Is Mild Cognitive Impairment Reversible?

A high level of education, superior academic performance and excellent written language skills may predict the reversal of mild cognitive impairment (MCI) to normal cognitive function, new research shows.

Investigators found individuals with these factors, which are all markers of cognitive reserve, had a significantly greater chance of reversion from MCI to normal cognition (NC) than progression from MCI to dementia.

Dr Suzanne Tyas

In a cohort study of more than 600 women age 75 years or older, about a third of those with MCI reverted to NC at some point during follow-up, which sends "an encouraging message," study author Suzanne Tyas, PhD, associate professor, School of Public Health Sciences, University of Waterloo, Ontario, Canada, told Medscape Medical News.

"That's a positive thing for people to keep in mind when they're thinking about prognosis. Some of these novel characteristics we've identified might be useful in thinking about how likely a particular patient might be to improve versus decline cognitively," Tyas added.

The findings were published online February 4 in the journal Neurology.

Highly Educated Cohort

As the population ages, the number of individuals experiencing age-related conditions, including dementia, increases. There is no cure for most dementia types so prevention is key — and preventing dementia requires understanding its risk factors, Tyas noted.

The analysis included participants from the Nun Study, a longitudinal study of aging and cognition among members of the School Sisters of Notre Dame in the United States. All were 75 and older at baseline, which was from 1991 to 1993; about 14.5% were older than 90 years.

Participants were generally highly educated, with 84.5% attaining an undergraduate or graduate degree. They also had a similar socioeconomic status, level of social supports, marital and reproductive history, and alcohol and tobacco use.

Researchers examined cognitive function at baseline and then about annually until death or end of the 12th round of assessments. They used five measures from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery to categorize subjects into NC, MCI, or dementia: Delayed Word Recall, Verbal Fluency, Boston Naming, Constructional Praxis, and the Mini-mental State Exam.

The current analysis focused on the 619 participants with data on APOE-4 genotyping and education. From convent archives, investigators also had access to the nuns' early high school academic performance in English, Latin, algebra, and geometry.

"Typically we only have data for [overall] education. But I know from teaching that there's a difference between people who just pass my courses and graduate with a university degree vs those who really excel," Tyas said.

The researchers also assessed handwriting samples from before the participants entered the religious order. From these, they scored "idea density," which is the number of ideas contained in the writing and "grammatical complexity" which includes structure, use of clauses, subclauses, etc.

Dementia Not Inevitable

Results showed 472 of the 619 participants had MCI during the study period. About 30.3% of these showed at least one reverse transition from MCI to NC during a mean follow-up of 8.6 years; 83.9% went on to develop dementia.

This shows converting from MCI to NC occurs relatively frequently, Tyas noted.

"This is encouraging because some people think that if they have a diagnosis of MCI they are inevitably going to decline to dementia," she added.

The researchers also used complicated modeling of transition rates over time between NC, MCI, and dementia and adjusted for participants who died. They estimated relative rates (RRs) of reversion vs. progression for age, APOE, and potential cognitive reserve indicators.

Not surprisingly, younger age (90 years or less) and absence of APOE-ɛ4 allele contributed to a significantly higher rate for reversion from MCI to NC vs progression from MCI to dementia.

However, although age and APOE are known risk factors for dementia, these have not been examined in the context of whether individuals with MCI are more likely to improve or decline, said Tyas.

Higher educational attainment, the traditional indicator of cognitive reserve, was associated with a significantly higher relative risk for reversion from MCI to NC vs. progression from MCI to dementia (RR ratio, 2.6) for a Bachelor's degree vs less education.

There was a greater RR ratio for even higher education after adjusting for age and APOE-ε4 status.

Language Skills Key

Interestingly, the investigators also found a significant association with good grades in high school English but not other subjects (RR ratio for higher vs lower English grades, 1.83; 95% CI, 1.07 - 3.14).

In addition, they found both characteristics of written language skills (idea density and grammatical complexity) were significant predictors of conversion to NC.

"Those with high levels of idea density were four times more likely to improve to normal cognition than progress to dementia, and the effect was even stronger for grammatical structure. Those individuals with higher levels were almost six times more likely to improve than decline," Tyas reported.

The RR ratio for higher vs lower idea density was 3.93 (95% CI, 1.3 - 11.9) and the RR ratio for higher vs lower grammatical complexity was 5.78 (95% CI, 1.56 - 21.42).

These new results could be useful when planning future clinical trials, Tyas noted. "MCI in some people is going to improve even without any treatment, and this should be taken into consideration when recruiting participants to a study and when interpreting the results," she said.

"You don't want something to look like it's a benefit of the treatment when in fact these individuals would have just reverted on their own," she added.

Research Implications

Commenting on the findings for Medscape Medical News, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer's Association, noted that in "this study of highly educated, older women," transitions from MCI to NC "were about equally common" as transitions from MCI to dementia.

"As advances are made in early detection of dementia, and treatments are developed and marketed for people living with MCI, this article’s findings are important to inform discussions of prognosis with patients and [to the] design of clinical trials," Sexton said.

The study was funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Funding for the Nun Study at the University of Kentucky was provided by the US National Institute of Aging and the Kleberg Foundation. Tyas has disclosed no relevant financial relationships.

Neurology. Published online February 4, 2022. Abstract

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