The first 25 years of the Northwestern University SuperAging Program.

During late life, "average" does not mean "intact." For example, cross-sectional data from a common word list learning test show that average delayed word recall raw score at age 80 (5/15) is approximately half that at age 56 to 66 (9/15). Cognitive and neurobiological dissolution is therefore implicitly incorporated into concepts of the aging brain. This position is being challenged through investigations on "superaging," a term that was coined at the Northwestern Alzheimer's Disease Research Center (ADRC) to define persons ≥ 80 years with delayed word recall raw scores at least equal to those of individuals 20 to 30 years younger. During the first 25 years of this program we established that superagers constitute not only a neuropsychological but also a neurobiological phenotype distinctive from cognitively average age peers. With respect to brain structure, superagers have cortical volumes no different than neurotypical adults 20 to 30 years younger in contrast to neurotypical peers who do show such age-related shrinkage; they also have a region in the cingulate gyrus that is thicker than younger neurotypical adults. With respect to cellular biology, superagers have fewer Alzheimer's disease-type changes in the brain, greater size of entorhinal neurons, fewer inflammatory microglia in white matter, better preserved cholinergic innervation, and a greater density of evolutionarily progressive von Economo neurons. In the future, deeper characterization of the superaging phenotype may lead to interventions that enhance resistance and resilience to involutional changes considered part of average (i.e., "normal") brain aging. This line of work is helping to revise common misperceptions about the cognitive potential of senescence and has inspired investigations throughout the United States and abroad. HIGHLIGHTS: "Normal cognitive aging" is a term that spans a broad spectrum from average for age to well beyond. "Superaging" at the Northwestern University Alzheimer's Disease Research Center (ADRC) refers to a unique cognitive and biological phenotype. Post mortem findings support resilience and resistance to neuropathologic changes of aging.