04 Mar 2020

For most of us, cognition declines with age, but a few lucky individuals remain sharp even at advanced ages. Is there a way to figure out who is likely to keep their faculties? In the February 26 JAMA Network Open, researchers led by Henne Holstege at Vrije University in Amsterdam put forward a simple litmus test. They found that, in a cohort of cognitively healthy centenarians, those who scored 26 or higher on the MMSE at baseline were likely to maintain their thinking skills over the next two years, while those who scored lower were more likely to decline. “Now we have a way to select for these people at an earlier age, so we can start investigating the group who are most likely to stay cognitively healthy until death,” Holstege told Alzforum. This is important, because identifying the factors that keep these superagers’ brains keen may suggest new ways to stave off cognitive aging and Alzheimer’s disease for everyone else, researchers believe.

In a small group of centenarians, baseline MMSE scores of 26 or higher predicted future cognitive health.

This resilient group also stayed independent.

The finding may help identify protective genetic factors.

In the general population, the incidence of dementia rises continuously with age, reaching 40 percent in centenarians (Corrada et al., 2010). By this age, up to three-quarters of people have at least some cognitive impairment (Poon et al., 2012). Even so, a few cognitively hardy folks remain sharp even at very advanced ages.

Holstege and colleagues evaluated 340 centenarians in Dutch 100-plus, a prospective cohort study that aims to uncover resilience factors in this population. All were cognitively healthy at baseline, as determined by self and informant reports. Their median age was 100.5 years; nearly three-fourths were women. First author Nina Beker found that almost half scored 26 or higher on the MMSE at baseline, and these 156 people also had a 44 percent lower risk of death over the next two years.

Does baseline MMSE predict cognitive health, too? Only 79 of the 340 participants returned for two years of repeated cognitive testing; the others died or dropped out of the study. Among these 79, 58 people had scored 26 or higher at baseline. They declined more slowly, sliding an average of 0.71 points on the MMSE, compared with a 1.68 point drop for low baseline scorers. Indeed, among the 58 high scorers, 43 stayed cognitively stable, with no notable change over two years.

High scorers were also more likely to remain independent and functional. On the Dutch Barthel Index, which measures activities of daily living, high scorers declined by 0.81 per year, compared with 1.88 for low scorers.

Claudia Kawas at the University of California, Irvine, who has been studying centenarians for many years (Jan 2012 webinar), noted that the cut point of 26 on the MMSE may be specific to this particular population. They are an exceptional group selected for preserved function, and are not reflective of Dutch centenarians in general, the authors acknowledge.

Even so, the general finding that high baseline cognitive scores predict preserved cognition holds true across many populations, age groups, and studies, Kawas said. For example, an early study of 80-year-olds found that those who made few errors on a mental status exam had a very low risk of developing AD over the next five years, while those with five or more errors ran a 12 percent risk per year (Katzman et al., 1989). Likewise, in the Heidelberg Centenarian Study, 71 percent of those with high baseline cognitive scores remained stable for 1.5 years (Kliegel et al., 2004). Thus, high test scores in general could be useful to help select centenarians most likely to have resilience factors for further study.

Why would “cognitive maintainers” not score perfectly, i.e., 30, on a simple screening test such as the MMSE? Stacy Andersen at Boston University, who studies centenarians, noted that many have hearing and vision problems that can affect test scores. “This cut point of 26 likely reflects the noncognitive contributions to cognitive test performance among centenarians,” she wrote to Alzforum (full comment below).

Were there other explanations, beyond unknown genetic factors, that might explain the better cognitive and physical health of the high scorers? Holstege and colleagues ruled out several obvious possibilities, including comorbidities and the ApoE4 allele. The high scorers had the same prevalence of diabetes, cardiovascular disease, and hypertension as low scorers. The ApoE4 allele in general is less common among centenarians than the general population, at 16.3 and 27.2 percent, respectively. However, ApoE4 was more common among high than low scorers, at 18.6 versus 5.6 percent.

Sofiya Milman at Albert Einstein College of Medicine, New York City, considers this the most intriguing finding. “Likely, these ApoE4 carriers carry protective genetic factors,” she told Alzforum.

Ron Petersen at the Mayo Clinic in Rochester, Minnesota, took a slightly different view. “The effect of ApoE4 has likely played itself out before people reach 100. I suspect these survivors have some unique polygenic resilience factors. We have much to learn from them,” he said (full comment below).

To find these resilience factors, Holstege and colleagues are analyzing genetic, proteomic, and immune profiles from the centenarians with preserved cognition. One possible genetic factor is the immune gene phospholipase C g-2 (PLCG2). Holstege and colleagues previously reported that a rare protective variant associates with longevity and halves a person’s risk of AD, Lewy body disease, and frontotemporal dementia (May 2019 news). One centenarian in her study had inherited this variant along with two ApoE4 alleles, and remained cognitively healthy at the age of 104. None of the participants had the Christchurch mutation in ApoE, which has also been linked to cognitive preservation, but is likewise rare (Nov 2019 news).

Environment and lifestyle factors are another possible contributor. Kawas noted that the 43 people who remained cognitively stable in this study were more educated than the 36 decliners, with 18.6 versus 5.6 percent, respectively, having some college education. Analyses of these cohorts continues, Holstege said. —Madolyn Bowman Rogers