A 25-year study at Northwestern University identified a group of older adults, termed “superagers,” whose cognitive and biological profiles differ from typical age-related decline. To qualify as a superager, study participants aged 80 or older had to recall at least 9 of 15 words on the Rey Auditory Verbal Learning Test, a level that is typical of adults at ages 56 to 66. Only about 10% of cognitively normal older adults met this threshold. In one case study, a woman maintained a delayed recall score of 11/15 over 15 years, despite later developing cancer and stroke. Postmortem analysis of her brain showed minimal tau pathology, no amyloid plaques, and preserved hippocampal and amygdalar structures.

Among 290 participants screened, 101 qualified as superagers. Their mean age was 90 years. Despite varying medical conditions and lifestyles—including some who smoked, avoided exercise, and did not have healthy diets—superagers consistently reported strong social connections and higher levels of extraversion. Cognitive performance in other domains remained normal for age, but their memory stood out significantly. "Superagers did not seem to be medically healthier than their peers, as evinced by the similarity of medication regimens in neurotypical and superager groups," the authors noted, led by Sandra Weintraub, PhD, of Northwestern University’s Mesulam Institute for Cognitive Neurology and Alzheimer’s Disease.

Neuroimaging revealed that superagers showed no cortical thinning compared with younger adults. In particular, the anterior cingulate cortex—a region associated with attention, motivation, and social behavior—was thicker in superagers than in adults 20 to 30 years younger. This region also contained a higher density of von Economo neurons, which are specialized cells that are involved in social and emotional processing. These neurons were more numerous in superagers than in both age-matched and younger participants, "suggesting that superagers may be born with a higher density of these neurons," wrote the authors.

Neuropathological findings from 77 brain autopsies showed superagers had fewer tau tangles—the abnormal proteins linked to Alzheimer’s disease. While some brains displayed mild pathology, they were more likely to fall within the lower Braak stages, which indicated less neurofibrillary degeneration than in cognitively average peers. The cholinergic system also appeared better preserved: Superagers had fewer tangles in the basal forebrain, where acetylcholine-producing neurons originate.

Further, they had fewer axonal abnormalities and reduced acetylcholinesterase activity, which may enhance synaptic signaling that is important for memory. Superagers’ brains also showed lower levels of neuroinflammation: Fewer activated microglia—the brain’s immune cells—were found in their white matter compared with age-matched controls. Preliminary lab data suggested these microglia may behave differently in superagers, the authors explained. "Nearly all known neurodegenerative diseases causing dementia are associated with intense microgliosis," they wrote. "Microglia isolated from superager cortex display unique characteristics and different rates of proliferation in culture when isolated from postmortem brains. The impact of this phenomenon on cortical involution remains to be determined."

They continued, "These features are starting to coalesce into a clinicobiological phenotype that can be investigated in depth, with significant implications for clarifying, by contrast, the regressive pressures upon brain and memory during what is otherwise deemed normal aging." Areas for future research include the possible influence of KLOTHO, BDNF, APOE, REST, and TMEM106b genes, as well as the ability to promote the superager phenotype to delay regressive correlates of average aging that, the authors conclude, "eventually take over if longevity permits."

The authors reported no conflicts of interest.

Source: Alzheimer’s Association