The title of this work reveals my conviction that at least a partial solution to the tragedy of Alzheimer's disease (AD) is likely in the next 20 years. The double meaning of the title is meant to introduce two themes. First, there is a ยฎnite risk period for AD, which has its end in extreme old age. Second, strategies for prevention may soon endรor at least dramatically reduceรthe present morbidity of AD. Both ideas derive from an evolving understanding of AD as an extended degenerative process that is predominantly under genetic control.
Given what is known about the extensive neurodegenerative changes that precede the dementia of AD , it is unlikely that treatments will restore the integrity of the brain once dementia is apparent. Instead, we should look for ways to prevent these changes, or to delay their progress, before dementia is apparent. Our fundamental aim is therefore prevention.
How should we proceed? There are two traditional approaches termed rational' and empirical' that are sometimes considered as opposites, but I regard them as complementary. The rational perspective begins with understanding of the pathogenetic mechanism of a disease and then, working from theory, devises interventions to attenuate its eect. These interventions are then tested (empirically) in a randomized controlled trial. The empirical approach begins not with theory, but instead with associations in nature that may suggest interventions. These interventions may also be tested empirically. But if eective, they typically provoke a (rational) scientiยฎc search for a theory to explain their success. No matter where we start, therefore, we end up with a mixture of theoretical and empirical knowledge that leads to understanding of the disease process.
Let me begin with theory and ask, what do we know about the causes of AD? An epidemiological approach considers the classic triad of agent, host and environment. Because eorts to ยฎnd an infectious cause for AD have failed, we restrict our inquiry to host (genetic or other constitutional) and environmental (neurotoxic or neuroprotective) factors. Twin studies are an especially useful way of teasing apart genetic and environmental inยฏuences and there are now four population-based twin studies of AD (Breitner