The Relationship between abeta Deposition, Neurodegeneration and Cognitive Function in Normal and Impaired Individuals

MCI Symposium 2014

Clifford R Jack Jr MD The Alexander Family Professor of Alzheimer's Disease Research Mayo Clinic, Rochester, MN
No relevant disclosures

AD Biomarkers are Proxies for AD pathophysiology 5 major biomarkers 2 categories

Measures of brain A deposition amyloid plaques

Amyloid PET CSF A 42

Measures of Neurodegeneration (defined as progressive

loss of neurons or their processes (axons and dendrites) with a corresponding progressive impairment in neuronal function) FDG PET CSF tau (t-tau and p-tau) Structural MRI

Background for temporal modeling: state of biomarker studies ~ 2008 was Cross sectional relationships between biomarkers and confusing clinical symptoms were not same for different biomarkers
Direct relationship with neurodegenerative biomarkers Indirect, less clear relationship with amyloid biomarkers

Longitudinal dissociations
Change in cognition closely coupled to rate of neurodegenerative biomarker progression (esp MRI) not to rate of amyloid deposition

One explanation time shifts or ordering of events (Inglesson 2004, Jack 2009, Mormino 2009, Perrin 2009)

Lancet Neurol 2010

Ab Amyloid = CSF Ab42 or amyloid PET imaging; Tau Mediated Neuron Injury and Dysfunction = CSF tau or FDG PET; Brain Structure = structural MRI

Summary of evidence: 2010-2013

Support most of the basic features of our 2010 model Order: Amyloid then neurodegeneration then symptoms (Jack 2011; Buchhave 2012; Forster 2012; Landau 2012; Bateman 2012; Fleisher 2012; Prestia 2013; Villemange 2013) Shape: Amyloid follows sigmoid shape ie plateaus at high levels (Caroli 2011; Jack 2012; Bateman 2012; Villain 2012; Jack 2013; Fleisher 2012; Villemange 2013)

But, new evidence, as well as experience using the 2010 model also pointed to need for some revisions - 2013 horizontal axis, expressed as time not clinical disease stage cognitive impairment, expressed as a range ordering, slight modifications shape, all biomarkers are still configured as sigmoids, but the shapes of the sigmoid curves are no longer identical spacing, biomarker curves are drawn closer together indicating less distinct temporal separation NFT without amyloid, at autopsy brainstem and MTL NFT usually precede amyloid in middle/old age

Lancet Neurology, Feb, 2013

Lancet Neurology, Feb, 2013

Additional problem with 2010: brainstem and medial temporal tauopathy usually precedes A deposition
(discussed but not incorporated into 2010 model)

Brainstem and allocortical tauopathy - brain stem, entorhinal cortex, hippocampus, NFT common in middle age and older subjects with no amyloid plaques (Braak 1997, 2011; Price and Morris 1999; Haroutunian 1999) Braak & Del Tradici, 2011 by 40s ~100% have AT8 ir in brainstem vs < 5% have amyloid plaques

Lancet Neurology, Feb, 2013

Amyloid-First and Neurodegeneration-First Profiles Characterize Incident Amyloid PET Positivity

Neurology 2013

15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG PET and hippocampal volume However, 11/26 (42%) of incident amyloid positive subjects had biomarker evidence of neurodegeneration prior to incident amyloid positivity These 11 may have combinations of pre-existing non-Alzheimers pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway Incident amyloid positivity = incident pre clinical AD, therefore both amyloid-first and neurodegeneration-first biomarker profile pathways to pre-clinical AD exist

3 practical problems with neurodegeneration biomarkers in the elderly that current biomarker modeling studies do not adequately address

(discussed but not incorporated in 2013 model)

Pathological heterogeneity in old age (Chetelat 2013) Lack of biomarkers for important causes of age related neurodegeneration Non specificity of biomarkers for AD neurodegeneration

Pathological heterogeneity in old age

Most demented (& many cog normal, Sonnen Archives 2011) have multiple pathologies: AD (NP and neocortical NFT), brainstem/MTL NFT with no amyloid, LB, CVD, HS, grain disease, TDP43, yet unknown pathologies Nelson, Acta Neuropath 2011

Pure AD is an abstraction in elderly (Markesbery 2006, Schneider 2009, Sonnen 2011) yet this is precisely what we assume when modeling AD biomarker behavior (without autopsies in all subjects)

Non specificity of neurodegenerative biomarkers for AD neurodegeneration

Abeta amyloid biomarkers: sensitive and specific autopsy biomarker correlations (Strozyk, 2003; Tapiola, 2009; Ikonomovic, 2008; Fleisher, 2011; Sojkova, 2011; Clark 2011, Driscoll 2012) Neurodegenerative biomarkers are sensitive to NFT mediated neurodegeneration in AD autopsy biomarker correlations (DeCarli, 1992; Jack, 2002; Tapiola, 2009; Buerger, 2006; Tapiola, 2009; Bobinski, 2000; Zarow, 2005; Vemuri, 2008; Whitwell, 2008 & 2012; Josephs, 2008) Neurodegenerative biomarkers not specific for AD (esp. atrophy and FDG PET): elevated t-tau, decreased FDG, atrophy occur in non-AD conditions that cause cognitive impairment/dementia in elderly persons eg. CVD, LBD, TBI, FTLD, CJD, hippocampal sclerosis, MTL NFT with no amyloid ? (Jack, 2002; Jagust 2009; Dawe 2011; Erten-Lyons 2013) NFT not specific for AD FTLD, FCD, prion dz, CTE, viral encephalitis, etc

Neurodegenerative biomarkers need to be interpreted in context age and genetics

Pure AD mutation carriers, APOE 4 homozygotes, clinical onset under 70: abnormal neurodegenerative biomarker study is likely AD related Mixed pathology clinical onset in late 70s and beyond: precise substrates of abnormal neurodegenerative biomarker study can not be known in an individual but it is likely that non AD conditions contribute

Early onset: pure AD no confounding pathologies

Context and AD biomarker modeling: 3 scenarios

Jack and Holtzman

Context and AD biomarker modeling: 3 scenarios

Late onset AD, incl preclinical: amyloid first: exact

composition of neurodegeneration unknown

Jack and Holtzman

Contest and AD biomarker modeling: 3 scenarios

Late onset AD incl preclinical: neurodegeneration first: exact composition of neurodegeneration unknown

Jack and Holtzman