The size of the human brain has increased over time, a new finding that may help explain a previously reported decline in incident dementia.

A secular trends analysis using brain imaging data from the long-running Framingham Heart Study, revealed an increase in intracranial volume (ICV), cortical gray matter, white matter, and hippocampal volumes, as well as cortical surface area in people born in the 1970s vs those born in the 1930s.

“We hypothesize that the increased size of the brain will lead to increased ‘reserve’ against the diseases of aging, consequently reducing overall risk of dementia,” Charles DeCarli, MD, director of the Alzheimer’s Disease Research Center and Imaging of Dementia and Aging Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis, told Medscape Medical News.

The study was published online on March 25, 2024, in JAMA Neurology.

Dementia Protection?

As previously reported by Medscape Medical News, an earlier paper from the Framingham Heart Study suggested dementia incidence is declining.

“This difference occurred among persons with at least high school education and was not affected by differences in vascular risk. Our work was stimulated by this finding and the possibility that differences in brain size might be occurring over the three generations of the Framingham Heart Study which might explain an increased resilience to dementia,” said DeCarli.

The cross-sectional study used data from 3226 Framingham participants (53% women) born in the decades 1930-1970. None had dementia or a history of stroke. At a mean age of 57.7 years, they underwent brain MRI.

Compared with the 1930s birth decade, the 1970s birth decade had a 6.6% greater ICV (1321 mL vs 1234 mL), 7.7% greater white matter volume (476.3 mL vs 441.9 mL), 5.7% greater hippocampal volume (6.69 mL vs 6.51 mL), and 14.9% greater cortical surface area (2222 cm2 vs 1933 cm2).

Cortical thickness was thinner by 21% over the same period, coinciding with larger intracranial volume, cerebral white matter volume, and cortical surface area. 

“We were surprised to find that the brain is getting larger, but the cortex is thinning very slightly. The apparent thinning of the cortex is related to the increased need for expansion of the cortical ribbon. This is based on hypotheses related to the effects of evolution and cortical development designed to make neuronal integration most efficient,” said DeCarli.

Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean age, 60 years) and 1950s (mean age, 59 years) resulted in similar findings.

“These findings likely reflect both secular improvements in early life environmental influences through health, social-cultural, and educational factors, as well as secular improvements in modifiable dementia risk factors leading to better brain health and reserve,” the authors wrote.

While the effects observed are “likely to be small at the level of the individual, they are likely to be substantial at the population level, adding to growing literature that suggests optimized brain development and ideal health through modification of risk factors could substantially modify the effect of common neurodegenerative diseases such as stroke and Alzheimer disease on dementia incidence,” they added.

Limitations included the predominately non-Hispanic White, healthy, and well-educated population that is the Framingham cohort, which is not representative of the broader US population. The cross-sectional nature of the study also limited causal inference. 

Exciting Work 

“If these results are confirmed by others and the observed differences by decade are as large as those reported, it has important implications for aging and dementia studies,” Prashanthi Lemuria, PhD, with Mayo Clinic, Rochester, Minnesota, wrote in an accompanying editorial. 

“First, studies that use brain charts for the human life span to understand the mechanisms of aging, by stitching together data from individuals across the decades, are significantly overestimating the degree of brain health decline using volumes across the life span because the baseline brain health in individuals who are in their older decades is likely lower to begin with,” Lemuria noted.

“Second, cortical thickness measurements, often used in dementia studies as a cross-sectional marker for neurodegeneration, showed greatest decline due to secular trends and are not scaled for ICV. Therefore, these should be traded in favor of gray matter volumes after consideration of ICV to estimate the true degree of neurodegeneration,” Vemuri added.

The data also suggest that longitudinal imaging study designs should be preferred when testing hypotheses on brain health, Vemuri wrote.

Although this work is “exciting and will bring attention to secular trends in brain health, much work is yet to be done to validate and replicate these findings and, more importantly, understand the mechanistic basis of these trends,” she added. 

“Do these secular trends in improvement of brain health underlie the decrease in dementia risk? The jury may be still out, but the authors are commended for investigating new avenues,” Vemuri concluded.

Support for this research was provided by the National Institute on Aging and the National Institute on Neurological Disorders and Stroke and the National Institutes of Health. DeCarli reported serving as a consultant to Novartis on a safety study of heart failure during the conduct of the study and receiving consultant fees from Eisai and Novo Nordisk outside the submitted work. Lemuria had no disclosures.

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