Is Alzheimer’s Disease aUniquely Human Disorder?

Lary WalkerCynthia LemereMarc Dhenain

Patrick HofElizabeth HeadPeter Nelson

Moderator: Tom Fagan

Alzforum, Wednesday, December 7, 12 p.m. U.S. Eastern time

Aged Rhesus monkeyHuman AD

Aβ

Walker and Jucker, in prep

Human AD Aged Rhesus monkey

Aβ

Tau

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 allmajor phospho sitespresent 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

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 primatesis proportional to lifespan

After Finch and Sapolsky, 1999

Fibrillization

Soluble protein Strain 1

Misfolding andaggregation

Strain 2Amino acid differences

TruncationsLocal environmental factors

Proteopathic strains?

Ann Rev Genet 2016

Amyloid

Something else?

-ApoE

-Proteostatic controls

-Post-translational modifications

-Biometals

-Inflammation

-Metabolic / cardiovascular state

-Environment:

Life-long activity levels

Stress

Diet / Microbiome

…

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