Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/

1. Is Alzheimer’s Disease a
Uniquely Human Disorder?
Lary Walker
Cynthia Lemere
Marc Dhenain
Patrick Hof
Elizabeth Head
Peter Nelson
Moderator: Tom Fagan
Alzforum, Wednesday, December 7, 12 p.m. U.S. Eastern time

2. Aged Rhesus monkeyHuman AD
Aβ

3. Walker and Jucker, in prep
Human AD Aged Rhesus monkey
Aβ
Tau

4. 1 695Aβ
Sequence of Aβ, tau?
APP695 sequence identity to human:
Chimpanzee: 100%
Rhesus monkey: 100%
[Mouse: 96.8%]
E2
E2 E3
E10
E10
E10
All 6 isoforms and all
major phospho sites
present in simians
Tau longest isoform identity to human:
Chimpanzee: 100%
Rhesus monkey: 98%
[Mouse: 88%]
After Levy et al. 1995, Uniprot; Brunden et al., 2009;
Nelson et al., 1996; Holzer et al., 2004

5. Human (Homo sapiens)
Mouse lemur (Microcebus murinus)
Squirrel monkey (Saimiri sciureus)
Rhesus macaque (Macaca mulatta)
Chimpanzee (Pan troglodytes)
Lifespan?
25 50 75 100 125
Years
Onset of Aβ deposition ( ) in primates
is proportional to lifespan
After Finch and Sapolsky, 1999

6. Fibrillization
Soluble protein Strain 1
Misfolding and
aggregation
Strain 2Amino acid differences
Truncations
Local environmental factors
Proteopathic strains?
Ann Rev Genet 2016
Amyloid

7. Something else?
-ApoE
-Proteostatic controls
-Post-translational modifications
-Biometals
-Inflammation
-Metabolic / cardiovascular state
-Environment:
Life-long activity levels
Stress
Diet / Microbiome
…

8. Alzheimer’s disease (diagnostic): A state of dementia that is
associated with characteristic Aβ plaques and tau tangles in the
brain.
Alzheimer’s dementia: The insidious onset and gradual
progression of substantial impairment in learning and memory and
at least one other cognitive domain that interferes with
independence in everyday activities.
Dementia definition modified from the Diagnostic and Statistical
Manual of Mental Disorders [DSM-5] (Walker and Jucker, in prep)
Definitions