We compare clinicopathologic data from 10 subjects identified in the very mild stage of senile dementia of the Alzheimer type with findings from similar studies in four cognitively normal subjects. We based the diagnosis of very mild dementia in the 10 subjects on informant reports and the judgment of experienced clinicians. Deficits of some psychometric measures of memory, language, and speeded psychomotor performance were observed for these subjects. The histologic markers of Alzheimer's disease, including neurofibrillary tangles and both the "diffuse" and classic subtypes of senile plaques, were present in the neocortex in all 10 subjects but essentially were absent in the four controls. These findings indicate that even "questionable" dementia can be diagnostic for Alzheimer's disease. Furthermore, because truly normal aging may be unaccompanied by neocortical senile plaques and neurofibrillary tangles, the presence of these lesions should suggest the possibility of clinically undetected Alzheimer's disease.

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The design of trials of interventions intended to slow or arrest the progression of senile dementia of the Alzheimer type must be based on analysis of the natural history of the disease. Using a random coefficients statistical model, we analyzed the natural history of senile dementia of the Alzheimer type in carefully defined subjects with mild disease (n = 68) for periods of up to 10 years. Subject performance was assessed longitudinally on batteries of clinical and psychometric measures. The characteristics of these measures were analyzed relevant to their utility as outcome measures for long-term trials in patients with senile dementia of the Alzheimer type. Estimates were made of sample sizes required to show arrest, and 50% or 25% slowing in the progression of mild disease. We suggest that a clinically relevant global measure, such as the Sum of Boxes of the Clinical Dementia Rating scale, and a performance-based clinical scale or psychometric measure would be appropriate in a 12- or 24-month trial enrolling subjects with mild senile dementia of the Alzheimer type.

Sixty-six subjects diagnosed by validated criteria as having senile dementia of the Alzheimer type (SDAT) were assessed with clinical measures commonly used to study dementia. The severity of the SDAT was mild in 24, moderate in 24, and severe in 18. The data from these three groups in a cross-sectional study were compared with results in our earlier study of 43 subjects enrolled with mild SDAT and followed longitudinally. We concluded that the cross-sectional method underestimates the severity of progression as indicated by some of the clinical measures. Additionally, the 24 new subjects with mild SDAT were assessed longitudinally. This replication study confirmed our earlier conclusions that four of six clinical measures showed similar patterns over time and were useful throughout the study, global measures being more informative than brief individual measures with ceiling or floor effects.