Age-Related Cognitive Decline Not Inevitable?

Batya Swift Yasgur, MA, LSW

April 06, 2021

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer's disease (AD), many centenarians maintained high levels of cognitive performance.

"Cognitive decline is not inevitable," senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands, told Medscape Medical News.

"At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline," she said.

The study was published online January 15 in JAMA Network Open.

Escaping Cognitive Decline

Holstege said her interest in researching aging and cognitive health was inspired by the "fascinating" story of Hendrikje van Andel Schipper, who died at age 115 in 2015 "completely cognitively healthy." Her mother, who died at age 100, was also cognitively intact at the end of her life.

"I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages," Holstege said.

To discover the secret to cognitive health in the oldest old, Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine "the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline."

The goal of the research was to investigate "to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features," she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-β (Aβ) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.

Resilience and Cognitive Reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 (interquartile range, 100.2 – 101.7) years. A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found "varying degrees of neuropathology" in the brains of the 44 donors, including Aβ, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a "slight" decrement in memory function (β −.10 SD per year; 95% CI, -.14 to -.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (β .37 SD per year; 95% CI, .24 – .49; P < .001), or higher educational level (β .41 SD per year; 95% CI, .29 – .53; P < .001).

Despite findings of neuropathologic "hallmarks" of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE ε4 or an APOE ε3 alleles were also not significantly associated with cognitive performance or decline, suggesting that the "effects of APOE alleles are exerted before the age of 100 years," the authors note.

"Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline," the authors write. They also speculate that resilience may be attributable to greater cognitive reserve.

"Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals," said Holstege.

"Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health," she added.

A "Landmark Study"

Commenting on the study for Medscape Medical News, Thomas Perls, MD, MPH, professor of medicine, Boston University School of Medicine, Boston, Massachusetts, called it a "landmark" study in research on exceptional longevity in humans.

Perls, who is the author of an accompanying editorial and was not involved in the research, noted that "one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age — in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems."

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, he said.

"People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that," he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Holstege and Perls report no relevant financial relationships. The other authors’ disclosures are listed on the original article.

JAMA Netw Open. Published online January 15, 2021. Full text, Editorial

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