Sharp Centenarians Shrug Off Effects of Alzheimer’s Pathology

People who reach the ripe old age of 100 with their cognition intact tend to maintain their faculties over the next several years, even when their brains are riddled with plaques and tangles. This encouraging finding comes from the Dutch 100-plus study, now in its eighth year. In the January 4 JAMA Network Open, researchers led by Henne Holstege and Sietske Sikkes at Vrije University, Amsterdam, reported that the only measurable change in cognitively healthy centenarians over follow-up periods as long as four years was a slight slide in memory. Notably, participants with a high burden of Alzheimer’s pathology fared as well as did peers with less. “Dementia is not inevitable at extreme ages, which may be explained by resilience against AD hallmarks and risk factors,” Holstege wrote to Alzforum.

  • Cognitively healthy centenarians experience but a slight decline in memory over time.
  • Plaques, tangles, and the APOE4 allele have no effect.
  • Likely, these individuals possess resilience factors that keep their minds sharp.

The 100-plus study enrolls cognitively healthy centenarians living in the community. Because many people in the general population have cognitive impairment by this age, these participants likely represent super-agers, selected for preserved health and cognition. They take a battery of cognitive tests at annual visits, and nearly 30 percent agree to donate their brains after death. Previously, Holstege reported that the highest-performing centenarians in this cohort, who scored 26 or better on a baseline MMSE, stayed just as sharp over the next two years (Mar 2020 news). 

Hendrikje van Andel-Schipper was the oldest woman in the world when she died at age 115.

In the new study, the researchers add more longitudinal data as well as postmortem findings. The cohort now consists of 330 centenarians with a median age of 100.5. About three-quarters are women. More than half of them live independently, meaning they do not depend on caregivers. Most still hear and see well, and are mobile. As might be expected, however, the group’s attrition rate is high, with half of them dropping out or dying within their first year. This left 160 participants who took part in at least one follow-up assessment, with the median follow-up time 1.6 years and the maximum four.

First author Nina Beker found no change in executive function, verbal fluency, processing speed or visuospatial abilities in the whole group, irrespective of baseline MMSE, over the median 1.6 years. Memory, on the other hand, nudged downward by an average of 0.1 standard deviations over the course of the study. For comparison, memory drops 0.03 standard deviations per year in cognitively healthy people between the ages of 65 and 85, and 0.9 standard deviations per year in AD patients aged 65 (Salthouse, 2019; Smits et al., 2015). 

The authors separately examined the subset of 43 centenarians who posted baseline MMSEs of 26 or higher. This group outperformed the cohort as a whole on every cognitive domain at baseline, but had about the same rate of memory decline. In their third year in the study, they also notched a small decline in processing speed.

In fact, nothing the authors tested influenced the memory decline. Better physical health and independent living associated with higher baseline cognitive scores, but not with the rate of decline. Likewise, a high level of education and cognitive activity correlated with high baseline scores but not decline.

Neuropathology had no effect, either. Of the 44 participants who came to autopsy, most had plaques and tangles. The majority, 23 people, were Braak stage III, and most of the rest stage 2 or 4. CERAD scores, which assess dense-core neuritic plaques and range from 0 to 3, averaged 1. Thal phase, on the other hand, measures all amyloid deposits, including diffuse and dense-core plaques, and ranges from 0 to 5. Participants averaged 3 on this scale. Intriguingly, several participants were at the highest Thal phase, but none were at the highest Braak or CERAD stage. This suggests a greater resilience against pure amyloid pathology than against tangles or neuritic plaques, which contain dystrophic neurites, the authors noted.

The participants resisted other risk factors, as well. Age was the predominant one, given that in the population at large, dementia risk for centenarians reaches 40 percent per year, or a cumulative 60 percent risk over two years (Corrada et al., 2010). This makes the preserved cognition in the 100-plus cohort remarkable, the authors noted.

Cognition also seemed unaffected by genetic risk factors. Nearly a quarter of the cohort carried a protective APOE2 allele, and 17 percent carried APOE4, but neither genotype affected decline. This implies that the effects of these genes play out before the age of 100, or that the APOE4 carriers in this long-lived cohort may have inherited protective factors that compensate, Holstege noted. She is analyzing genetic and proteomic data to search for them.—Madolyn Bowman Rogers

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References

News Citations

  1. Resilience Redefined: Sharp at Age 100, Still Sharp at 102

Paper Citations

  1. Salthouse TA. Trajectories of normal cognitive aging. Psychol Aging. 2019 Feb;34(1):17-24. Epub 2018 Sep 13 PubMed.
  2. Smits LL, van Harten AC, Pijnenburg YA, Koedam EL, Bouwman FH, Sistermans N, Reuling IE, Prins ND, Lemstra AW, Scheltens P, van der Flier WM. Trajectories of cognitive decline in different types of dementia. Psychol Med. 2015 Apr;45(5):1051-9. Epub 2014 Sep 17 PubMed.
  3. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol. 2010 Jan;67(1):114-21. PubMed.

External Citations

  1. 100-plus study

Further Reading

Papers

  1. Perls TT. Cognitive Trajectories and Resilience in Centenarians-Findings From the 100-Plus Study. JAMA Netw Open. 2021 Jan 4;4(1):e2032538. PubMed.

Primary Papers

  1. Beker N, Ganz A, Hulsman M, Klausch T, Schmand BA, Scheltens P, Sikkes SA, Holstege H. Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline. JAMA Netw Open. 2021 Jan 4;4(1):e2031654. PubMed.

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