JOURNAL OF INSURANCE MEDICINE Copyright ᮊ 2002 Journal of Insurance Medicine J Insur Med 2002;34:127±130

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Images in Pathology: Alzheimer’s Disease Venita Jay, MD, FRCPC

The review describes the histopathology and pathophysiology of Al- Address: Manulife Reinsurance, 200 zheimer’s disease. Bloor Street East, Toronto, Ontario M4W1E5, Canada. Key words: Alzheimer’s disease, dementia, histopathology.

early a century ago, Alois Alzheimer de- occupational status and fewer years of edu- Nscribed the first case of the disease that cation.3 now bears his name.1 Alzheimer’s first en- A clinical diagnosis of AD can be quite ac- counter with this fateful case was in 1901, curate in the hands of an experienced physi- when a 51-year-old woman was admitted cian. Clinical workup includes screening for with aphasia, poor memory, lack of orienta- other causes of dementia in the elderly and tion, paranoid ideation, unpredictable behav- exclusion of other etiologies (eg, hypothy- ior, hallucinations and severe cognitive defi- roidism, drug-induced encephalopathy, cits. After her death in 1906, Alzheimer re- chronic subdural hematoma, brain tumor). ported the autopsy findings in a landmark While neuropsychological testing, metabolic presentation entitled, ‘‘On a Peculiar Disease neuroimaging, and cerebrospinal fluid tau Process of the Cerebral Cortex.’’ Alzheimer’s levels have been used to increase confidence original pathological description of cerebral in the probability that the dementia is due to atrophy, neurofibrillary change and loss of AD, an unequivocal diagnosis of AD can be neurons, remains remarkably accurate to this rendered only on neuropatholgical examina- day.1 tion of brain tissue.5,6 By CT or MR imaging, Today, Alzheimer’s disease (AD) is recog- there is evidence of cortical atrophy (notably nized as the most common cause of dementia the medial temporal lobe), with parietotem- in the elderly, accounting for over 50% of cas- poral hypoperfusion on positron emission to- es.2,3 The most potent risk factor for AD is mography (PET) and single photon emission increasing age and the presence of the apo- computed tomography (SPECT).2 This selec- lipoprotein ⑀4 allele. The lifetime risk of AD tive early involvement of the medial temporal for an individual without the ⑀4 allele is 9%, lobe is utilized in the diagnosis of AD by neu- while the lifetime risk of an individual car- roimaging.5 rying at least one ⑀4 allele is 29%.4 AD is From a pathological perspective, the brain more common among women than men with in AD is reduced in weight, with especially a ratio of 1.2 to 1.5.3 Other risk factors impli- pronounced atrophy of the medial temporal cated in some studies include head injury, lobe, and atrophy of the temporal, parietal family history of dementia, lower income and and frontal association cortices.5,6 Primary

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cortical areas (primary motor, sensory and vi- phorylated as well as abnormally phosphor- sual cortex) and most subcortical structures ylated tau protein.7 Normal adult tau is a sol- are relatively preserved. The lateral ventricles uble microtubule binding protein that is pri- are dilated secondary to cerebral atrophy. The marily localized in axons and plays an im- hippocampus and amygdala are atrophic. portant role in the polymerization and The locus ceruleus often shows loss of pig- stabilization of microtubules.5 The abnormal- ment. ly phosphorylated tau of AD is less able to At a microscopic level, there is diffuse loss bind microtubules, presumably leading to of large pyramidal neurons in the cerebral microtubule depolymerization, disrupted ax- cortex in AD, especially involving the multi- onal transport, compromised synaptic trans- modal association cortices.6 There is also neu- mission, and ultimately neuronal death.5 ronal loss in the hippocampus, amygdala, As shown in Figure 1B, another patholog- basal forebrain, and locus ceruleus. There is ical hallmark of AD is the neuritic plaque. a substantial loss of synapses, which corre- Neuritic plaques have a dense core of extra- lates with the degree of cognitive impair- cellular amyloid surrounded by an amyloid ment. Concomitant with the cerebral atrophy, corona, in which dystrophic neurites (con- there is astrocytic gliosis. taining abnormal tau/paired helical fila- Alois Alzheimer used the newly developed ments) and processes of reactive microglia Bielschowsky’s silver staining method to are incorporated. Large numbers of neuritic demonstrate the neurofibrillary tangles in plaques accumulate in the cerebral cortex in neurons of the cerebral cortex of his famous AD. Senile plaques of aging (nonneuritic se- patient.1 The Bielschowsky stain continues to nile plaques or diffuse plaques) are seen in be widely used to demonstrate AD patholo- elderly people without dementia—they lack gy. Figures 1A and 1B illustrate the classical the amyloid core, dystrophic neurites, and pathological findings in AD—neurofibrillary the inflammatory microglial response. On tis- tangles and neuritic plaques in a section of sue sections, amyloid is demonstrated by the cortex stained by the Bielschowsky stain. congo red stain or by fluorescence after thio- The neurofibrillary lesions of AD present flavin staining. in the form of neurofibrillary tangles, neuro- Other pathological findings on microscopy pil threads, and neuritic plaques.2,5,6 Neuro- include Hirano bodies and granulovacuolar fibrillary tangles are filamentous inclusions degeneration (GVD) in the neurons of the within the neuron body and proximal den- hippocampus (clear vacuoles pushing the cy- drites (Figure 1A). Whereas, neuropil threads toplasm and containing a basophilic granule). (which have a thread-like appearance) are In some studies, the number of neurons af- found in distal dendrites and axons.5 fected by GVD correlated with the duration At an ultrastructural level, neurofibrillary of dementia.2 In AD patients, there is also ce- tangles are composed principally of paired rebrovascular pathology with deposition of helical filaments, which are intraneuronal amyloid in blood vessels (cerebral amyloid proteinaceous structures composed of an ab- angiopathy). normal form of the tau protein.2,5,6 Paired he- In AD, there is a highly selective distribu- lical filaments accumulate in neuronal cell tion of neurofibrillary lesions and to a lesser bodies (neurofibrillary tangles), in neuronal extent of neuritic plaques. Regions most af- processes throughout the cortex (neuropil fected with neurofibrillary tangles are the me- threads), and in distended neuronal process- dial temporal lobe, amygdala, the association es (dystrophic neurites) around the extracel- cortices, and the nucleus basalis of Meynert. lular amyloid deposits in the neuritic plaque Within the entorhinal cortex, there is also a of AD. selective involvement of certain neuronal lay- Biochemically, neurofibrillary tangles are ers (layers II and IV) with relative sparing of composed of a poorly soluble hyperphos- layers III, V, and VI. It is noteworthy that the

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Figures 1A and 1B. Section of cerebral cortex stained by the Bielschowsky stain demonstrating neurofibrillary tangles (arrowheads) (A, high power view) and several neuritic plaques (arrowheads) (B, medium power view).

large projection neurons in layers II and IV In terms of correlating pathology with clin- link the hippocampus with the association ical severity, there is a strong correlation be- cortices.5 This disruption of the neural link be- tween the density of neurofibrillary tangles tween the hippocampus and the rest of the and the severity of dementia (specifically brain contributes to the amnesia in AD.5 neurofibrillary tangles in the neocortical as-

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sociation areas).5 Correlations between senile 21) have been found.3 Other mutations have plaques and dementia have been more con- been found to involve genes on chromosome troversial, but mature neuritic plaques with 14 (presenilin-1 gene) and chromosome 1 an amyloid core do correlate with dementia, (presenilin-2 gene).3 albeit not as strongly as neurofibrillary tan- A problem in terms of a diagnosis based gles.5 on tissue pathology alone is the fact that the The neurofibrillary tangles and neuritic microscopic lesions of AD may occur to a plaque lesions of AD are accompanied by an minimal or modest degree in nondemented inflammatory reaction including proliferation elderly people. As a practical guide, the find- of microglia and astrocytes, prompting re- ing of neurofibrillary tangles in a neocortical search into the role of anti-inflammatory brain biopsy allows for a relatively certain di- medication in AD.2 agnosis of AD.2 If neurofibrillary tangles and Several neurotransmitter systems are af- neuritic plaques are abundant throughout the fected in AD. There is a severe loss of cholin- neocortex and the hippocampus at autopsy, ergic neurons in the nucleus basalis of Mey- then a neuropathologic diagnosis of AD is nert of the forebrain.5 Abnormalities of the relatively straightforward.2 Neurofibrillary cholinergic systems form the basis of phar- tangles without neuritic plaques are also en- macotherapeutic interventions aimed at en- countered in a number of other ‘‘tauopathies’’ hancing cholinergic activity. Cholinesterase such as supranuclear palsy and dementia inhibitors are the only medications approved pugilistica,2,7 but a combination of tangles, by the U.S. Food and Drug Administration as neuritic plaques, vascular amyloid, and gran- treatment for AD.3 In addition to cholinergic ulovacuolar degeneration is diagnostic of AD. neurons, other neurotransmitter systems are This article is intended only as a brief overview also affected including the locus ceruleus of the pathology and does not represent an ex- (norepinephrine) and the raphe nuclei (sero- haustive review of the pathological or clinical lit- tonin).5 erature on the subject. The amyloid protein in the neuritic plaques and vessels in AD is beta-amyloid (beta/A4 REFERENCES protein, amyloid ␤-peptide). It is derived from a larger protein, the A4 (amyloid pre- 1. Jay V. Alois Alzheimer. J Histotechnology. 2002;25: 113. cursor protein or APP), encoded by a gene on 2. Vinters HV, Farrell MA, Mischel PS, Anders KH. chromosome 21.2,8 The amyloid ␤-peptide Diagnostic neuropathology. New York: Marcel Dekker, was first sequenced from meningeal blood Inc.; 1998. vessels of patients with AD and individuals 3. Cummings JL, Cole G. Alzheimer disease. JAMA. with Down’s syndrome.9 Subsequently, the 2002;287:2335–2338. 4. Seshadri S, Drachman DA, Lippa CF. Apolipopro- same peptide was found in the neuritic tein E epsilon 4 allele and the lifetime risk of Al- plaques of AD, launching a new era of AD zheimer’s disease. What physicians know, and what research, which culminated in the cloning of they should know. Arch Neurol. 1995;52:1074–1079. the APP gene and its localization to chro- 5. Arnold SE. Part III. Neuropathology of Alzheimer’s mosome 21.9 It is noteworthy that individuals disease. Dis Mon. 2000;46:687–705. with trisomy 21 (Down’s syndrome) invari- 6. Dickson DW. Neuropathology of Alzheimer’s dis- ease and other dementias. Clin Geriatr Med. 2001;17: ably show AD type neuropathology. Accord- 209–228. ing to the amyloid hypothesis of AD, accu- 7. Trojanowski JQ, Lee VM. The role of tau in Al- mulation of amyloid ␤-peptide in the brain is zheimer’s disease. Med Clin North Am. 2002;86:615– the primary influence driving AD pathogen- 627. esis.9 8. Sinha S. The role of beta-amyloid in Alzheimer’s disease. Med Clin North Am. 2002;86:629–639. Mutations account for less than 5% of all 9. Hardy J, Selkoe DJ. The amyloid hypothesis of Al- 3 cases of AD. In familial AD, mutations of the zheimer’s disease: progress and problems on the gene encoding APP (APP gene, chromosome road to therapeutics. Science. 2002;297:353–356.

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