Sci. Aging Knowl. Environ., 3 October 2001
Vol. 2001, Issue 1, p. dn2
[DOI: 10.1126/sageke.2001.1.dn2]


Alzheimer's Disease

Lawrence S. Honig, and Steven S. Chin

The authors are at Columbia University College of Physicians and Surgeons, in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, The Alzheimer's Disease Research Center, the Sergievsky Center, and the Department of Neurology, and the Department of Pathology, New York, NY 10032, USA. E-mail: lh456{at} (L.H.);2001/1/dn2

Abstract: In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with Alzheimer's disease (AD). AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than was memory impairment. Throughout the limbic system and neocortex of the patient were large numbers of senile plaques and neurofibrillary tangles, the pathological hallmarks of AD.

Introduction Back to Top

Mr. A. presented to a neurologist at age 68. He had expressed no particular concerns, but his wife had urged him to visit a doctor for evaluation of what she noticed as difficulties with verbal communication over the previous 4 years. In particular, his wife said that he seemed to have difficulties finding words during speech, frequently used the wrong words, and had trouble remembering names. When questioned, Mr. A. admitted to some problems of this nature; he estimated the problems had been ongoing for "about 10 years."

The neurologist elicited a detailed history of Mr. A.'s cognitive and social functioning and found only mild changes in his activities of daily living or his social functioning. Mr. A. still handled the household finances without noticeable problems. He performed well-learned chores without difficulty but increasingly asked his wife for instructions, particularly when faced with more daunting or less familiar tasks. He dressed, ate, and performed usual self-care tasks, such as shaving and toiletry, without prompting. He continued to work in his long-time profession as an engineer, although he may have experienced some mild difficulties at his job. For example, he complained that he couldn't understand "the logic" of what some people said to him. Also, he found that his writing was slower, messier, and more difficult (dysgraphia). Friends had not noticed any changes in his behavior or function.

Only when questioned did Mr. A. express any concern about memory. In retrospect, he and his wife both noted some changes in his ability to remember the content of recent conversations (short-term memory loss). Mrs. A. mentioned that he had become somewhat more repetitious (perseverative) and tended to dwell on past events. Mrs. A. had noticed some changes in his driving: He had been an excellent navigator but now seemed much less confident when driving to new locations. He also seemed somewhat more irritable than he used to be, and he expressed less interest in new things or activities. Otherwise, his personality seemed relatively unchanged.

Medical History Back to Top

Mr. A. suffered from high blood pressure. Ten years earlier, he had undergone a foot operation and a procedure for stomach reflux, neither of which was judged relevant to his current mental condition. Medications included drugs for blood pressure and stomach ulcers, and a sleeping pill.

Social History Back to Top

Mr. A. had completed college (education = 16 years) and was employed as an engineer. He had no recent history, for several decades, of alcohol use or tobacco smoking.

Family History Back to Top

Mr. A.'s mother died at age 67 in a nursing home. She suffered from dementia originally said to be due to "hardening of the arteries" but possibly due to Alzheimer's disease (AD). His father died at age 79 of a heart attack. Mr. A. had two older siblings, aged 71 and 73, with no known mental abnormalities.

Neurological Examination Back to Top

Mr. A. suffered from mild difficulties in concentration and attention in a neurological exam. For example, he was unable to spell a five-letter word backward. Language was also abnormal; he frequently used the wrong word in his spontaneous speech and when answering questions. These errors of expression (paraphasia) consisted of both words that sound similar to the correct word and those that are in the same category as the correct word. For example, when trying to name a pictured pretzel, he called it a "bagel." He had significant difficulty naming pictured objects (anomia); he was often able to describe the object but unable to say the correct name. In some cases, he used sounds to describe objects, for example, describing a tennis racket as "phut." He had some difficulty repeating a complicated sentence. Comprehension and simple reading and writing were unimpaired. He was somewhat disoriented in that he could not name the address where he was being examined, although he was able to state the day, date, and time. Memory testing showed significant impairments. He was unable to remember several objects shown to him a few minutes earlier. He was also unable to remember items of general knowledge, such as the names of recent presidents of the United States. His arithmetic abilities were impaired; he was unable to perform multiple subtractions or sum up several numbers. Thus, although Mr. A. continued to work and was generally unaware of his impairments, a neurological examination revealed that he suffered from abnormalities in a variety of cognitive functions.

The remainder of the neurological examination was normal. A slight tremor was present in the arms when outstretched, but this was judged to be either physiological tremor or a mild degree of benign essential tremor. The general physical examination was unremarkable. An example of an audiotaped examination of another similar patient can be heard in the audio clip.

Laboratory Testing Back to Top

Blood tests to check cell counts, kidney and liver function, vitamin B12 and thyroid hormone levels, and serological evidence of past infection with syphilis were all normal. Cerebrospinal fluid examination was performed as part of an ongoing research project that the patient and wife elected to join; the results of this testing were also normal. Other general medical studies that were available included chest x-rays, which revealed only a hiatial hernia (upward extension of the stomach), and electrocardiograms, which showed normal heart rhythm. An electroencephalogram study of brain activity was performed, and it showed some slowed activity. This finding was not specific for any particular disorder but was consistent with diffuse mild brain dysfunction. Magnetic resonance imaging (MRI), showed that the brain's structure and size were normal for the patient's age.

Detailed neuropsychological testing confirmed moderately severe impairments of memory for words and images and difficulties with naming objects, repeating words, and expressive speech, especially in word-generation tests. He also performed poorly in complicated reading and writing tasks, and his arithmetic abilities were impaired. However, he was relatively unimpaired in abstract reasoning, visuospatial, and drawing abilities.

Clinical Diagnosis Back to Top

Mr. A. was diagnosed with AD. The examination showed that his memory was severely impaired, which is most consistent with AD. In addition, he displayed prominent language problems. No evidence from the neurological examination or from associated laboratory, electrophysiological, or brain imaging studies suggested any other brain disorder.

The patient enrolled in drug treatment research studies. Nonetheless, his cognitive abilities continued to decline; his thinking and memory progressively worsened. For example, over the 2 years after his presentation, his Columbia modified mini-mental status examination score declined from 37 (out of a maximum of 57 points, which he would normally be expected to score given his age and education) to 23. His performance on a word-generating task dropped from the 10th percentile (for his education, he would originally have been expected to score above average; that is, above the 50th percentile) to below the 1st percentile. Conversation became increasingly difficult for him, both in making himself understood and in understanding others. His cognitive changes increasingly frustrated him. He had "ups and downs": on some days his symptoms were more pronounced than others.

Between the second and third year after his presentation, he became more confused. His posture changed as well; he became somewhat stooped and developed some stiffness in his limbs. He started having some unexplained falls. These findings of parkinsonism were not thought to be due to Parkinson's disease (see Anderson review) but rather to AD, which can cause some of the same symptoms. He began to lose control over urination. During years three to four, he increasingly suffered from agitation and required hospitalization for outbursts. He was prescribed antipsychotic drugs (dopaminergic antagonists) to treat these symptoms. He could no longer follow instructions or express himself verbally in a meaningful way. He became completely disoriented to both place and time. During year five, he broke his hip, apparently from an unwitnessed fall. He had a total hip replacement operation but never walked again. He developed fever, indicative of infection. Within a month, he died.

Neuropathologic Examination Back to Top

An autopsy allowed a definitive diagnosis of AD. Examination of the entire brain revealed normal brain structures but some overall shrinkage (atrophy). This can be seen somewhat even in an external view of the removed brain, as in Fig. 1A. However, atrophy is more evident in a brain slice. There is an increase in the size of the fluid-filled cavities of the brain (the ventricles), as well as of the fissures and sulci (crevices), as can be seen in Fig. 1B. Microscopic examination before application of special stains revealed that most brain regions were normal. For example, there was no loss of cells in a brainstem area depleted by Parkinson's disease (the substantia nigra) and no sign of brain tissue destruction due to strokes.

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Fig. 1. Anatomic pathological examination of the human brain. (A) A lateral external view of the removed brain of a patient with AD. The front of the brain (frontal lobe) is on the left, and the rear (occipital lobe) is on the right. Atrophy, or loss of brain substance, is evident in that the brain gyri are somewhat thinned and the brain sulci and fissures are somewhat widened. (B) A coronal 1-cm section of the right hemisphere of the same brain. Enlargements of the fluid spaces, including the lateral ventricle (asterisk), Sylvian fissure (arrow), and sulci (arrowheads) are evident.

However, stains revealed large numbers of amyloid plaques (senile plaques) and neurofibrillary tangles, the pathological hallmarks of AD, throughout the limbic system and neocortex. Plaques are accumulations of protein outside of brain cells. Although evident to a trained pathologist using standard histological stains, they show up most clearly when viewing a silver salt-impregnation stained section under the light microscope (Fig. 2). They are also easily revealed through examination of sections stained with the fluorescent stain thioflavine S by fluorescence microscopy (Fig. 3). Characteristically, antibody reagents showed that these plaques contained protein. Both kinds of plaques typical of AD appeared throughout multiple brain regions: diffuse plaques, which consist mainly of {beta}-amyloid, and neuritic plaques, which include fragments of abnormal brain cell processes and may develop from diffuse plaques.

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Fig. 2. Amyloid plaques in a brain section viewed at low magnification by light microscopy. A silver-stained (modified Bielschowsky) histological section from the brain of Mr. A. reveals many senile plaques (arrows).


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Fig. 3. Amyloid plaques visualized in a brain section with fluorescence microscopy at low magnification. A section of brain was stained with the amyloid-binding dye thioflavine S. Plaques are seen through their bright blue-white fluorescence (arrows). Tangles and neuritic threads also stained (yellowish-green). The bright yellowish-orange fluorescent spots (arrowheads) are nonspecific autofluorescence, seen in unstained material, and can be due to the presence of neuronal lipofucsin pigment.

Neurofibrillary tangles are visible under a light microscope after staining with silver or thioflavine S. They appear as dense filamentous accumulations inside of neurons (Fig. 4). At the electron-microscope level, they are seen to consist of twisted, paired helical filaments (Fig. 5). These fibers are now known to be composed of abnormally aggregated, hyperphosphorylated tau protein, which is normally found in the cell's microtubule transport system. This protein identification may be demonstrated through immunological staining.

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Fig. 4. Neurofibrillary tangles visualized in a brain section with light microscopy at moderate magnification. In this silver-stained section, many neurons are noted to have filamentous inclusions, termed tangles (arrows), whereas some neurons do not have such abnormal inclusions (arrowhead).


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Fig. 5. An electron micrograph of a neuron containing a neurofibrillary tangle. Paired helical filaments are evident, filling the cytoplasm.

In addition to the classic findings of plaques and tangles, the neuropathological examination revealed other abnormalities characteristic of AD pathology. These included granulovacuolar degeneration of the pyramidal cells of the hippocampal formation (in which dying neurons contain particle-filled bubbles) (Fig. 6) and the presence, particularly in the temporal lobes, of large numbers of neuropil threads (Fig. 7), which are twisted, abnormal neuronal processes filled with tau. Finally, the presence of {beta}-amyloid immunoreactivity in the walls of blood vessels, a finding that indicates amyloid angiopathy (Fig. 8), was also noted.

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Fig. 6. Granulovacuolar degeneration in a histological section of the hippocampus. This light micrograph shows a standard histological stained section (stained with hematoxylin and eosin), revealing the pattern of granulovacuolar degeneration in certain pyramidal hippocampal neurons (arrows).


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Fig. 7. Neuropil threads visualized in a brain section. This light micrograph is of a section stained with the Gallyas silver stain, emphasizing neuritic processes.


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Fig. 8. Amyloid angiopathy in a brain section light micrograph. This histologic brain section was stained immunohistochemically using the mouse monoclonal antibody 4G8 directed towards {beta}-amyloid protein, with visualization using a peroxidase method with brown diaminobenzidine substrate. (Hematoxylin provides a pale blue nuclear counterstain.) The brown stain indicates the presence of beta-amyloid in the walls and small and medium blood vessels (arrows), as well as in the senile plaques (arrowheads).


Discussion Back to Top

AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than memory impairment. But on initial presentation, neurological and neuropsychological examiners did find significant memory impairments. More often than not, patients themselves, like Mr. A., have little insight into their cognitive dysfunction. Family members are often the first to notice cognitive change. Because the disease progresses gradually and insidiously, some patients don't seek medical attention until more advanced stages of the disease. In this case, like most, the pattern of deficits, including memory and language difficulties of a gradually progressive nature, in the absence of other relevant disease, allowed the clinical diagnosis of AD to be made while the patient was alive.

During the disease course, symptoms (reported patient complaints) and signs (neurological findings during an exam) of parkinsonism also developed. These included limb stiffness, postural changes, and balance and walking difficulties. However, their nature did not signal that a clinical diagnosis of Parkinson's disease should be made. The parkinsonism together with dementia also could have suggested the possibility of dementia with Lewy bodies. However, symptoms typical of Parkinson's disease are not uncommon in AD. Indeed, in this case the neuropathological examination showed no evidence of brainstem degeneration definitive of Parkinson's disease. The parkinsonism in such cases is likely to be "postsynaptic," or due to AD-induced damage of the striatum and cerebral cortex, rather than "presynaptic," or caused by degeneration of the brainstem neuronal projection from the substantia nigra to the striatum, as in Parkinson's disease.

Another noteworthy feature of this case is that the patient's mother died at a similar age of a similar illness. Because of the era in which she died, she was originally given a diagnosis of "hardening of the arteries," also known as "dementia of multiple little strokes"--although she never had a diagnosed stroke. Because she was not autopsied, we will never know what disease was actually responsible for her illness. However, we now know that the large majority of such patients suffer from AD rather than from brain injuries resulting from cerebrovascular disease. The likelihood that two afflicted persons in the same family, parent and child, suffered similar illnesses is not sufficient to conclude that this is truly a case of inherited AD. Only two people in the family were affected. The majority of AD cases in this age group are not strictly inherited. However, there is about a two- to fivefold lifetime increased risk of AD when a first-degree relative, such as a parent or sibling, has the disease. But even without this added risk, AD is extremely common among all people who live long enough. Population-based surveys indicate that among people between the ages of 85 and 100, dementia afflicts 40 to 60% of the population. Most of these people suffer from AD.

Acknowledgements Back to Top

Fig. 1 and Fig. 5 were kindly provided by James E. Goldman in the Department of Pathology (Neuropathology) at Columbia University and Robert D. Terry in the Department of Neurosciences at the University of California at San Diego.

October 3, 2001

Abbreviations: Activities of daily living. Daily tasks such as bathing, eating, and dressing. Clinicians often assess activities of daily living to determine what kind of care a patient needs. • Amyloid angiopathy. Accumulation of {beta}-amyloid protein in the walls of small-to-medium-sized blood vessels of the brain or its coverings (meninges). • Amyloid plaques. Abnormal neuropathological features consisting predominantly of {beta}-amyloid protein but also containing other proteins, and often aberrant neuronal cell processes (neurites), as well as reactive astrocytes and microglial cells. Amyloid plaques can be found throughout the brain in AD but are often particularly concentrated in the temporal lobes. Plaques are extracellular structures (found outside of neurons); together with neurofibrillary tangles, which are intracellular (found inside neurons), they are defining neuropathologic features of AD. • Anomia. Difficulty in finding words or naming things. • Antibody reagents. Markers that show whether a particular protein is present in a sample. Antibodies are very selective in sticking to a unique protein. • Atrophy. Shrinkage. In AD, brain atrophy is evident in enlarged ventricles (normal fluid-filled cavities of the brain) and enlarged brain sulci (crevices), which are wider and deeper than in healthy brains. Atrophy associated with AD is often particularly prominent in the temporal lobes. {beta}-amyloid. {beta}-amyloid is a short protein, also called A{beta}, that clumps into plaques in AD. This protein consists of a particular 39- to 43-amino acid-long sequence derived from a normal transmembrane cellular protein, called {beta}-amyloid precursor protein. The two most common forms are the 40-amino acid peptide A{beta} 40, which is less associated with AD, and the 42-amino acid peptide A{beta} 42, whose deposition appears to be more associated with the symptoms of AD. • Benign essential tremor. A medium-frequency tremor, often in the hands, seen especially when someone is maintaining a posture or performing a movement. It runs in families and can be intensified by stress, fatigue, or certain drugs but is not in itself disease-related. • Cerebral cortex. Thin mantle of gray matter covering the cerebral hemispheres, folded into ridges and furrows (gyri and sulci). The cortex is involved in cognition, memory, consciousness, behavioral reactions, and speech. Deficits associated with lesions of the cerebral cortex depend on the specific area affected. • Cerebrospinal fluid. The fluid that bathes and cushions the brain and spinal cord. If the brain shrinks, cerebrospinal fluid fills up the space. This is often seen as an enlargement of the cerebrospinal fluid-filled ventricles. • Dementia. The loss of cognitive and intellectual capacities characterized by deficits in memory, attention, orientation, language, judgment, and motor and spatial skills, and altered emotional behavior and personality. Dementia is most commonly caused by conditions that injure the brain at tissue or cellular levels, notably by AD. • Diffuse plaques. Early-stage amyloid plaques that appear less dense than neuritic plaques and do not have associated neurites. These plaques consist primarily of amyloid protein and have little associated detritus from nearby dead or dying neurons. • Dopaminergic antagonists. Drugs that block the activity of the neurotransmitter dopamine; they are often used to treat the psychotic symptoms of schizophrenia. • Dysgraphia. Impairment in handwriting abilities. • Electroencephalogram. An electroencephalogram, or EEG, is a recording of electrical potentials arising from the activity of neurons within the brain, using electrodes attached to the scalp. Electroencephalography can be useful in the diagnosis of epilepsy and other brain diseases, including herpes simplex encephalitis, toxic and metabolic encephalopathies, and dementias. • Granulovacuolar degeneration. In neurons, bubblelike vacuoles partially filled with small particles; granulovacuolar degeneration is found in certain dying neurons in the hippocampal formation, most commonly in AD. • Hippocampal formation. Part of the limbic system located in the inner (medial) temporal lobe and important in memory formation. It includes the hippocampus and adjacent special cortex. Hippocampal lesions lead to an inability to transfer contents of short-term memory to long-term memory (anterograde amnesia). • Immunoreactivity. Evidence of specific antibody attachment or "stain" of a tissue structure, usually by use of a fluorescent or optically dense "tag." • Limbic system. Interconnected brain structures including the hippocampus, cingulate gyrus, hypothalamus, and amygdala; it is thought to play a crucial role in processing emotions. • Magnetic resonance imaging. An MRI is a diagnostic technique based on the physical principle of nuclear magnetic resonance. The body to be imaged is inserted into a magnetic field, causing the magnetic spin of the hydrogen nuclei to align with the magnet. Radio signals are used to transiently perturb this alignment. As the nuclei snap back to alignment, weak electromagnetic signals are produced. Multiple signals are integrated by computer to construct an image of the tissue. MRI provides excellent sensitivity and resolution for detecting and localizing brain pathologies. • Microtubule. Rigid, hollow, protein polymeric rod inside the cell. Groups of microtubules stabilize axons and dendrites and help transport vesicles and organelles throughout the cell. • Mini-mental status examination. One of several standardized, commonly used, quick "screening" assessment measures of a person's thinking and memory function. The test includes asking the patient for today's month, day, and year; to spell a word backward; and to remember some words and recall them some minutes later. • Neocortex. Six-layered portion of the cerebral cortex that has arisen most recently during evolution. Frontal, temporal, and parietal lobes all have neocortex tissue, but some brain cortex tissue such as in the olfactory, hippocampal, and piriform regions, is more primitive and is not "neocortex." The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and integrative association functions. • Neuritic plaques. Pathologic protein clumps found outside of cells in the brains of people with AD. The clumps consist of {beta}-amyloid protein knit together with twisted, irregularly shaped axons and dendrites from neurons, as well as portions of other brain cells called glia. Neuritic plaques and diffuse plaques are two subsets of amyloid plaques. Neuritic plaques are more associated with symptoms of AD. • Neurofibrillary tangles. Abnormal structures located in various parts of the brain composed of dense arrays of paired helical filaments, now known to be composed of a hyperphosphorylated form of the microtubule-associated protein tau. Tangles, along with amyloid plaques, are major pathologic hallmarks of AD. There appears to be some correlation of the number of these tangles seen postmortem with the degree of dementia during life. • Neuropil threads. Abnormal, often contorted, nerve cell processes (axons and dendrites). They are found in the neuropil, a dense feltwork in the gray matter of the central nervous system, made up of interwoven dendrites and axons--the cytoplasmic processes of nerve cells--and neuroglial cells. • Neuropsychological testing. Standardized measures of memory, attention, visuospatial abilities, problem solving, and other mental performance. Tests can include paper-and-pencil tasks, answering questions aloud, drawing a figure seen previously, or building patterns with blocks. Many of the tests have been used for decades, and a variety of neurological and psychiatric disorders have been correlated with characteristic patterns of scores. • Paraphasia. Producing an unintended word, related to the intended word, while speaking. • Parkinsonism. Symptoms of the type seen in Parkinson's disease, such as rigidity, loss of balance, certain tremors, or bent posture. • Parkinson's disease. A degenerative disorder of the central nervous system distinguished by slowness of movement, rigidity, postural instability, and resting tremor. Other symptoms include specific changes in speech and gait, stooped posture, and "masklike" facial expression. This disease is caused by a progressive loss of brainstem neurons in the substantia nigra and the resultant depletion of the neurotransmitter dopamine in the brain. • Perseverative. Repeating the same sentence, question, or idea inappropriately. Perseveration can be a symptom of damage to the frontal part of the brain, which is responsible for self-control and decision making, among other things. • Physiological tremor. A low-amplitude, high-frequency oscillation that most people show when they hold out their hands. Stress, fatigue, or certain drugs can exaggerate the tremor. • Senile plaques. Another name for amyloid plaques. • Short-term memory. Memory for events that took place in the preceding minutes or few hours. • Striatum. A specific subcortical brain region consisting of gray matter, with interspersed white matter, that plays an important role in processing the brain's motor commands. • Substantia nigra. A pigmented brainstem nucleus that has projecting neurons that synthesize the neurotransmitter dopamine. This region is important to movement control. Cellular degeneration in the substantia nigra, as seen in Parkinson's disease, can result in symptoms of motor slowness, rigidity, and tremor. • Tau. A protein that normally stabilizes microtubules in the cell. In AD and some other neurodegenerative diseases, tau is present in an abnormal polymerized filamentous form, such as is in neurofibrillary tangles. • Temporal lobes. Lower lateral portions of the cerebral hemispheres involved in auditory perception, visual recognition, emotion, and the processing and retrieval of memory. In most people, right temporal lobe damage may result in greater interference in nonverbal memory (e.g., pictures), whereas left temporal lobe injury may be more associated with difficulties with verbal memory (e.g., words and stories) and with understanding spoken or written language. • Ventricles. Four fluid-filled cavities situated centrally in the brain, including the two lateral ventricles, the third ventricle, and the fourth ventricle. They contain cerebrospinal fluid. Ventricle size may be increased in various neurodegenerative disorders in which there is a loss of brain substance, offsetting this tissue loss in the context of the fixed size of the cranial vault.

Suggested ReadingBack to Top

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