Can Childhood Enrichment Slow Late-Life Cognitive Decline?

Erik Greb

July 10, 2020

Higher levels of early-life cognitive enrichment (ELCE) are associated with better cognitive health in later life, new research shows.  

The latest results from the Rush Memory and Aging Project, an ongoing community-based cohort study of chronic conditions of aging, showed that in part, the link between ELCE and better late-life cognitive health was tied to fewer pathologic changes related to Alzheimer's disease (AD), including deposition of beta amyloid and tau proteins.

Dr Shahram Oveisgharan

"In many visits, care providers for patients with dementia, who are mostly patients' family members, are anxious and ask the clinicians what they can do for prevention of dementia in themselves or in their children," study investigator Shahram Oveisgharan, MD, assistant professor of neurological sciences at Rush University, Chicago, Illinois, told Medscape Medical News.

"Here, we are introducing a lifestyle factor that is associated with slower late-life cognitive decline not only through a higher reserve, but also through making the brain less vulnerable to the accumulation of Alzheimer's disease pathological changes. This finding is novel and encourages families to enrich cognitively their children's [environment]," he added.  

The study was published online June 29 in JAMA Neurology.

Autopsy Data

Indicators of ELCE, such as childhood socioeconomic status and school performance, have previously been associated with slower cognitive decline and decreased dementia in late life.

However, the investigators note that the mechanisms underlying this association are unclear. Oveisgharan said there are data from animal studies that suggest environmental enrichment is associated with lower levels of tau, phosphorylated tau, and oligomeric amyloid beta.

"The association," he said, "is partly through upregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B pathway that results in downregulation of glycogen synthase kinase-3-beta, which is implicated in the formation of neurofibrillary tangles, a hallmark of Alzheimer's disease pathology."

He also noted that the mechanisms underlying the association between ELCE and cognitive decline have not been studied in humans before.

For the study, the researchers examined data from the Rush Memory and Aging Project. Participants undergo annual clinical assessments and agree to organ donation.

Between January 1, 1997, and June 30, 2019, a total of 2044 participants enrolled, of whom 1018 died. Of these, 838 underwent brain autopsy and neuropathologic examination. At the time of the analysis, complete data on the neuropathologic exam and ELCE were available for 813 participants.

For each participant, the investigators calculated a global AD pathology score based on the number of diffuse plaques, neuritic plaques, and neurofibrillary tangles.

They used image analysis and stereology to quantify beta amyloid and tau levels, respectively. The investigators also evaluated eight other common dementia-related pathologic changes.

At baseline, participants answered questions about four indicators of ELCE: early-life socioeconomic status, availability of cognitive resources at age 12 years, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction.

Participants also underwent 19 neuropsychological tests at baseline and at annual visits. The investigators also collected information about demographics and comorbidities.

Enrichment Slows Decline

Of the 813 participants, 562 (69%) were women, and 96% were White and non-Hispanic. Mean age at death was 90.1 years. Mean educational level was 14.6 years.

A linear regression model adjusted for potential confounders suggested that increased ELCE was associated with less annual cognitive decline compared with lower levels of ELCE.

Linear regression models showed that every one-unit increase in ELCE score was associated with a lower global AD pathology score (estimate, −0.057) and lower levels of tau (estimate, −0.188) and beta amyloid (estimate, −0.136).

This per-unit effect size is the equivalent of being 8 years younger, the researchers note. APOE carrier status did not affect the association, nor did sex or age at death.

A one-unit increase in ELCE also was associated with a 25% decrease in the rate of cognitive decline. Pathologic change related to AD attenuated the association between ELCE and cognitive decline, suggesting that part of the association was independent of AD pathologic changes.

The investigators found that 80% of the association between ELCE and cognitive decline was direct and 20% indirect as indicated by AD pathology scores.

With the exception of tau and beta amyloid deposition, ELCE was not associated with any of the other eight dementia-related pathologic changes.

The study extends previous findings by examining ELCE, which is modifiable, rather than cognitive function, which is predominantly inherited, said Oveisgharan.

The number of brain autopsies included in the study exceeds those of previous studies. In addition, previous research has not examined whether ELCE is linked to other causes of late-life dementia. The long follow-up period enabled the investigators to estimate reliable rates of late-life cognitive decline.

"We leveraged path analysis to estimate how much of the association between a higher level of ELCE and a slower rate of late-life cognitive decline was through lower levels of Alzheimer's disease pathological changes, and how much of the association was a direct one," said Oveisgharan.

Replication Difficult

Commenting on the findings for Medscape Medical News, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minnesota, said the study "comes from a group at Rush with an outstanding track record of carefully done studies that use thoughtful statistical methodology. This may be the first and only replication of a claim made by the Nun Study in the 1990s."

Although the retrospective acquisition of events from childhood is one of the study's weaknesses, "there is no other way to acquire this sort of data," he said.

"There is no reason to believe the data were biased at the time of collection, but it's undoubtedly noisy," said Knopman, who was not involved with the research.

Another weakness inherent to autopsy studies is participants' advanced age.

"People who make it to the high 80s should be thought of as survivors who are not necessarily representative of typical aging. The people in this study represent only a fraction of their own birth cohort, so one must wonder whether the result here represents a survival-induced bias," Knopman said.

The finding that higher ELCE reduces the burden of late-life neurodegenerative disease "is a pretty major claim," Knopman said. The complexity of the statistical analysis that the investigators used, along with the difficulty in replicating the findings, should encourage caution about drawing that conclusion, he added.

The study was supported by a grant from the National Institute on Aging. Oveisgharan reported receiving grants from the National Institutes of Health during the study. Knopman has reported no relevant financial relationships.

JAMA Neurol. Published online June 29, 2020. Abstract, Editorial

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