The natural history of cognitive decline in Alzheimer's disease

Abstract

The study aim was to describe the temporal course of cognitive decline in Alzheimer's disease (AD). We selected 226 persons from 2 longitudinal clinical-pathological studies who were cognitively healthy at baseline, followed at least 4 years (M = 10.2, SD = 3.5), and clinically diagnosed with AD at some point during follow-up. Each evaluation included a battery of 17 cognitive tests from which a previously established composite measure of global cognition was derived. In those who died, a uniform neuropathologic examination established the pathological diagnoses of Alzheimer's disease and other common conditions that impair cognition. Mixed-effects models with 2 change points were used to assess trajectories of cognitive decline. In the main analysis, there was no change in cognitive function until a mean of 7.5 years before dementia was diagnosed (95% confidence interval [CI]: -8.3, -6.7). The global cognitive measure declined a mean of 0.087-unit per year (95% CI: -0.099, -0.073) until a mean of 2.0 years before the diagnosis (95% CI: -2.2, -1.7) when it increased more than 4-fold to a mean loss of 0.370-unit per year (95% CI: -0.417, -0.334). Of 126 individuals who died and underwent autopsy, 101 (80%) met pathologic criteria for AD, of whom 67 had at least one other pathologic condition. Pathologic measures of AD and cerebral infarction were not strongly related to cognitive trajectories. The results indicate that cognitive decline in AD begins many years before dementia is diagnosed and accelerates during the course of the disease.

Figure 1

Crude paths of change in global cognition (thin black lines) and the mean path predicted by the one (thick dashed line) and two (thick solid line) change point models.

Figure 2

Crude data points (open circles) and paths of cognitive change predicted by the model for 8 individuals with pathologic AD and no other pathologic conditions (randomly selected from 34) arranged in order of AD pathologic burden. The predicted path reflects both group means and person specific deviations from those means.

Figure 3

Crude data points (open circles) and paths of cognitive change predicted by the model for 8 individuals with pathologic AD and 1 (upper 4 plots in order of AD pathologic burden) or >1 (lower 4 plots in order of AD pathologic burden) cerebral infarcts (randomly selected from 27). The predicted path reflects both group means and person specific deviations from those means.

Figure 4

Crude data points (open circles) and paths of cognitive change predicted by the model for 8 individuals without pathologic AD or other pathologic conditions arranged in order of AD pathologic burden. The predicted path reflects both group means and person specific deviations from those means.