Getting older can bring a frightening question: will our memories—and the parts of ourselves they hold—stay with us? A group of Catholic sisters helped scientists explore that question by agreeing to an unusual partnership: researchers would study their thinking and memory during life, then examine their brains after death. This became known as the Nun Study.
What researchers found was not always what they expected. Some sisters who had continued to think and remember well had brains containing substantial signs of Alzheimer’s disease. Somehow, the damage visible under a microscope had not translated into the difficulties the researchers might have anticipated.
That puzzle is where our story begins. Does a resilient brain have more to spare? Does it make better use of what remains? Or can it learn to work differently when disease gets in the way?
Act I: An unusual agreement
David Snowdon began working with the School Sisters of Notre Dame in 1986. The formal Nun Study followed in 1991, enrolling 678 sisters who agreed to repeated assessments, access to personal records, and brain donation. Researchers could follow changes in memory and thinking, then compare those observations with what they found in the brain after death.
The sisters had shared much of their adult lives: similar housing, food, healthcare, and community support. That made some comparisons easier, although it did not erase differences in childhood circumstances or make this predominantly White, highly educated female cohort representative of everyone.
Each year brought tests of memory, language, and everyday abilities. Later, the neuropathologist examined donated brains without knowing the cognitive results. The microscope did not get to read the report card first.
And sometimes the two seemed to disagree.
Act II: What the microscope could not prove
Some sisters who had remained cognitively intact had substantial plaques and tangles—the characteristic deposits associated with Alzheimer’s disease. Brain damage generally went along with greater cognitive difficulty, although its effects varied between sisters.
Some of that variation became clearer in a later analysis, which found severe tangle pathology in 12% of Nun Study participants who had not developed dementia. Many of those women nevertheless had significant memory impairment. They also tended to have somewhat less advanced or differently distributed tangles than participants with dementia.
Still, the mismatch demanded an explanation. Perhaps some sisters had more neurons and connections available before disease began—what researchers call brain reserve. Perhaps others used their remaining resources more efficiently or flexibly, a possibility captured by cognitive reserve, the concept closest to what is often called functional reserve. Both the available brain tissue and the way it functions may help explain preserved cognition.
But where would such differences come from? For one clue, researchers turned away from the autopsy room and toward something the sisters had written long before anyone was studying their memories.
Act III: The young women in the archives
The convents had preserved autobiographies written before the sisters took their vows. Researchers scored the writing for grammatical complexity and “idea density”—roughly, how much meaning was packed into the language. The women had written these accounts at an average age of 22; their cognitive assessments came nearly six decades later.
Lower early-life linguistic scores were associated with poorer late-life cognitive performance. In the initial autopsy sample, all sisters with low idea density had neuropathologically confirmed Alzheimer’s disease, while none with high idea density did. The autopsy sample contained only 14 brains, limiting how confidently the result could be generalized.
The finding raised an appealing possibility: perhaps a lifetime of intellectual activity helped some women cope better with disease. But the writing might also reflect earlier developmental advantages or circumstances that influenced both language and later brain health. Later analyses linked low idea density with lower brain weight, greater atrophy, and Alzheimer-type pathology. The autobiographies could not neatly separate having more reserve from developing less damage.
Act IV: More than plaques and tangles
Another clue came from the injuries that accompanied Alzheimer’s. Among sisters with Alzheimer-type pathology, those who also had brain infarcts—areas injured by interrupted blood supply—had poorer cognition and more dementia. Certain small, deep infarcts appeared to lower the amount of Alzheimer pathology needed for dementia to become evident. An account focused only on plaques and tangles could miss an important part of the explanation.
Work outside the Nun Study added another complication. In the separate Religious Orders Study, researchers compared people with substantial pathology and good cognition with people who had substantial pathology and dementia. Despite comparable measured frontal plaque and tangle burdens, the resilient group retained markers of synapses, the connections between neurons, at levels similar to controls. Similar disease deposits did not mean that everything else in the tissue was equally damaged.
Functional brain imaging offered a way to explore whether surviving networks also worked differently. Studies have associated reserve with differences in activity and connectivity, but the findings vary by task and brain region. One systematic review found that all its included studies were cross-sectional and rated fair or poor quality. In one study it discussed, an apparent reserve–activity association disappeared after accounting for gray-matter volume. This made it difficult to separate functional advantages from differences in brain structure.
Act V: Had their brains changed to cope?
This is where neuroplasticity enters the story: the possibility that changes in cells, connections, or networks helped preserve function. It could contribute to both structural and cognitive reserve. But good performance despite disease does not, on its own, show that the brain changed in response to it.
Some asymptomatic Alzheimer cases showed enlarged hippocampal nerve cells and their internal structures. Investigators proposed that this might be a protective response. Yet an autopsy could not establish whether the cells had enlarged as disease developed or had differed beforehand.
Experiments can get closer to that question. In a randomized trial involving 120 older adults, aerobic exercise increased anterior hippocampal volume and improved spatial memory. Older brains were evidently capable of change. But later trials did not consistently reproduce favorable volume effects, and none of this established that exercise—or any particular activity—explained the sisters’ resilience.
The missing evidence is the sequence: what was present before disease, what changed as it developed, and whether that change actually helped thinking and memory. The Nun Study’s repeated cognitive tests were invaluable, but its autopsies could not supply that entire history.
What the sisters left us
The Nun Study helped establish that people can retain useful thinking and memory despite substantial Alzheimer-type changes in the brain. It also showed how additional injuries, including small infarcts, can make those changes more disabling. Together, these findings helped explain why people with apparently similar Alzheimer pathology can have different cognitive outcomes.
Its particular strength was the connection between the sisters’ life histories, repeated cognitive assessments, and donated brain tissue. Researchers could investigate how early abilities related to later cognition, and then examine the underlying disease. That combination made the study especially valuable for investigating reserve, although it could not establish whether education or intellectual activity caused protection.
The next question is what actually preserves those abilities. Do some people begin with more neural resources, maintain their connections better, or adapt their brain activity as disease develops? Structural and cognitive reserve offer overlapping explanations; neuroplasticity could help connect them. Answering this requires following brain structure, activity, disease markers, and cognition together over time, alongside experiments that test whether an intervention produces changes that improve function. The Nun Study could reveal resilience, but its autopsies could not establish when or how that resilience arose.
That opens a practical research direction: identifying ways to preserve memory and everyday abilities even when some disease is already present. Whether those connections can be protected or strengthened enough to sustain cognition is a question to test—and a reason the sisters’ findings continue to matter.
References
Kyra M Clarke et al. (2025). The Nun Study: Insights from 30 years of aging and dementia research.
K. Santacruz et al. (2011). Alzheimer Disease Pathology in Subjects Without Dementia in Two Studies of Aging: The Nun Study and the Adult Changes in Thought Study.
Y. Stern et al. (2018). Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance.
Y. Stern et al. (2019). Brain Reserve, Cognitive Reserve, Compensation, and Maintenance: Operationalization, Validity, and Mechanisms of Cognitive Resilience.
D. Snowdon et al. (1996). Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study.
D. Snowdon et al. (1997). Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.
S. Arnold et al. (2012). Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease.
Mia Anthony, F. Lin (2018). A Systematic Review for Functional Neuroimaging Studies of Cognitive Reserve Across the Cognitive Aging Spectrum.
K. Erickson et al. (2011). Exercise training increases size of hippocampus and improves memory.
G. Balbim et al. (2023). Aerobic exercise and volumetric change in the human hippocampus: A meta‐analysis of randomized controlled trials in healthy older individuals.
Monica E. Nelson et al. (2021). Cognitive Reserve, Alzheimer’s Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis.