Cognitive Aging: Defining normal vs. disease?

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1 Cognitive Aging: Defining normal vs. disease? Reisa Sperling, M.D. Harvard Aging Brain Study Center for Alzheimer Research and Treatment Brigham and Women s Hospital Massachusetts General Hospital Harvard Medical School

2 Disclosures and Funding Consultant to: Janssen, Merck, Eisai, Roche, Boehringer-Ingelheim, Lundbeck, Eli Lilly (unpaid) Clinical Trial Site Investigator: Bristol-Myers-Squibb, Janssen, Avid, Navidea, Eli Lilly Research funding from: National Institute on Aging: P01AG036694; R01AG027435; K24AG U19AG010483; P50AG Alzheimer s Association, American Health Assistance Foundation American Academy of Neurology Brain Foundation, Fidelity Biosciences

3 Disambiguating Aging and Alzheimer s Disease Cognitive function Preclinical MCI (Prodromal AD) Normal Aging Dementia Years

4 Pathology of Alzheimer s Disease

5 PET Amyloid Imaging Harvard Aging Brain Study Sperling, Johnson NeuroMolecular Med 2010

6 Preclinical Alzheimer s Disease? 60 Prevalence of PiB+ PET in HC 50 Prevalence (%) Prevalence of plaques in HC (Davies, 1988, n=110) (Braak, 1996, n=551) (Sugihara, 1995, n=123) ~15 yrs Prevalence of AD (Tobias, 2008) Age (years) Rowe C et al Neurobiology of Aging 2010

7 Evidence of Amyloid-Related Alterations in Neural Function and Structure in Normals PiB-PET fmri FDG-PET vmri Sperling RA Neuron 2009; Hedden J Neurosci 2009; Shelline Bio Psych 2010; Becker JA Ann Neurol. 2011; Mormino Cerebral Cortex 2011; Drzezga Brain 2011; Vannini Neurobiology of Aging 2011; Vannini Cerebral Cortex 2012; Kennedy NeuroImage 2012; Chételat G Neurology. 2012; Dickerson BC Cereb Cortex. 2009; Dickerson BC, Neurology. 2011; Schott JM, Ann Neurol. 2010; Fjell A Cereb Cortex 2010; Sabuncu MR, Arch Neurol. 2011; Knopman D JAMA Neurology 2013; Andrews KA PLoS One 2013; Villeneuve S Neurology 2014; Mosconi L Neurology 2014; Huijbers W J Neuroscience 2014

8 Cognition in Amyloid Pos vs. Neg in HC > 70 years old WMS Immediate WMS Delayed Digit-Symbol * * Sperling R et al Neurobiology of Aging 2013

9 Subjective memory concerns associated with amyloid burden among normal elderly Amariglio R et al Neuropsychologia 2012 Perrotin A et al Arch Neurology 2012

10 Amyloid β and APOE4 related cognitive decline Combined cohorts: HABS, ADNI, AIBL (n=490) FDG+ N=25 FDG- N=47 florbetapir- N=49 Mormino E et al Neurology (In press)

11 Age-related Variation within Older Adults: Unique and Shared Variance Estimates N=186 Executive Function Episodic Memory Unrelated to brain markers 25.4% DTI FA 14.3% Shared among brain markers 52.6% Unrelated to brain markers 26.2% Hippocampal volume 7.7% Shared among brain markers 58.7% 7.7% Striatum volume PIB 3.2% WMH 2.1% Entorhinal thickness 2.1% Hedden et al., in review

12 Amyloid + Neurodegeneration Stages of Preclinical AD Stage 0 Aβ /ΝD Stage 1 Aβ+/ΝD Stage 2 Aβ+/ΝD+ SNAP Aβ /ΝD+ Vos et al Lancet Neurology 2013 Mormino E (under review)

13 Tau PET 70 y/o MMSE =27 SUVR PiB T807 Keith Johnson CTAD 2013

14 68y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Ab= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ= y Aβ=1.09 Aβ Age SUVR=1 2 K. Johnson CTAD 2013

15 Tau PET and Memory K. Johnson (in prep)

16 Terminology and Consequences The A word is frightening but public discussion is critical (lessons from the C word) Ideally separate Alzheimer s disease pathology from the dementia syndrome Pre does not necessarily mean inevitable progression to symptomatic stage of disease Defining disease at an asymptomatic or preclinical stage enables early intervention secondary prevention trials to delay memory loss

17 Anti-Amyloid Treatment in Asymptomatic AD (A4) A4 Normal Aging Cognition Preclinical } MCI Dementia Years Sperling R et al Sci Trans Med 2014

18 The A4 Study Anti-Amyloid Treatment Amyloid - Cognition A4 Amyloid + Treated } Amyloid + Placebo Sperling R et al Sci Trans Med 2014

19 Recommendations Need more crosstalk between cognitive aging and early Alzheimer s disease communities Is AD accelerated brain aging? Pathology that is common in normal aging may still be an important target for intervention Hypertension, Arthritis Need to go after multiple factors that influence cognitive decline Aβ, tau, cerebrovascular disease, other causes of neurodegeneration combination therapy!

20 Keith Johnson, MD Trey Hedden, PhD Gad Marshall, MD Jas Chhatwal, MD J. Alex Becker, PhD Randy Buckner, PhD Harvard Aging Brain Study Dorene Rentz, PsyD Rebecca Amariglio, PhD Brad Dickerson, MD Brad Hyman, MD, PhD Deborah Blacker, MD Dennis Selkoe, MD Aaron Schultz, PhD Beth Mormino, PhD Willem Huijbers, PhD Kate Papp, PhD Brendon Boot, MD Patrizia Vannini, PhD Lauren Wadsworth, Natacha Lorius, Caroline Sullivan, Sarah Wigman, Andrew Ward, Margaret Chute, Catherine Munro, Alex Dagley, Alayne Younger, Nayiri Arzoumanian, Emily Shaw, Tamy-Fee Meneide, Jackie Maye, Chris Gidiscin, Lesley Pepin, Rose Bamfo, Steve Weise, Ali Atri, MD,, Mykol Larvie, MD, Donald McLaren, PhD, Jorge Sepulcre, MD Support: NIA, Alzheimer s Association, AFAR, AHAF

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