Alzheimer's Disease
Genetics, Prevention, and Treatment

Slides from Talk by  Adam Rosenblatt, MD

Johns Hopkins Neuropsychiatry and Memory Group

 

Risk factors for AD
!   Head injury
!   Age
!   Affected relatives
$   risk is ~19% in first-degree
$  10% in second
$  5% in controls

 

Two Kinds of AD?
!  Familial
$ 10% of all cases
$ early onset 40-50's
$ 50% risk of inheritance
!  Sporadic
$ 90% of cases
$ late onset 70-80's

 

One kind of AD?
!    Late onset makes AD look less genetic
$   death from competing causes
!   Theoretical 90 year risk is 50%
$   especially if rigorous criteria are used
!  Actual risk is about 19% for relatives

 

 

 

 

 

 

Many kinds of AD?
!   3 early onset genes
$   chromosome 21 APP
$    chromosome 14 pre-senilin 1
$   chomosome 1 pre-senilin 2
!   One late onset gene
$   chromosome 19 APOE

 

 

 

 

 

 

 

APOE
!   3 alleles: e2, e3, e4
!   Most people have e3/e3
!    Risk doubles with one e4, xl5 with 2 e4
!    e2 may be protective
!   APOE is commonest known genetic cause

 

 

 

 

 

 

Environmental Factors
!  Known genetic causes only account for ~50%
!  Identical twins are only 58% concordant
!  Many people with e4/e4 do not get AD
!  May be provocative and preventative factors.

 

 

 

 

 

 

Purpose of Prevention
!   Prevent disease
!  Delay onset of disease
$   with late onset often the same
$   5 year delay could reduce harm by 50%
!   Don't confuse prevention and treatment

 

 

 

 

 

 

Prevention- NSAIDS
!   Several restrospective studies
!   Twin study looks at discordant pairs
$   the non-AD twins took more AI medicine
!   NSAIDS may delay the onset of AD
!   Prospective data would be more convincing

 

 

 

 

 

 

Prevention - Estrogen
!   Retrospective studies mostly
!   One suggestive treatment trial
!   Better prevention and treatment trials are on
!   There are other reasons to take estrogens

 

 

 

 

 

 

Treatment- Acetylcholinesterase Inhibitors
!   Increase activity in remaining neurons
$ improves performance
$ probably does not change final results
!   Tacrine-Cognex
$ effective but difficult to use
!   Donepezil-Aricept
!  More in the works

 

 

 

 

 

 

 

 

Treatment-Vitamin E
!   A single study of Vit E and selegiline
!   Prospective double-blind study
!   Randomization failed
$   placebo group started out higher
$   no significant differences seen
!   Effect only appears if this is corrected for
!   Vit E and selegine may slow progression

 

 

 

 

 

 

 

 

Should I be tested?
!  Limitations
$   most people will be negative
$     positives will not all get AD
$   lack of interventions
$     psychosocial consequences
!  Uses
$   diagnostic dilemmas
$   very strong family history

 

 

 

 

 

 

 

 

 

Should I take medicine?
!   Strong scientific support is lacking
!   The risk may be low
!   The interventions are not harmless
$   cost, side effects, confusion
!   Estrogen, aspirin for other indications

 

 

 

 

 

 

 

Hope
!   Need to understand genetics/environment
$   make better predictions
$   intervene in the process
!  Test promising treatments thoroughly
$   find out how best to apply them
$   prevent harm from adverse effects
! The future looks good