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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