A central concept that has been introduced in degenerative neurological disease is that certain types of protein deposition in the brain are toxic to adjacent neurons. Amyloid, tau, and synuclein are most often cited as implicated in this way. Moreover, “spread” of toxic species of normal proteins contiguously by physiochemical interactions (summarized by Hardy and Revesz), more typical of the induction of prion diseases (Chap. 32), are implicated and it has been suggested that there may be transynaptic spread of misfolded proteins. The toxic hypothesis is central in particular to Alzheimer disease, in which attempts to remove or reduce the production of the implicated amyloid proteins are driving clinical trials of new agents.
The basis of aging changes is also explainable at the neuronal level, but the nature of these alterations is not understood. A fundamental problem, as mentioned, is the distinction of these aging deteriorations from degenerative disease. When a degenerative neurological disease appears in adult life, one must assume that the clinical presentation is modified to some extent by life-cycle phenomena—the patient’s function being a sum of both processes. However, their separation is of fundamental importance in diagnosis and therapeutics. One has to reconcile the fact that most degenerative diseases manifest themselves in later life, leading to the tentative conclusion that some aspect of the aging process is entwined with the cellular degenerations of disease. This creates a problem for the clinician, who may be inclined to attribute changes in a person’s function to aging alone rather than searching for a disease that may allow for treatment or for specific prognostication and counseling. Moreover, a long-standing uncertainty pertains to certain degenerative conditions such as Alzheimer disease, which becomes so prevalent in later age as to offer the possibility that the disease is an invariable aspect of aging rather than an acquired perturbation in cellular function. For most degenerative diseases of the nervous system, however, this inevitability of occurrence with aging is clearly not the case. For example, the incidence of Alzheimer pathologic change is attenuated after the age of 75 according to Savva and colleagues. This is in part because of the competing risk of death from other causes but there remains a likelihood that the disease arises less frequently in the oldest old. This polemic regarding aging and degenerative disease is irresolvable and exposes difficulties with meaning of the term “disease.” If the human being lived another 50 years beyond the current expectation, would all nervous structures show the changes of degenerative disease? The answer is probably “no,” as there are distinctive cellular and subcellular features of degenerative diseases that are different from the uncomplicated, programmed loss of cells that is due to aging.
Much new and essential information has been gained regarding the biologic derangements that lead to neuronal death and dysfunction as a result of investigating the inherited forms of degenerative diseases. The application of the techniques of molecular genetics to these diseases has given stunning results. Even when the hereditary form of a degenerative condition is rare in comparison to the sporadic type, general principles have been exposed that are common to the mechanisms of both forms of the disorder. This approach holds promise for effective treatment of what heretofore have been considered progressive and incurable diseases.