1. Majid Fotuhi, MD, PhD
Director, Center for Memory and Brain Health,
The Sandra and Malcolm Brain & Spine Institute
Assistant Professor of Neurology,
Johns Hopkins University School of Medicine
Memory, Aging, and
Question of Alzheimer Diagnosis
3. Objectives
• To explain the history of the diagnosis
of Alzheimer disease
• To describe the limitations of current
diagnostic criteria for oldest old
• To define factors that contribute to
late-life dementia
• To review strategies for prevention
6. Role of Amyloid Plaques in
Late-life Dementia
“Plaques are not the cause
of senile dementia, but only
an accompanying feature
of senile involution of the
central nervous system.”
Alois Alzheimer (1911)
9. Limitation of AD Diagnostic
Criteria among Oldest Old
• Plaques and tangles don’t differentiate
dementia from no-dementia.
• With each decade of life, relevance of
plaques and tangles diminishes.
10. AD Pathology Cannot Distinguish
Dementia from No Dementia
Dementia
No Dementia
Schneider et al., Neurology 69:2197–204, 2007
18. Brain is a Highly Vascular Organ
Zlokovic et al. Neurosurgery 43(4), 877–78, 1998
19. The Nun Study
• AD pathology
causes atrophy in
the hippocampus
and cortical areas
• Small or large
strokes cause
atrophy in
cortical and
subcortical areas
• Worse outcome with
both AD and strokes
20. Higher Risk of AD for Those with Midlife
Hypertension plus High Cholesterol
• Longitudinal Study
(1972, 1977, 1982, 1998)
• 1449 participants
• 57 cases of dementia,
48 with AD
• Mild hypertension: <140
• Severe hypertension: >160
• High cholesterol: >250
BMJ 2001; 322:1447–51
22. Obstructive Sleep Apnea
• OSA patients have far more cases of
– Myocardial infarction
– Stroke
– CHF
– Pulmonary HTN
• May be due to a combination of
– Hypercoagulopathy
– Chronic hypoxia
– Inflammation and endothelial injury
– Hyperactive sympathetic response
23. Less Grey Matter Brain Volume in
Patients with OSA
Am J Respir Crit Care Med 2002; 166:1382–7
25. Vascular Factors Contribute to
Late-life Dementia
Hypertension
Obesity – OSA
WMD
Stroke
AD
Diabetes or
Metabolic
Syndrome
26. Other Factors that Contribute to
Late-Life Dementia
• Apoliporotein E
• Inflammation
• High homocysteine
• Head trauma
• Depression/PTSD
• Kidney failure
• Congestive heart failure
31. Why is Hippocampus so Vulnerable?
Differential
expression of the
different subtypes of
metabotropic
glutamate receptors
may account for the
selective vulnerability
of CA1 neurons in
the hippocampus.
Fotuhi et al., Mol Brain Res 21:283–92, 1994
40. Cache County Study Design
Wave 2
3,314
Wave 1
4,580
5,677
Eligible
Elderly in
Cache Co.,
Utah
Wave 3
2,246
Drug inventory
– Current OTC and Rx medicines
(Validated by medicine chest review)
– Prior OTC and Rx medicines
1995–1996 1998–2000 2003–2004
47. Protective Factors
• Diet high in antioxidants
• Fish 2–3 times a week
• 1–2 glasses of wine with dinner
• Exercise
• Leisure activities
• Education, cognitive stimulation
• Smile more often
48.
49. Thanks
• Peter Zandi, Kathleen Hayden,
Kostas Lyketsos, and all
members of the
Cache County Study
(NIA, NIH, NIMH)
• Payam Mohassel
• David Do
• Marilyn Albert, Jason Brant,
Barbara Crain, Argye Hillis,
Carlos Pardo, Richard O’Brien,
Donald Price, Peter Rabins,
Ola Selnes, Sol Snyder, and
Michael Williams
• Tzipora Sofare
• Vladimir Hachinski
(University of Western Ontario)
• Miia Kivipelto
(Karolinska Institute)
• Peter Whitehouse
(Case Western University)
• Kristine Yaffe
(UCSF)
• Anne Young
(Harvard Med School,
Mass General Hospital)
