The genetic answer came back, and it was nothing. A study of 142 adults in their 80s and 90s with the memory of people decades younger found that they could not be distinguished from cognitively average peers by APOE status, by any of the three Alzheimer's polygenic risk scores tallying thousands of variants, or by rare protective variants previously linked to resilience.
That result closes a door, which is useful. It also makes a different body of evidence considerably more interesting. Northwestern's SuperAging program has been examining donated brains from these individuals since the 1990s, and those brains are anything but ordinary.
What the Genetics Ruled Out
The negative finding is worth stating precisely because it is easy to overread.
Researchers at the Healthy Aging and Alzheimer's Research Care Center at the University of Chicago and the Translational Genomics Research Institute, part of City of Hope, studied 142 SuperAgers and 89 cognitively average older adults across five sites in the United States and Canada. Superagers are defined as adults aged 80 and older whose delayed word recall is at least as good as that of the average person in their late 50s and early 60s.
Using DNA from blood samples, the team examined APOE and calculated three polygenic risk scores drawn from successive large genome-wide association studies. None distinguished the groups. Carrying at least one APOE ε4 allele was slightly less common among SuperAgers, at 15.7 percent against 19.0 percent in controls, but the difference was not statistically significant. The research letter, published in Alzheimer's Research and Therapy, also found no enrichment of rare protective variants: screening for the APP Icelandic, PLCG2 P522R, and APOE Christchurch variants turned up a single carrier among 142 SuperAgers.
Matt Huentelman of TGen, co-senior author with Emily Rogalski, said the work "establishes an important boundary for Alzheimer's disease genetics." The authors also note that a handful of SuperAgers carried high genetic risk, including APOE ε4 homozygosity, yet maintained youthful memory.
The evidence is not unanimous. The authors cite a multi-cohort preprint reporting lower ε4 and higher ε2 frequencies among people with superior cognition, and an earlier Northwestern paper found a lower ε4 frequency in SuperAgers than in the general population. Reconciling those is unfinished.
What the Tissue Shows
The neuropathology has been consistent for longer and is more striking.
A 25-year review of the Northwestern program reports that SuperAgers have significantly lower density of neurofibrillary tangles and pre-tangles in the entorhinal cortex than neurotypical elderly peers. Tamar Gefen has reported a hippocampal difference of roughly three times fewer tau tangles.
Amyloid plaques, by contrast, do not differ much. That asymmetry is pointed, given how much of the therapeutic pipeline targets amyloid.
Two structural findings stand out. Neurons in layer 2 of the entorhinal cortex, the region that feeds the hippocampus and one of the first areas Alzheimer's damages, are physically larger in SuperAgers. Gefen has said larger neurons there suggest the cells are more "structurally sound" and may better withstand tangle formation. And the anterior cingulate cortex, involved in attention, is thicker in SuperAgers not only than in age-matched peers but also than in cognitively healthy adults 20 to 30 years younger.
That cortex also contains an unusual cell. Von Economo neurons, spindle-shaped cells found in humans, great apes, cetaceans, and elephants and associated with social and emotional processing, occur at more than four times the density in SuperAgers compared with average peers, Rogalski has said, and at a higher density than in younger adults. The 25-year program review adds fewer inflammatory microglia in white matter and better-preserved cholinergic innervation to the list.
Born with It or Built
The obvious question is whether these features are inherited endowments or accumulated protections, and the honest answer is that nobody knows.
Von Economo neuron density does not appear to decline with age in neurotypical adults, which the Northwestern authors read as consistent with SuperAgers being born with a higher density. Confirming that would require measuring those cells across a whole lifetime, which is not a study anyone can run.
The field distinguishes resistance, meaning the pathology never develops, from resilience, meaning it develops but does not produce symptoms. SuperAgers appear to show both. The new genetics result argues that common inherited Alzheimer's risk variants are not the explanation, pushing attention toward rare variants not yet identified and toward what the authors call experiential factors: vascular health, physical activity and other modifiable exposures.
Behavioral observations from the program have consistently flagged strong social relationships, and the concentration of von Economo neurons in a socially oriented brain region is a tempting connection. It is also, at this stage, a correlation between an autopsy finding and a self-reported trait.
The Limits of Studying Exceptional People
The methodological problems here are structural and not easily fixed. Recruiting adults over 80 with exceptional memory is difficult, and the genetic study's authors list modest power for small genetic effects among their limitations, along with the inability of cross-sectional analysis to establish temporal precedence. The neuropathology work is smaller still, drawn from participants who volunteered and agreed to donate their brains, a group unlikely to represent the general population.
Autopsy findings are also, by definition, cross-sectional. They show a brain at the end of a life, not the sequence that produced it. Larger neurons could be a cause of preserved memory, a consequence of it, or a product of something else.
Nothing in this work identifies a modifiable factor, a supplement, a drug or a behavior that produces SuperAging. There is no test to determine whether someone is on this trajectory, and no intervention derived from these findings. The practical takeaway for families is narrower and still meaningful: exceptional memory in the ninth decade is a documented biological phenomenon rather than a fluke of good genes, and what drives it is now an active question rather than a settled one.
Anyone concerned about memory changes in themselves or a family member should raise it with a physician rather than benchmarking against an exceptional group.
Key Questions Answered
What is a SuperAger? An adult aged 80 or older whose delayed word recall is at least as good as the average for people two to three decades younger, with other cognitive domains within normal limits.
What did the genetic study find? Neither APOE status, three Alzheimer's polygenic risk scores, nor rare protective variants distinguished 142 SuperAgers from 89 cognitively average peers.
What is different about their brains? Autopsy work reports significantly fewer tau tangles in the entorhinal cortex, larger entorhinal layer 2 neurons, a thicker anterior cingulate cortex, and more than four times the density of von Economo neurons.
Do they have less amyloid? Not markedly. Plaque density is similar to peers, while tangle burden is lower, a contrast with implications for amyloid-targeted drug development.
Are these traits inherited or acquired? Unknown. In Economo, neuronal density does not decline with age in typical adults, which hints at a lifelong trait, but confirming that would require measurements across the entire lifespan.
Is there a way to become a SuperAger? No intervention has been derived from this research, and no test identifies who is on this trajectory. Established brain health measures include exercise, blood pressure control, hearing care, sleep, and social engagement.
Why do studies disagree about APOE? A multi-cohort preprint has reported APOE differences in people with superior cognition, as did an earlier Northwestern paper. The studies used different cohorts, definitions, and methods, and the discrepancy is unresolved.
