Pathobiological Similarities and Differences Between

Down Syndrome and Alzheimers Disease

Golbal Down Syndrome Meeting

Elliott J. Mufson, PhD
Director, Alzhiemers Disease Laboratory
Depts. Neurobiology and Neurology
Barrow Neurological Institute
Phoenix, AZ

John Down and Family

John Langdon Haydon Down, a

Cornish physician described a genetic
disorder now termed Down syndrome
in 1862

Dr. Down s daughter and

grandson with DS,whi died at age 65

Down Syndrome Facts

DS occurs when an individual has a full or partial extra copy of
chromosome 21.
Triplication of amyloid precusor protein (APP) in Ch 21 leads to
increased APP expression and A peptides in DS.
Three types of Down syndrome: trisomy 21 (nondisjunction) accounts for
95% of cases, translocation accounts for about 4% and mosaicism for
about 1%.
One in every 691 babies in the United States is born with DS.
Incidence of births of children with DS increases with age of the mother.
Life expectancy for people with DS has increased dramatically in recent
decades - from 25 in 1983 to 60 today.
People with DS have an increased risk for congenital heart defects,
respiratory and hearing problems, and Alzheimer's disease.

Down Syndrome and Alzheimer disease: 

Prevalence in US Population

Downs Syndrome

American Journal on Mental Retardation: March 2004, Vol. 109, No. 2, pp. 126-141

Alzheimers Disease: Impact on Society

US life expectancy: 13% of
population > 65 today, 18%
expected by 2025
most common cause of dementia in
10% of over 65yrs, 50% of over
85yrs
affects ~ 5 million
cost of care (home or skilled care)
~ $50,000/year
societal cost ~ $172 billion/year

Down Syndrome (DS)

Alzheimers disease (AD)

Triplica(on of chromosome 21
defect

Early onset (<65)

chromosome 21 muta(on in the
APP gene locus

Stubby brain

Gyral widening/sulcal shrinkage

Abundant amyloid beta plaques

Abundant amyloid beta plaques

Sparse neurobrillary tangles

Profuse neurobrillary tangles

consistent

Down SyndromeDementi

Alzheimers disease

NeurotransmiIer defects
Cholinergic
Norepinephrine Control
Gluatmatergic

NeurotransmiIer defects (e.g.

Cholinergic,
Norepinephrine
Gluatmatergic Control

DS
AD

00.2 0.4 06. 0.8

Neurotrophin defects
proNGF/tubulin

Neurotrophin defects

NCI

MCI

Axoplasmic transport defects

Axoplasmic transport defects

Cellular stress (e.g. oxida(ve stress)

Cellular stress (e.g. oxida(ve stress)

Inamma(on

Inamma(on

Demen%a

Demen%a

AD

Preclinical and clinical drug trials of adults with Down syndrome

Drug:

Mechanism:

Mouse model:

Results:

Clincal trials
(yes/no)

Estrogen

An%-oxidant/protec%ve

Ts65Dn

Protec%on
Rescue

No

Meman%ne

NMDA reverse agonist

Ts65Dn

Symptoma%c

On going

Vitamin E

An%-oxidant

Ts65Dn

Preven%ve

Yes

Fluoxe%ne

Serotonin reuptake
inhibitor

Ts65Dn

No formal trial

GABA5-selec%ve
inverse agonists
Roche
L-DOPS

GABA inhibi%on

Ts65Dn

NE precursor

Ts65Dn

Choline

Acetylcholine
precursor

Ts65Dn

ELND005
Transi%on
Therapeu%cs

Reduce beta-amyloid
aggrega%on

PS1xAPP AD

Increased
neurogenesis
Normalize
GABA release
Rescue
learning and
memory
Rescue AD
pathology and
memory
Rescue AD
pathology and
memory

No adverse
side aects
Rescue AD
pathology

Ongoing

No

NO

On going

Potential clinical trials

Down syndrome

Alzheimers disease

Green tea extracts

Grape seed polyphenols

An(-amyloid vaccine trials

An(-amyloid vaccine trials (not

ecacious)

Gamma secretase inhibitors/
modulators
(not ecacious to date)

Neurotrophin gene therapy

Neurotrophin gene therapy trials

showed some ecacy

Collaborators
Rush University Med. Ctr
Jack Fox
Scott Counts
Sue Leurgans
Cassia Overk
Sylvia Perez
Joanne Wuu (Univ. Miami Med. School)
Rush ADC
Nathan Kline Institute
Steven Ginsberg
Shaoli Che
Northwestern University
Lester (Skip) Binder
Laurel Vana
Eli Lilly
Kelly Bales (Pfizer)
Christian Felder

University of Pittsburgh
Stephen DeKosky (UVA)
Milos Ikonomovic
University of Kentucky
Stephen Scheff
Emory University
Alan Levey
James Lah
Michelle Gillmor
McMaster University
Margaret Fahnestock
Shiyong Peng
McGill University
Claudio Cuello
Martin Bruno

We are indebted to members of the clergy participating in the Rush Religious Orders Study.
Support by NIA Grants PO1 AG14449, RO1AG043375 and P50AG10610.