Early brain changes affiliated with genetic Alzheimer’s risk factor recognized

Some of the earliest brain changes associated with the major genetic risk factor for late-onset Alzheimer’s disease (AD) have been identified in a study published on Nov. 25 in JAMA Neurology.

Recent research indicates that brain structure alterations may occur before observable cognitive impairment in AD by several decades. Early detection and evaluation of these alterations could hold incredible value for the development of preventive treatment therapies.

The apolipoprotein E (APOE) ε4 allele, which is found in 60 percent of AD patients, has been shown to affect the cerebral metabolic rates of glucose in areas of the brain preferentially affected by AD in young adults that carry the allele. 

“These findings, as well as those from other structural, functional, and functional connectivity magnetic resonance imaging (MRI) studies of older children and young adults at differential genetic risk for AD, led us to postulate that APOE ε4 carriers have neurodevelopmental alterations that provide a foothold for the neuropathological changes associated with the subsequent course of AD,” wrote the study’s lead author, Douglas C. Dean III, MSc, of Brown University in Providence, R.I., and colleagues.

The researchers designed a cross-sectional brain imaging study to compare MRI measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the APOE ε4 allele.

The study performed quiet MRI at an academic research imaging center on 162 healthy, typically developing two to 25 month-old infants with no family history of AD or other neurological or psychiatric disorders. Cross-sectional measurements were compared in both the APOE ε4 carrier and noncarrier groups.

White matter MWF was compared in the 162 sleeping infants, 60 of whom were ε4 carriers and 102 of whom were noncarriers. GMV was compared in 59 infants, between six and 25 months old, 23 of whom were ε4 carriers and 36 of whom were noncarriers. The subjects remained asleep during the scanning sessions. The carrier and noncarrier groups were matched for the following components: age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.

Results indicated that infant carriers of the allele had lower MWF and GMV measurements than noncarriers in areas preferentially affected by AD: precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions. Greater MWF and GMV measurements in extensive frontal regions were significant in the two to six month-old subset. Infant ε4 carriers exhibited a weakened relationship between MWF and age in posterior white matter regions.

“Findings from this study raise new questions about the role of APOE in normal human brain development and the earliest processes involved in the predisposition to AD, their possible relationship to subsequent AD pathology, and the extent to which they can be targeted by AD prevention therapies,” wrote the study’s authors.