Aging, Memory and Alzheimer’s Disease

Kinga Szigeti, MD, PhD

Aging and Alzheimer’s disease• The biggest challenge in AD: it is superimposed on

normal aging• Insidious onset• No blood test; diagnosis is putting a puzzle together

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1997 2007 2027 2047

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Projected prevalence of AD

No intervention

2 year delay

5 year delay

Major PublicHealth Problem

Red-yellow = diff small-diff big

Mild AD MMSE 20-26

Single domain amnestic

-Forgetting where we put things-Forgetting appointments-Repeatiing questions or conversations

Multidomain Z score <-2

Symptoms late in the disease: cells are damagedWe cannot recover nerve cells; goal is to prevent

We need biomarkers before the symptoms start

PET metabolism and amyloid imaging

Alzheimer disease as a model of complex genetics

Not two patients are exactly alike

APP storyMendelian genetics

Amyloid hypothesis

Linkage

Trisomy 21

Partial trisomy 21 not including APP-no AD

Candidate gene: APP

• Precursor protein to amyloid in AD brain

• Mutations found

• Disease and mutation went together within families

• Interestingly some of these mutations affect sites where gamma cleavage occurs

Linkage

Chr 14 Chr 1

Amyloid hypothesis: genetic confirmation

D Mutations in APP regulatory sequences

40 and 42

APP

PSEN1

PSEN2

Genetics proves it is heterogeneous

Research at the University at Buffalo

Copy number variation

Pieces of chromosomes (genetic material)Missing or in extra copies

Olfactory receptor association with AD age at onsetOlfactory receptor association with AD age at onset

Research at the University at Buffalo

Deletion upstream from CREB1 association with ADDeletion upstream from CREB1 association with AD

CHRFAM7A association with ADCHRFAM7A association with AD

Raminathan et al,PlosOne

Namenda might work better is this group

Alzheimer’s disease model: induced pluripotent stem cells

The goal: prevention

• Age 65 well visit/ part of the prevention panel• Primary care physician asks about memory issues• Screening memory test• Blood test for genetic risk factors (gene chip)• Assess family history of dementia

Then risk stratification:Low risk Monitor

Intermediate risk Consider amyloid imaging then Rx

High Risk Amyloid imaging then Rx

The goal: personalized treatment

• If memory problem is present:

• Clinical workup

• Gene chip to determine which drugs work best

Until we have the breakthrough: ADMDC patient care

• Diagnose early

• Modify risk factors to slow progression

• Treat to change slope of decline

• Buys us time

• Gives years of close to normal life