High Cognitive Performance at Age 100


— Some centenarians show resilience to cognitive decline, despite brain pathology

by Judy George, Senior Staff Writer, MedPage Today January 15, 2021


Cognitively healthy centenarians appeared to have resilience mechanisms that helped them maintain high levels of cognitive performance despite risk factors for decline, a Dutch cohort study showed.

Of 330 people 100 years old or older, no decline was seen in most cognitive domains over a mean follow-up of 1.6 years except a slight drop in memory function (β −0.10 SD per year, 95% CI −0.14 to −0.05 SD, P<0.001), reported Henne Holstege, PhD, of Amsterdam University Medical College in the Netherlands, and co-authors in JAMA Network Open.

Cognitive reserve and physical health factors were tied to levels of cognitive performance, but not to decline in function. Postmortem findings in 44 participants showed varying loads of amyloid beta, neurofibrillary tangles, and neuritic plaques, none of which were linked to cognitive performance or decline.

Dementia risk increases exponentially with age and reaches approximately 40% per year for people 100 years old, Holstege and colleagues said: “This exponential increase implies that a person who lives between 70 and 95 years is exposed to the same dementia risk as a person who lives between age 100 and 102: an estimated 60%.”

“Thus, 25 years of dementia risk in the younger population is compressed into 2 years in centenarians,” the researchers added. “This indicates that prolonged stability of cognitive functioning in centenarians may be considered more extraordinary than in nonagenarians.”

“While a mean follow-up of 1.6 years might at first blush seem short, for a segment of the population where annual mortality is approximately 30%, this is a relatively long time and an important positive feature of the work,” noted Thomas Perls, MD, MPH, of Boston University School of Medicine, in an accompanying editorial.

People who enroll in centenarian studies often are better off than centenarians in general because of volunteer bias, but “this is acceptable because the authors explicitly state that they studied a population of cognitively healthy centenarians,” Perls wrote. “As extreme outliers, these centenarians are likely an informative cohort for discovering behavioral, environmental, and/or biological mechanisms of resistance and resilience to Alzheimer’s disease and related dementias.”

The research included neuropsychology test data and postmortem neuropathology reports about Dutch centenarians who participated in the 100-plus Study between January 2013 and April 2019. Participants self-reported being cognitively healthy, which was confirmed by a proxy.

Median age was 100.5 and most participants (72%) were women. Mini-Mental State Examination scores were a median of 25.2, suggesting normal cognition. Most people in the study could walk independently (79%), and had good vision (66%) and good hearing (56%). Nearly one in three (30%) had a prior stroke or transient ischemic attack, and 63% had hypertension.

Follow-up was up to 4 years. Higher global cognition was linked to higher scores on the Barthel index, a measure of independence in activities of daily living (β 0.37 SD per year, 95% CI 0.24-0.49, P<0.001). Higher global cognition also was tied to higher education, a factor associated with cognitive reserve (β 0.41 SD per year, 95% CI 0.29-0.53, P<0.001).

Carrying an APOE4 or APOE2 allele was not significantly associated with performance in any cognitive domain or with rate of decline. “This may suggest that the effects of APOE alleles are exerted before the age of 100 years,” Holstege and co-authors noted, and is in line with populations studies that show the fraction of APOE4 carriers decreases progressively in 80- and 90-year-olds.

While postmortem levels of amyloid beta, neurofibrillary tangles, and neuritic plaques varied widely, it’s “intriguing that the highest stages of amyloid beta pathology were present in the brains of high performing centenarians, while the highest tau (i.e., neurofibrillary tangles) and neuritic plaque levels were not,” the researchers observed. “This indicates that maintained cognitive health may be explained by resilience to the effects of even the highest levels of amyloid beta pathology, and a combination of resilience and resistance against neurofibrillary tangles and neuritic plaques.”

The study had several limitations, Holstege and colleagues noted: the sample is not representative of all centenarians, and unmeasured confounders may have influenced results.

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow 


The study was supported by Stichting Alzheimer Nederland, StichtingDioraphte, and Stichting VUMC Fonds.

The researchers reported relationships with AC Immune SA, Alkermes, Alnylam Pharmaceuticals, Alzheon, Anavex Life Sciences, Biogen, Brainstorm Cell, Cortexyme, Denali Therapeutics, EIP Pharma, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Noridisk, PeopleBio Co, Renew LLC, Roche Holding AG, Cognition Therapeutics, Inc., FUJIFILM Toyama Chemical Co Ltd, IONIS Pharmaceuticals Inc., UCB, Vivoryon Therapeutics AG, Brain Research Center, Boehringer Ingelheim, Lundbeck, and Janssen Pharmaceuticals.

The editorialist reported no conflicts of interest.

Primary Source

JAMA Network Open

Source Reference: Beker N, et al “Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline” JAMA Netw Open 2021; DOI: 10.1001/jamanetworkopen.2020.31654.

Secondary Source

JAMA Network Open

Source Reference: Perls T “Cognitive Trajectories and Resilience in Centenarians — Findings From the 100-Plus Study” JAMA Netw Open 2021; DOI: 10.1001/jamanetworkopen.2020.32538.



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