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Alzheimer Disease: Current Concepts and Emerging Diagnostic and Therapeutic Strategies

Christopher M. Clark, MD; and Jason H.T. Karlawish, MD
[+] Article, Author, and Disclosure Information

From the University of Pennsylvania, Philadelphia, Pennsylvania.

Grant Support: By National Institute on Aging (NIA) grants AG10124 and AG09215. Dr. Karlawish was funded by a Paul Beeson Fellowship and by NIA grants K01-AG00931 and P01-AG10124.

Corresponding Author: Christopher M. Clark, MD, Memory Disorders Clinic, Penn-Ralston Center, the University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104.

Potential Financial Conflicts of Interest: Dr. Clark has been a paid participant in advisory board meetings for Janssen Pharmaceutica, Parke-Davis, Eisai, and Elan (formerly Athena Neurosciences). He has received honoraria from Parke-Davis, Eisai, and Pfizer for giving educational presentations on the diagnosis and treatment of Alzeheimer disease. Dr. Clark has also participated in research studies sponsored by Elan, Eisai, and Parke-Davis. Dr. Karlawish has received an educational grant from Ortho-McNeil.

Current Author Addresses: Drs. Clark and Karlawish: Memory Disorders Clinic, Penn-Ralston Center, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104.

Ann Intern Med. 2003;138(5):400-410. doi:10.7326/0003-4819-138-5-200303040-00010
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Dementia is the fourth depth of dissolution. Such a person may have a highly developed brain, but not the full use of it … He may have many fine thoughts, and yet no system of thinking; his brain soon falls out of gear when dealing with complex subjects. At the bottom … there is no person, but only a living creature (1).

–John Hughlings Jackson, 1894

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Figure 1.
Topography of density rankings of neurofibrillary tangles (NFT) and neuritic plaques (NP) plotted onto Brodmann's lateral and medial views of the cerebral hemisphere(13).

From Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. 1991; 1:103-16. By permission of Oxford University Press.

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Figure 2.
Micrograph demonstrating neuritic plaques in the neocortex of a patient with Alzheimer disease (silver stain; original magnification, ×400).
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Figure 3.
Schematic diagram of the proteolytic processing of the amyloid precursor protein (APP).

The numbers above the fragments indicate the amino acid sequence relative to the first amino acid of the Aβ domain. Aβ = β-amyloid; α-secretase = the enzyme that cleaves APP within the Aβ domain, preventing the formation of amyloid fibrils; γ-secretase = the enzyme that cleaves both sAPP-α and sAPP-β to form the p3, C57/59, and Aβ fragments; sAPP-α = soluble APP-α; sAPP-β = soluble APP-β.

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Figure 4.
Micrograph demonstrating neurofibrillary tangles in the neocortex of a patient with Alzheimer disease (Bielschowsky stain; original magnification, ×200).
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