1. Chapter 4 Aging, Dementia, and Alzheimer Disease
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2. Figure 1 Auguste D., the patient that Alzheimer described in 1906 and who served as the name-defining case.
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3. Wiki Commons, based on 2004 World Health Organization Data.
Figure 2 Worldwide disease burden of dementias, expressed as the disability-adjusted life year (DALY), which shows the number of years lost due to ill health, disability, or early death per 100,000 inhabitants in 2004.
Wiki Commons, based on 2004 World Health Organization Data.
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4. Figure 3 Images courtesy Dr Peter Anderson, University of Alabama Birmingham, Department of Pathology & Pathology Education Informational Resource (PEIR) Digital Library (
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5. Figure 4 Forms of memories
Figure 4 Forms of memories. Declarative memories involve the hippocampus and are often termed the “where” memories. Nondeclarative or procedural memories are the “how” memories, and do not involve the hippocampus.
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6. Figure 5 Declarative memories are distributed throughout the cortical–mediotemporal lobe network and require information flow through the hippocampus and the surrounding entorhinal and perirhinal cortices.
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7. Adapted from a picture from National Institute for Aging (NIA).
Figure 6 Schematic depiction of the spread of AD throughout the brain. During preclinical phases the primary affected areas are the hippocampus and entorhinal cortex. This spreads to include the frontal lobe and ultimately the entire cortex and even cerebellum.
Adapted from a picture from National Institute for Aging (NIA).
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8. Figure 7 Autopsy shows extensive brain atrophy in a patient who died from AD (right) compared to a similar-aged individual who died from natural causes (left). Images in A nd B show overall brain atrophy, while C and D show marked thinning of the cortical gray matter and enlargement of the ventricles in the AD patient. Images courtesy of Dr Peter Anderson, University of Alabama Birmingham, Department of Pathology & Pathology Education Informational Resource (PEIR) Digital Library (
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9. Figure 8 Neuropathological hallmarks of Alzheimer disease, neuritic plaques and neurofibrillary tangles visualized with modified Bielschowsky stain. These are from the autopsy of an 83-year-old woman with AD.
Courtesy of Dr Steven L. Carroll, Medical University of South Carolina.
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10. From National Institute for Aging (NIA).
Figure 9 Schematized role of tau protein in healthy (left) and diseased (right) brain. Tau stabilizes the microtubules along which cargo such as neurotransmitter vesicles are moved. The hyperphosphorylation of tau causes a loss of microtubule stability, disrupting transport of cargo vesicles.
From National Institute for Aging (NIA).
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11. Figure 10 Sequential cleavage of Amyloid Precursor Protein (APP) by β- and γ-secretase produce oligomeric Ab40 and 42 fragments. N and C designate the N- and C-terminal of the APP protein. Note that γ-secretase cleaves within the membrane, whereas β-secretase cleaves on the extracellular plasma membrane site. Cleavage by α-secretase produces a soluble longer form of amyloid that is not toxic.
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12. Figure 11 The dynamic relationship between plaques and oligomers with differential effects on brain physiology and pathophysiology. Oligomers may affect signaling functions of neurons, while plaques either act as storage sites or directly attract and activate microglia, eliciting an inflammatory response.
From Ref. 11.
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13. Figure 12 Dual role of γ-secretase cleaving both Notch and APP
Figure 12 Dual role of γ-secretase cleaving both Notch and APP. The same enzyme that produces toxic forms of amyloid serves to produce Notch, an important protein that acts as a nuclear gene regulator required for normal development and cell polarity. Notch signaling depends on three endoproteolytic cleavages (S1–S3). Notch maturates in the Golgi by furin-mediated cleavage at site 1 (S1). At the cell surface, Notch is cleaved at S2 (after binding to its ligands Delta/Serrate/Lag-2. Finally, cleavage at S3 liberates the notch intracellular domain (NICD), which translocates to the nucleus, thereby regulating the transcription of target genes by binding to transcription factors. β-APP is processed by a similar pathway. Initial cleavages of β-APP by α- or β-secretase lead to the generation of a membrane-bound complex. γ-secretase cleavage then liberates Aβ and the APP intracellular domain (AICD). The biological function of AICD remains to be determined.
Figure generated from Ref. 12.
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14. Figure 13 Blood vessel association of Aβ visualized in a hAPP mutant mouse in vivo using a fluorescent dye (benzothiazole) that binds to amyloid plaques (white).
Provided by Ian Kimbrough, Department of Neurobiology, University of Alabama Birmingham.
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15. Figure 14 Structural changes detected in Alzheimer disease by noninvasive imaging. Examples of structural T1-weighted MRI comparing two 75-year-old individuals, one control (left) to one with AD (right) showing marked mesiotemporal lobe atrophy (circle).
From Ref. 20.
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16. Figure 15 FDG-PET used to noninvasively distinguish patients suffering from AD and FTLD. In AD, glucose utilization determined by FDG-PET is lowest in the occipital and parietal lobes of the cortex (arrows), while in FTD the frontal lobe shows the greatest reduction in glucose utilization.
Image courtesy of Drs Frederik Barkhof, Marieke Hazewinkel, Maja Binnewijzend, and Robin Smithuis, Alzheimer Center and Image Analysis Center, Vrije University Medical Center, Amsterdam and the Rijnland Hospital, Leiderdorp, The Netherlands.
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17. Image courtesy of Prof. Rowe and Villemagne, Austin Health, Australia.
Figure 16 Patient diagnosis using the Pittsburg compound which directly binds to amyloid deposits in the brain of AD patients. The example illustrates abundant amyloid labeling in the AD pateint not seen in the control.
Image courtesy of Prof. Rowe and Villemagne, Austin Health, Australia.
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18. Figure 17 Future treatments for Alzheimer disease are exploring four major targets. (1) the cleavage of APP into plaque-prone amyloid by inhibition of the b-or (2) y- secretases (b and y symbol). (3) Interference of plaque formation using inhibitors of Ab. (4) Enhancing the clearance of Ab using immunotherapy.
From Ref. 11.
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19. Figure 18 Schematic depiction of disease progression
Figure 18 Schematic depiction of disease progression. Ab aggregation into plaques precedes disease symptoms by as many as 15 years, while tau hyper-phosphorylation may occur up to 5 years prior to symptoms. As pathology develops, mild cognitive impairment (MCI) eventually gives way to AD-dementia, a stage at which pathological signs tissue changes are abundant.
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20. Figure 19 Averaged FDG PET scans in four subjects treated with NGF, overlaid on standardized MRI templates. Representative axial sections, with 6–8 months between first and second scan, showing widespread interval increases in brain metabolism. Flame scale indicates FDG use/100 g tissue/min; red color indicates more FDG use than blue.
From Ref. 27.
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21. Box Figure 1 Neurochemical basis of memory (LTP and LTD)
Box Figure 1 Neurochemical basis of memory (LTP and LTD). High-frequency stimulation dislodges Mg2+ from NMDA receptors, allowing enhanced influx of Ca2+, which leads to the insertion of AMPA receptors into the postsynaptic membrane, causing an increase in postsynaptic current (LTP). Low-frequency stimulation, on the other hand, leads to much lower postsynaptic Ca2+ and removal of postsynaptic AMPA receptors, leading to a reduced postsynaptic current (LTD).
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