A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease.

The gap between symptoms and pathology in Alzheimer's disease has been explained by the hypothetical construct of "cognitive reserve"--a set of variables including education, intelligence, and mental stimulation which putatively allow the brain to adapt to-and hence mask--underlying pathologies by maintaining cognitive function despite underlying neural changes. This review proposes a hypothesis that a biological mechanism may mediate between these social/psychological processes on the one hand, and apparently reduced risk of Alzheimer's disease on the other, namely repeated activation of the noradrenergic system over a lifetime by the processes implicated in cognitive reserve. Noradrenaline's neuroprotective effects both in vivo and in vitro, and its key role in mediating the neuroprotective effects of environmental enrichment on the brain, make noradrenaline's key role in mediating cognitive reserve--by disease compensation, disease modification, or a combination of both--a viable hypothesis.