Dementia is defined as “the progressive deterioration of intellectual and cognitive abilities associated with (organic) damage to the brain”.
The deficits seen in Alzheimer's disease patients are a consequence of the massive and widespread death or atrophy of nerve cells (neurons) of the brain, but particularly affecting the cerebral cortex and hippocampus. Since cognitive function is the result of communication between the cells within the cerebrum and other parts of the brain, the loss of these cells and their inter-connections leads to the clinical features seen in Alzheimer's disease. The neuritic plaques and neurofibrillary tangles (which are the post-mortem neuropathologic hallmarks of Alzheimer's disease) represent the “tombstones” of the dead and dying neurons and their connecting axons and dendrites. Since each area of the brain performs a unique function, the death of the neurons in any particular area results in loss of whatever function or ability is sub-served by that area.
All central nervous system neurons normally are formed by about the twentieth week of fetal life (mid-second trimester) and no new neurons can be produced thereafter. The subsequent growth of the brain from late fetal life through adulthood is the result of increasing complexity of the connections between neurons. This is associated with increasing number and size of neuronal processes (axons and dendrites) and an increase in the amount of myelin surrounding axonal processes.
Since neurons are not produced after that twentieth week of fetal life, redundancy has been built into the system. There is approximately a five-fold excess of neurons produced during development, with the extra cells serving as a “backup” throughout life. These extra cells are not ordinarily used but serve as “spares” when other neurons in an area are lost (an analogy is the spare tire carried in an automobile – the spare tire is not functional until one of the other tires is damaged). The five-fold excess of neurons means that about 80% of neurons must be lost in a particular area before symptoms appear (this is the so called “80% safety margin for nervous system function”). Thus, symptoms and signs of nervous system dysfunction (such as motor, sensory, or cognitive deficits) will not be apparent until there are fewer than 20% of the neurons remaining in a particular area of the brain.
Studies that have carefully compared neuronal counts in young (less than age 20 years) and old (over age 60 years) individuals have shown that normal aging (the wear-and-tear of normal life) produces about a 30% loss of neurons in many areas of the brain; however, since at least 70% of nerve cells remain, there are no clinical deficits.
See: Brumback RA, Leech RW: Alzheimer's Disease: Pathophysiology and the hope for therapy. Journal of the Oklahoma State Medical Association 1994; 87:103-111
A disease process such as Alzheimer's disease causes accelerated death of neurons, but the affected individual will be asymptomatic until the number of remaining nerve cells is less than the 20% safety margin. Since neuronal loss continues after the initial onset of symptoms, an increasing number of neurologic deficits become evident, until death ensues from inanition, which usually occurs within 5 to 8 years after the onset of clinical symptoms.
The nerve cell loss in Alzheimer's disease is thought to occur over a period of at least 30 years before clinical symptoms become apparent. These assumptions are based upon findings from the study of Down's syndrome (trisomy of chromosome 21) patients; despite being mentally retarded, nearly all individuals with Down's syndrome acquire some cognitive and social skills (e.g., self-care, sheltered-workshop skills, etc.), however, those who live beyond age 40 years develop a progressive dementia in which they lose those skills, and at autopsy have Alzheimer's disease. Careful examination of the brains of Down's syndrome patients have demonstrated neuritic plaques and neurofibrillary tangles even in infancy which indicates that the destructive process of Alzheimer's disease in these patients begins in early childhood, even though clinical symptoms do not appear until 30 years later. Accordingly, it is assumed that non-Down's syndrome individuals who are just beginning to show clinical symptoms of Alzheimer's disease, really began experiencing neuronal destruction 30 or more years previously.
This long prodrome before the onset of clinical symptoms explains in part the overall increasing prevalence of Alzheimer's disease. In simple terms, we are living longer than we were in the past! The 30+-year destructive process of Alzheimer's disease generally does not begin until the brain has completed its growth at about age 20 years. Thus, if the average life expectancy were under 50 years, as it was until almost 1920, most individuals would die before clinical symptoms set in. With the current average life expectancy at 75 years (72 years for men and 78 years for women), many more individuals are living longer and therefore developing clinical dementia from Alzheimer's disease.
See: Brumback RA, Leech RW: Alzheimer's Disease: Pathophysiology and the hope for therapy.
Journal of the Oklahoma State Medical Association 1994; 87:103-111