July 22, 2010 — Patients with Alzheimer's disease (AD) and larger head circumference (>56 cm) experience less cognitive deterioration compared with patients with smaller head circumference (≤56 cm), even if the degree of brain cell loss is similar, a new study shows.

"Since head circumference is a good approximation to the maximal size of the adult brain, we argue that larger brains contain more nerve cells and synapses, which offers a reserve against the clinical manifestations of brain damage due to AD," Robert Perneczky, MD, from the Technical University of Munich in Germany, told Medscape Medical News.

As reported in the July 13 issue of Neurology, Dr. Perneczky's team studied 270 patients with AD participating in a family-based study of genetic and environmental risk factors for AD. They underwent cognitive testing, apolipoprotein E (APOE) genotyping, and magnetic resonance imaging of the brain, and head circumference was measured. Their average age was 75 years, 60% were women, and 69% were APOE ε4 allele carriers.

In a linear regression analysis, both atrophy (P < .001) and age (P = .02) were inversely associated with cognitive performance on the Mini-Mental State Examination. None of the other variables — duration of AD, sex, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity — exerted any statistical effects.

In a model testing for interaction between atrophy and head size, a significant interaction (P = .04) emerged between atrophy and head circumference.

"With greater levels of atrophy, cognition was higher for individuals with greater head circumference," the researchers report. In this model, none of the other variables, except for age, showed any significant effects.

Study Supports Concept of Brain Reserve

These findings suggest that larger head circumference (and presumably brain size) "offers protection against AD symptoms through enhanced brain reserve," write the researchers.

Optimal brain development before birth and during early life "is very important for the prevention of dementia," said Dr. Perneczky. Although brain growth is determined in part by genetics, it is also influenced by other factors: "Optimal brain development is supported by good nutrition, and the prevention of infections and concussions of the central nervous system, for example," he said.

"Intellectually, socially, and physically active lifestyles also seem to offer protection against dementia," he added.

James A. Mortimer, PhD, professor of epidemiology at the University of South Florida in Tampa, who was not involved in the study, noted that "people who exercise more, their brains shrink less. And education is actually a stronger protective factor than having a larger head."

Dr. Mortimer also noted that "there is abundant literature going back to the mid-1990s showing that people with small heads are at risk of getting AD earlier and having more severe AD. Smaller head size also leads to smaller IQ, which is evident by age 20 or so. It's just useful to have a larger brain."

Study Limitations

The fact that the study subjects came from specialized memory clinics makes it hard to generalize the findings to the AD population at large, Dr. Perneczky's group notes in their report. Another limitation is the use of a visual rating procedure, instead of automated volumetric procedures, to grade brain atrophy.

A third limitation is the use of head circumference to estimate maximal adult brain size. Although "broadly accepted as surrogate for intracranial volume and maximal attained brain size," volumetric measurement of intracranial volume may have provided more precise information on brain size, they note.

"Finally, although our cross-sectional study demonstrated that cognitive function of individuals with larger head circumference was better than that of patients with smaller circumference at any given [Mini-Mental State Examination] level, longitudinal studies are necessary to determine whether brain size modifies cognitive decline over time," the researchers conclude.

The study was supported by the National Institute on Aging. Dr. Perneczky and coauthors have reported several financial relationships. A full list of disclosures can be found in the original article. Dr. Mortimer has disclosed no relevant financial relationships.

Neurology. 2010;75:137-142. Abstract