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6. The Rediscovery of Alzheimer Disease During the 1960s and 1970s
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6 The Rediscovery of Alzheimer Disease During the 1960s and 1970s Robert Katzman and Katherine L. Bick The modern era of Alzheimer research began in 1948 with R. D. Newton’s argument on the clinical identity of Alzheimer disease (AD) and senile dementia but was not continued until the reports on the ultrastructure of the plaque and tangle by Terry (1963; Terry, Gonatas, and Weiss 1964) and Kidd (1963, 1964) and the classical prospective clinicopathologic study of Blessed, Tomlinson, and Roth reported in 1968. Further impetus was provided in 1976 by the recognition of the public health importance of AD by Katzman and the exciting discovery of the deficit in choline acetyl transferase made independently by Bowen, Davies, and the Perrys. Before we describe these events, it is important to understand the intellectual disarray about late-life cognitive changes that existed in the 1950s. This disarray was partly due to the failure to establish a clear clinicopathologic relationship between intellectual impairment and either brain weight or abundance of plaques and tangles. In the absence of that connection, the proposal was made that functional psychiatric conditions played a significant role in these disorders of late life. This story is described in the preceding chapter by Jesse Ballenger. An additional confound in the United States was the emphasis on cerebrovascular events as the major cause of late-life dementia. In 1946 Walter Alvarez, a prominent gastroenterologist at the Mayo Clinic and a prolific writer whose major interest was in patients with psychoso- The Rediscovery of Alzheimer Disease 105 matic symptoms not understood by medicine of his day (or today for that matter), published an extraordinary paper entitled ‘‘Cerebral Arteriosclerosis with Small Commonly Unrecognized Apoplexies.’’ Alvarez noted, ‘‘One of the commonest diseases of man is a slow petering out toward the end of life, and one of the commonest ways of petering out is that in which the brain is slowly destroyed by the repeated thrombosis of small sclerotic blood vessels.’’ In this article, Alvarez presented detailed clinicopathologic data on seven cases—two of them his own relatives for whom he had lifelong histories. He described this variety of multi-infarct dementia, the lacunar state, more than a decade before C. Miller Fisher’s more detailed analysis of this disorder. Alvarez’s impact on American medicine was extraordinary. His explanation of most late-life dementing illnesses as due to cerebral arteriosclerosis was almost universally accepted by U.S. physicians and persisted for almost forty years. That destruction of brain tissue rather than arteriosclerotic plaques in blood vessels is associated with dementia required further evidence, however. J. A. N. Corsellis (1962, 1965) analyzed brains of 300 patients who had died at Runwell, a psychiatric hospital in Wickford, Essex, and in this series, the average age at time of death was 70. He concluded that severe arteriosclerosis of the carotid and vertebral blood vessels was not related to either dementia or parenchymal neuropathology per se. Then, in the prospective clinicopathologic study to be described below, Tomlinson, Blessed, and Roth (1970) found that more than 50 ml. of cerebral tissue had to be infarcted for signs of dementia to have been observed prior to death. Hachinski et al. (1974) later coined the term multi-infarct dementia. By the time of the Hachinski publication, clinicians were willing to drop the term arteriosclerotic dementia. The first to argue for the identity of AD with senile dementia was R. D. Newton. His conclusion was based on 150 consecutive autopsies performed at a mental hospital located in Middlesex County, United Kingdom. He argued that although the brains of individuals with dementia showed differences in the number of plaques and tangles, and although individuals presented clinically with a variety of symptoms, the variations in pathological and clinical features were similar in subjects, whether they were older or younger than 65 years at onset. The modern era in AD research was ushered in by the first successful electron microscopic studies of the AD brain, carried out independently in the United Kingdom by Kidd (1963) and in the United States by Terry (1963). (We have had the opportunity of interviewing both of these pioneers, as well as Blessed, Kay, Roth, Tomlinson, and Wisniew- [44.220.245.254] Project MUSE (2024-03-19 10:32 GMT) 106 Robert Katzman and Katherine L. Bick ski.) The technology involved in such studies had just advanced to the point where brain pathology could be investigated at the ultrastructural level, although the techniques were still...