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FIGURE 5.6

Alzheimer's disease. Burnt-out neuritic plaque consists of amyloid core only, lacking dystrophic neurites (Bodian stain).

Neurochemical Pathology

Neuronal degeneration results in deficiencies of the major neurotransmitters. Neuronal losses in the basal nucleus of Meynert are responsible for deficiencies of acetylcholine and its enzyme, choline acetyltransferase in limbic and neocortical areas. Cholinergic deficiency is strongly implicated in the memory deficit of AD. Neuronal losses in the locus ceruleus account for nor-epinephrine deficiency in the cortex; and losses in the pontine raphe nuclei account for serotonin deficiency in the cortex and subcortical structures.

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FIGURE 5.7

Alzheimer's disease. Neurofibrillary tangles (NF). A. Argyrophilic cytoplasmic tangles showing torch- and basket-shaped configurations. B. Twisted bundles. C, D, and E. Residual ghost tangles and neuropil threads (Gallyas silver stain). F. Tau-immunoreactivity of tangles (immunostain).

FIGURE 5.8

Alzheimer's disease. Neuronal changes. Hippocampal pyramidal neurons showing (A) granulovacuolar degeneration and (B) Hirano body (HE).

FIGURE 5.8

Alzheimer's disease. Neuronal changes. Hippocampal pyramidal neurons showing (A) granulovacuolar degeneration and (B) Hirano body (HE).

FIGURE 5.9

Alzheimer's disease. Cortical neuronal losses. A. Severe cortical neuronal degeneration and status spongiosus (HE). B. Prominent replacement astro-cytic gliosis (Holzer stain).

FIGURE 5.9

Alzheimer's disease. Cortical neuronal losses. A. Severe cortical neuronal degeneration and status spongiosus (HE). B. Prominent replacement astro-cytic gliosis (Holzer stain).

FIGURE 5.10

Alzheimer's disease. Amyloid angiopathy. Congo red-positive amyloid deposits around and within the walls of small cortical blood vessels (Congo-red stain).

FIGURE 5.10

Alzheimer's disease. Amyloid angiopathy. Congo red-positive amyloid deposits around and within the walls of small cortical blood vessels (Congo-red stain).

TABLE 5.3.

Genetics of Alzheimer's Disease

APP: Chromosome 21 Early onset Autosomal dominant Presenilin 1: Chromosome 14 Early onset Autosomal dominant Presenilin 2: Chromosome 1 Early onset Autosomal dominant

APOE4: Chromosome 19

Susceptibility gene Late onset

Familial and sporadic APP, amyloid precursor protein; APOE4, apolipoprotein E4.

Etiology

The etiology of AD remains elusive. Aging, familial occurrence, Down's syndrome, elevated blood levels of apolipoprotein 4 (APOE4) and homocysteine, and head injury are risk factors. Among environmental factors, aluminum, zinc, and silicon toxicities have been associated with the disease, but none has been confirmed.

Genetic factors have a key role in the pathogenesis of AD (Table 5.3). Mutations in the APP gene on chromosome 21 and mutations in presenilin 1 and presenilin 2 genes on chromosomes 14 and 1, respectively, are implicated in early-onset autosomal dominant AD. A susceptibility gene—the gene of APOE4 on chromosome 19—is linked to late-onset sporadic and familial AD. APOE4, a blood lipoprotein, is elevated in about 45% to 60% of AD patients. Carriers of the gene are at risk for the disease.

Pathogenesis

AD is viewed as a protein metabolic disorder (Table 5.4). Several major steps in the formation of the neuritic plaques and neurofibrillary tangles have been identified, although others remain to be discovered.

Neuritic plaques. Amyloid precursor protein (APP), the generator of the neuritic plaques, is a neuronal membrane glycoprotein with an extracellular component. The overexpression of APP leads to its cleavage by the enzymes y- and p-secretase into Ap-peptides 40 and 42, respectively. It is postulated that an extracellular accumulation of Ap-peptides results from the secretion of Ap-40 by the neurons and from the release of excessively accumulated Ap-42 by the dying neurons. Ap-peptides are apt to aggregate into fibrillary structures that result in primitive (diffuse) plaques. Adding to the Ap-plaques are a-synuclein, a synaptic protein, and other nonamyloid components (proteoglycans, APOE, cholesterol). Ap-peptide is toxic to the neurons. Dystro-phic neurites derived from dendrites, axons, and synap-tic terminals of degenerating neurons congregate around the primitive plaques, converting them into classic, mature plaques. The appearance of activated microglia and astrocytes outside the dystrophic neurites completes the process of plaque formation.

Neurofibrillary Tangles

Tau protein, a microtubule-associated cytoskeletal protein, is normally present in a phosphorylated state. Abnormally phosphorylated tau protein aggregates into cytoplasmic filamentous structures—neurofibrillary tangles—that interfere with neuronal metabolism and eventually lead to neuronal death.

Clinical-Pathologic Correlates

Failing memory, the presenting cognitive deficit, correlates well with the early and severe involvement of the entorhinal-hippocampal structures of the limbic lobe, which is essential for memory and learning. As the neuronal degeneration gradually extends to the frontal, temporal, parietal, and occipital neocortex, the dementia evolves; more and more cognitive deficits appear, in conjunction with psychiatric symptoms and neurologic signs. Ultimately, the cerebral cortex becomes diffusely involved, and the dementia becomes global and profound.

Researchers dispute which of the basic pathologic lesions—neuritic plaques, neurofibrillary tangles, or synaptic losses—best correlates with the cognitive decline. Both the neurofibrillary tangles and the synap-tic losses are thought to be crucial for the development of dementia.

Clinical Application of Neuropathologic Features The discoveries of molecular pathology and neuro-chemical abnormalities in AD initiated vigorous clinical investigations in two major areas: diagnostic and therapeutic.

The neuropathologic features of AD also provide the basis for finding reliable biomarkers to make early and accurate diagnoses. P-Amyloid, a component of neuritic plaques, and tau protein, a component of neu-rofibrillary tangles, are commercially available CSF markers. P-Amyloid levels were found to be low and tau protein levels high in the CSF of a number of patients with suspected AD when compared with normal age-matched controls. Presently, the assays make the diag nosis more likely but not definite in subjects aged 70 or over with a clinical history of dementia.

The basic pathologic features of AD became targets for therapeutic strategies aiming to prevent or delay the progression of the disease, slow its course, and improve cognitive deficits. Several features already have been targeted for therapeutic application: (a) the cholinergic deficiency state in the limbic and neocortical regions initiated therapy with cholinesterase inhibitors; (b) the activation of microglia around neuritic plaques, implying an inflammatory element in the disease process, prompted therapy with nonsteroidal anti-inflammatory agents; (c) elevated blood levels of APOE4 in a number of AD patients became the rationale for using cholesterol-lowering drugs; and (d) immunization with P-amyloid peptide was intended to reduce the amyloid burden in the neuritic plaques. The treatment, however, was discontinued because a minority of patients developed neurologic complications consistent with menin-goencephalitis from which two patients died.

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