The development compound AV-45 binds to amyloid plaques for imaging of Alzheimer's disease. Image source: Avid Radiopharmaceuticals

Cognitively normal adults in their early 60s carrying the e4 allele of apolipoprotein E (APOE4), which is associated with Alzheimer's disease, showed brain connectivity disruptions in functional MRI (fMRI) prior to the onset of any clinical symptoms, suggesting that fMRI might play an important role in early identification of Alzheimer's, according to a study published Dec. 15 in the Journal of Neuroscience.

Researchers have localized functional abnormalities in brain activity associated with Alzheimer's disease (AD) to the precuneus (among other areas), in which the disruptions within the network with correlated spontaneous brain activity at rest, the default-mode network (DMN), constitute one of the earliest noticeable effects of AD. "Previous work has shown that, compared with brain activity in cognitively normal individuals (Greicius and Menon, 2004), brain activity in AD is associated with DMN resting-state fMRI functional connectivity (fcMRI) disruptions," according to Yvette I. Sheline, MD, and co-authors from Washington University School of Medicine in St. Louis.

Moreover, Sheline and colleagues have discovered similar brain activity disruptions in cognitively normal elderly patients with amyloid B plaques, detected using Pittsburgh Compound B (PIB) PET imaging. In the present study, the researchers sought to determine whether similar AD-associated disruptions in the DMN could be observed in carriers of the APOE4 genotype, independently of amyloid B plaque toxicity, as previously discovered.

Sheline and colleagues performed fMRI using a gradient echo sequence sensitive to blood oxygenation level-dependent (BOLD) contrast (T2* weighting). Thirty-six contiguous, 4.0 mm slices were acquired parallel to the anterior-posterior commissure plane along two, 164-volume fMRI runs.

The 100 cognitively normal participants, between 50 and 65 years old with a mean age of 62, were divided into APOE4+ and APOE4- groups. APOE4+ participants had genotypes of either APOE 4/4, APOE 3/4 or APOE 2/4, with 38 total APOE4+ subjects and 62 APOE4- subjects, with all participants PIB-.

"In the current study, participants carrying an APOE4 allele had clear-cut abnormalities in precuneus resting-state functional connectivity in the absence of any cognitive impairment, and in the absence of fibrillar cerebral amyloid B deposits detectable by PET PIB imaging."

Significant differences in regional connectivity of the bilateral precuneus to a priori regions were observed in the following regions: the left superior temporal gyrus/fronto-parietal operculum; left hippocampus and parahippocampus; dorsal anterior cingulate; caudal orbital cortex; middle temporal cortex; right hippocampus; medial prefrontal cortex (frontal pole); gyrus rectus; and in the dorsal occipital cortex. These regions of the precuneus were observed to either show significantly greater or significantly less functional connectivity in APOE4+ versus APOE4- participants, as measured by regional correlation magnitudes.

"As far as their brain amyloid burden and their cerebrospinal fluid levels, these individuals were completely normal. But the people who had the APOE4 variant had significant differences in the way various brain regions connected with one another," Sheline commented.

The authors said that their "results suggest that mechanisms resulting in increased neuronal toxicity might already be in place before lowered AB 42 CSF levels." The authors called for interpretive caution, however, saying that observations from exploratory analyses must be replicated in independent samples.

"The current belief is that from the time excess amyloid begins to collect in the brain, it takes about 10 years for a person to develop dementia," Sheline offered. "But this new study would suggest we might be able to intervene even before amyloid plaques begin to form. That could give us an even longer time window to intervene once an effective treatment can be developed."