ALZHEIMERS DISEASE

J.P. Mohr
Alzheimer's disease is a discouragingly common disorder of memory and behavior that
affects as much as 10 percent of the population over age 65 in America to varying degrees. Its
presence has been estimated to reduce the remaining life expectancy by about one-half and it is
listed as the fourth or fifth most common cause of death.
Decades ago, the term Alzheimers diseas was reserved for use in cases under age 65.
Those older were presumed to have senile dementia, a condition attributed to ischemic vascular
disease or other ill-defined entities casually ascribed to the aging process. This separation no longer
seems justified. In normal aging, the number of both small and large neurons declines throughout
the cortex, with much less loss noted in the brainstem. In the hippocampus, a scattering of
neurofibrillary tangles and neuritic plaques is also encountered in a high percentage of individuals
over age 70. In Alzheimers disease, both the extent of the cell loss and the number of
neurofibrillary tangles and neuritic plaques greatly exceed the normal and are scattered widely
through the neocortex. The numbers of tangles and plaques seem to correlate with the severity of
the dementia. Neurofibrillary tanglesare helically paired coils of the normal neurofibrils found in
neurons. Neuritic plaques (senile plaques) are made up of elements of neurons with amyloid at the
core. In patients afflicted with Alzheimers disease, the hippocampus also shows both a special
granulo-vacuolar change not encountered in the normal aging process and Hirano bodies; the latter
are thought to encase dormant ribosomes, preventing their participation in the protein synthesis that
forms the molecular basis for memory.
A wide variety of hupotheses have been put forward to account for Alzheimers disease.
They include genetic susceptibility as documented in a few families for whom a gene disorder has
been uncovered; toxic exposures, of which aluminum remains a leading candidate; occult head
trauma; reduced concentration of vasopressin; infection with a scrapielike agent; and even a greater
emphasis on the selective degeneration of subcortical cell groups that control neurochemical events
in the neocortex. This last group of hypotheses involves both cholinergic and adrenergic activity in
the cortex. Reduced activity of choline transferase (the enzyme responsible for acetylcholine
synthesis) has been documented in the neocortex in Alzheimers disease, but activity of muscarinic
cholinergic receptors is less affected. Some evidence has been put forward to suggest the
diminished cholinergic activity is the result of lesions affecting the nucleus basalis of Meynert,
whose cells stain for acetylcholinesterase and project diffusely to the neocortex. A link to neuritic
plaques has been made by neurochemical analysis showing a declining concentration of

acetylcholine esterase activity as the plaque matures: These findings suggest the plaques may form
from dystrophic neurites derived from the dying axonal projections of the nucleus basalis.
Another selective loss of neurons has also been documented in the locus ceruleus. In
this group of cases, the syndrome of Alzheimers disease presented with especially severe dementia
and early death. These findings are of especial interest, since the neurons from the locus ceruleus
project adrenergic as opposed to cholinergic fibers diffusely to the cerebral cortex. Because
these cases were younger than those with nucleus basalis lesions and abnormalities of adrenergic
metabolism have not been documented in the older cases, it has been suggested that Alzheimers
disease may have two metabolic forms.
Although the important advances in our knowledge of the microscopic and
neurochemical features can be documented at leisure in the autopsy specimen, access to neural
tissue during life involves the seemingly dramatic but rather safe intervention of brain biopsy. This
procedure was once considered quite radical but less so now that a genetic basis for some of the
cases has been uncovered. The possibility that the disease arises from the lack of a spesific
neurohormone could be tested by cell culture, but this suggestion has not yet reached the routine
laboratory stage. Tha aluminum content in the brain of patients with Alzheimers disease may be as
high as 30-fold greater than normal, but these changes are no reflected in blood tests. The many
viral these for the disorder have not yielded any tests tha permit a laboratory diagnosis for the
disease either.
Computerized tomography (CT) scanning lostmuch of its initial appeal when the degree
of gyral narrowing and sulcal widening, initially assumed to be atrophy, was found to vary widely
among brains of normal persons and those with Alzheimers disease. More weight can ben placed
on steadily increasing ventricular size, especially of the third ventricle. The absolute size of the
lateral ventricles on the scan slice at the point of their maximum width has a high correlation with
the diagnosis for those under 65, especially when tested by short term memory, abstract reasoning,
verbal fluency, and drawing to command. Some correlation also exists between the degree of
dementia and the amount of slowing on the electroencephalogram (EEG) and the amount of
reduction in rCBF, which falls at a rate that parallels the advance of the dementia, In positron
emission tomography (PET) studies, reduction in local cerebral metabolism for glucose is
widespread and reflects the cellular loss and replacement gliosis that has occured. In counseling
family members, the most that can be said is that the risk for the disorder is 7 to 8 percent for those
whose parent or sibling is affected as compared to 2 to 3 percent for the population over 65.
Faced with the inadequacy of the commonly available laboratory and radiologic tests,
the difficulty obtaining PET scan, and the requirement of hospitalization for biopsy, many clinicians
try to use clinical criteria alone. The clinical diagnosis is usually arrived at by exclusion, having

eliminated from consideration the treatable causes of dementia. These include endocrine, toxic, and
metabolic disorders; systemic and intracranial infections or tumors; subdural hematoma; and
depression, which all underlie dementia in a disappointingly small minority of cases. Balance,
coordination, strength, vision, and sensation are usually preserved throughout the course of the
disorder. The early stage features simple forgetfulness, a decline in self-initiated activities and in
reliability in the activities of daily living, and occasionally a paranoid behavior. As the disorder
progresses, dyspraxias and spatial disorientations impair activities of daily living, requiring the
constant attentions of a companion. Some clinical findings apart from the dementia include release
signs, olfactory deficit, a mild gait disorder, and tremor, thought to reflect some of the widespread
neuropathologic involvement. In the advaced stages, states akin to the Kluver-Bucy syndrome of
unawareness of the dangers of the environment make the victim a constant worry to those in the
same household. Global dysphasia, ideational dyspraxia, and severe memory loss eventually
develop in the more severe cases, causing even the most stalwart of spouses to seek placement for
the victim. The course may run months but usually is measured in years, the early stage of which is
easily attributed to depression or the strains of the patients occupation. Once the disorder is well
developed, the diagnosis poses no problem and is usually volunteered by those who accompany the
patient for evaluation. A vascular cause of dementia similar in clinical type to Alzheimers disease is
increasingly being diagnosed. Although the vascular cause is suspected clinically most often by its
more static and less relentless course, its radiologic features, at least by magnetic resonance
imaging, show a profusion of white matter lesions not encountered in Alzheimers disease.
Neuropsychologic batteries have been refined to detect a profile highly reliable for Alzheimers
disease: Memory deficits are prominent, but declining linguistic skills correlate best with
neuropathologuc studies counting plaques and tangles in a cerebral biopsy.
Effective treatment is still lacking. Vasodilators, vitamins, lecithin, stimulants, and
hyperbaric oxygen therapy have either no rationale or should be used only for their placebo value.
Trials of choline at 9 gm/day showed no effect. Encouraging results with a centrally acting
anticholinesterase, tetrahydroaminoacridine, have been reported in 15 randomized patients on doses
up to 200 mg/day over 7 to 10 days plus lecithin 1200 mg/day. Improvements on special tests of
higher cerebral function were modest on formal testing but some showed striking increases in
activities of daily living. The agent is longer-acting than physostigmine.