Editorial (Hot Topic: Epidemiology & Risk Factors for Alzheimer’s Disease)

Abstract

Clinical-pathologic studies have had an enormous impact on our understanding of aging and the conditions that lead to loss of cognitive and motor function in advanced age. In the mid to late 19th century, clinical-pathologic studies of persons with dementia demonstrated atrophy and a reduction of brain weight, which were thought to result from ‘hardening of the arteries’ [1]. Senile plaques were first identified by Blocq and Marinesco in 1892 but these investigators did not make the link to dementia [2]. However, in separate papers in 1906, Alzheimer and Fischer each reported that senile plaques and neurofibrillary tangles were associated with dementia [3, 4]. In 1910, Kraepelin introduced the term Alzheimer's disease (AD) in his textbook of psychiatry referring to a relatively rare cause of pre-senile dementia that was thought to be something quite distinct from senile dementia which resulted from hardening of the arteries [5]. The distinction between pre-senile and senile dementia lasted six decades until an elegant series of papers by Tomlinson, Blessed and Roth demonstrated that senile plaques and neurofibrillary angles were also a major cause of senile dementia [6-9]. Clinical and pathologic criteria for AD introduced in the mid 1980s set up a clinical-pathologic dichotomy in which the clinical diagnosis of AD required no evidence of known factors (including cerebrovascular disease) that may lead to dementia (i.e., a diagnosis of exclusion), and the pathologic diagnosis which required a moderate number of neocortical neuritic plaques [10,11]. Almost immediately, two studies published in 1988 challenged this dichotomy by identifying people without dementia during life who had significant AD pathology at autopsy [12, 13]. Thus, it became clear that a complete picture of AD would require the clinical study of people with a wide range of cognitive functioning, especially persons without dementia, who subsequently come to autopsy. Early efforts to assemble such a sample met with limited success. For example, between 1987 and 1995, the Consortium to Establish a Registry for AD (CERAD) which included 24 federally funded AD centers from across the United States conducted only 8 autopsies out of 25 deaths among those recruited without dementia [14]. It was clear that federally funded AD centers established at tertiary care medical centers had much expertise to contribute to the study of aging and AD, but their capacity to secure large numbers of autopsies from persons without dementia was limited. The need for such data led to the realization that community-based autopsy series could play a critical role in understanding AD, and more broadly, dementia-causing pathology, in addition to other age-related conditions associated with morbidity and mortality including parkinsonism and loss of motor function.