The Influence of Alzheimer Disease Family History and Apolipoprotein E ε4 on Mesial Temporal Lobe Activation

Abstract

First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E 4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (ϩFH)] and 64 age-and educationmatched controls without a first-degree family history of any dementia [no family history (ϪFH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 ϫ 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the ϪFH ϩ4 group exhibited the greatest signal change, and the ϩFH ϩ4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

“…Prior studies have reported fMRI alterations in cognitively normal (2,7,19,33,36,61,71) or mildly impaired (3,15) APOE*4+ individuals. However, there is considerable variability in both the direction and pattern of the differences.…”

“…Studies with fMRI have been less consistent; both increased (3,19,26,62,71), decreased (36,61) and unchanged (1) BOLD responses have been reported in APOE*4+ subjects and no clear anatomic region is reliably affected. Furthermore, recent fMRI studies suggest that a family history of dementia may modulate the effects APOE*4 on brain activation (33) or more robustly impact brain activation than APOE genotype (1).…”

Functional MRI in the early diagnosis of Alzheimer’s disease: is it time to refocus?

“…The interpretation is typically that reduced activation in this region corresponds to the memory deficits exhibited by these patients. However, this interpretation is complicated by a number of studies that have found increased MTL activation in MCI patients relative to healthy subjects [37,[40][41][42][43] as well as healthy older adults at genetic risk for AD versus those not at risk [44,45]. The interpretation of this increased activation, or 'hyperactivation', is that early in the progression of AD, there is a period of compensatory brain change, enabling patients to maintain function.…”

“…For example, family history may interact with APOE status to influence activation [45]. Additionally, measuring the extent of activation as opposed to the magnitude of activation may yield different findings.…”

Atorvastatin Therapy is Associated with Greater and Faster Cerebral Hemodynamic Response

“…Neuroimaging studies of people at risk for developing AD report either reduced BOLD signal (Johnson et al, 2006b) related to AD risk factors or increased signal attributed to putative compensatory phenomena (Bookheimer et al, 2000). The fMRI BOLD signal itself is sensitive to changes in baseline cerebral blood flow (CBF) and cerebral metabolism of oxygenation that tightly accompany focal neuronal activity (Hoge et al, 1999;Ogawa et al, 1990).…”