Scientists have extensively characterized brain biomarkers in ApoE4 carriers. Glucose metabolism, measured by fluorodeoxyglucose positron emission tomography (FDG-PET), falls in an ApoE gene-dose-dependent manner in people with mild to moderate AD (Mosconi et al., 2004), and in asymptomatic individuals (Rimajova et al., 2008). When Reiman and colleagues analyzed late middle-aged ApoE4 homozygotes with normal cognition, they found FDG-PET hypometabolism in posterior cingulate, parietal, temporal, and prefrontal regions—brain areas typically ravaged by AD—relative to age-matched controls (Reiman et al., 1996). The cortical hypometabolism showed up in advance of memory problems, whereas hippocampal volume, measured by magnetic resonance imaging (MRI), did not decrease until cognitive decline was underway (Reiman et al., 1998).

In the current analysis, first author Hillary Protas and colleagues confirm and extend these findings in a larger cohort. Whereas the prior research analyzed hippocampal volume and cortical metabolism in 11 ApoE4 homozygotes and 22 controls, the current study examined 149 people at three levels of genetic risk—42 ApoE4 heterozygotes, 31 ApoE4 homozygotes, and 76 non-carriers, all cognitively normal. The researchers also included a third measure—hippocampal metabolism. The Arizona team focused on the cortical FDG-PET results, while collaborators Michael Weiner and colleagues at the University of California, San Francisco, and Mony de Leon and Lisa Mosconi of New York University, analyzed hippocampal volumetric MRI and FDG-PET, respectively.

Of the three measurements, only cortical hypometabolism associated with ApoE4 gene dose. These findings provide “additional data to suggest that posterior cingulate hypometabolism may precede the other biomarkers in the preclinical stage of AD,” Reiman told Alzforum. “The [hippocampal] changes come later," he said. In a separate study, Reiman and colleagues found cortical metabolic decline in ApoE4 carriers as young as their twenties and thirties (Reiman et al., 2004), again suggesting these FDG-PET changes occur very early.

Is cortical hypometabolism in cognitively sound ApoE4 carriers evidence of preclinical AD? “The answer is not clear,” suggests William Jagust of the University of California, Berkeley, in an accompanying editorial. While “amyloid PET imaging has verified the association between ApoE4 and Aβ, and PET metabolic imaging demonstrates an association between ApoE4 and cortical hypometabolism, the association between Aβ and hypometabolism in ApoE4 carriers has not been shown,” he writes.

One shortcoming of the current study is that it does not use state-of-the-art methods for MRI data acquisition. Data collection began in 1994, and could not switch midway to the more powerful tools now used for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Hence, though the study includes three measurements—cortical metabolism (FDG-PET), hippocampal metabolism (FDG-PET), and hippocampal volume (MRI)—the use of suboptimal MRI methods makes it hard to directly compare MRI measures with PET measures, suggested James Brewer of the University of California, San Diego. The strength of the study lies in its power to reveal early FDG-PET hypometabolism in the cortex, he said. “Subregions of the cortex, particularly the precuneus, are an Alzheimer’s hotspot that should not be ignored.”

The present findings jibe with a recent study looking at brain amyloid and atrophy in seniors with mild AD or no cognitive impairment. Keith Johnson and colleagues at Massachusetts General Hospital, Boston, reported that Aβ deposition correlated more strongly with posterior cingulate/precuneus cortical thinning than with hippocampal volume loss (Becker et al., 2011).—Esther Landhuis.

Reference:
Protas HD, Chen K, Langbaum J, Fleisher AS, Alexander GE, Lee W, Bandy D, de Leon MJ, Mosconi L, Buckley S, Truran-Sacrey D, Schuff N, Weiner MW, Caselli RJ, Reiman EM. Arch Neurol. 3 Dec 2012.

Jagust W. Apolipoprotein E, Neurodegeneration, and Alzheimer Disease. Arch Neurol. 3 Dec 2012. Abstract