST
  • MEMANTINE (NAMENDA)

Immunotherapy

• Passive immunization
  • Polyclonal antibodies
    • IVIG
  • Monoclonal antibodies
    • bapineuzumab
    • solanezumab
    • crenezumab
    • gantenerumab
    • aducanumab

Secretase Inhibition

• Beta secretase inhibitors
  • Promising
• Gamma secretase inhibitors
  • Challenges

Clinical Trials in the Era of Prevention

API DIAN-TU	API	A4	SNIFF
Autosomal Dominant 1% of AD	E4/E4 asymptomatc 2% of population	Amyloid Positive asymptom 30% of population aged 65+	Symptomatic MCI and Dementia 25% of population aged 65+

 

Lifestyle Modifications

Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer's Disease: A Randomized Trial

• Nicola T. Lautenschlager; Kay L. Cox; Leon Flicker; et al.
• JAMA. 2008;300(9):1027-1037 (doi:10.1001/jama.300.9.1027)

Conclusions

• Moderate exercise (150 minutes/wk) resulted in improved cognitive function at 6 months
• Some benefits maintained at 18 mos

So, where are we?

 

 

• Clinical Spectrum -- CN - MCI - Dementia
  • Aß
  • TAU
  • Other
  • Vascular Disease
  • Alpha Synuclein
  • TDP-43

Clinical Pathology Biomarker Therapy

• Clinical Spectrum -- CN - MCI - Dementia
  • Aß
    • PET/CSF
      • Rx?
  • TAU
    • PET/CSF
      • Rx?
  • Other
    • ?
      • Rx?
  • Vascular Disease
    • MRI
      • Rx?
  • Alpha Synuclein
    • ?CSF
      • Rx?
  • TDP-43
    • ?CSF
      • Rx?

Overall Conclusions

• We can diagnose cognitive impairment fairly well
  • Clinical criteria
  • Biomarkers
• Screening tools evolving
  • Useful in practice
• Therapies being actively pursued

Thank You

 

MAYO CLINIC