We found decreased BOLD signal in the anterior cingulate gyrus bilaterally and the left frontal pole in presymptomatic FAD MCs compared with matched NC family members during blocks of novel stimuli. No areas were more activated in FAD MCs compared with NCs. We were therefore unable to demonstrate increased brain activity in presymptomatic persons destined to develop AD due to FAD mutations. Interestingly, we found areas of increased BOLD signal in carriers of the ϵ3/4 APOE genotype compared with carriers of the ϵ3/3 genotype and in carriers of the ϵ3/3 compared with the ϵ2/3 genotype. Our findings do not support the hypothesis that increased activation seen in persons at genetic risk for AD represents a compensatory phenomenon but rather suggest that APOE exerts an effect on activation-related BOLD signal that is at least partly independent of AD risk per se.
The novel versus repeated stimuli task used in this study is a well-studied paradigm that induces increased cerebral blood flow to the posterior hippocampus, parahippocampal gyrus, and the fusiform and lingual gyri (Worsley et al. 1992
; Bondi et al. 2005
). It is thought that the activation in the hippocampus is related to the novelty of the stimuli, whereas the activation seen in the fusiform and lingual gyri are related to recognition of complex visual stimuli (Stern et al. 1996
). We found grossly similar anatomical patterns of activation across subjects regardless of FAD mutation status and APOE
genotype, suggesting that there were no fundamental differences in the way stimuli are processed in the 2 populations.
The decreased task-related fMRI signal seen in presymptomatic FAD MCs is consistent with what is observed in persons with established AD (Dickerson et al. 2004
). Using the novelty encoding task in our population, the decreased BOLD signal was seen in the anterior cingulate gyrus, whereas prior fMRI studies have found decreased fMRI signal in the medial temporal lobe (Dickerson et al. 2004
) and frontal lobe (Li et al. 2009
), depending on what activation tasks are employed. The anterior cingulate plays a role in many cognitive tasks and is part of the salience network (Seeley et al. 2007
) that might be expected to be selectively activated during the processing of novel stimuli. Decreases in baseline glucose metabolism and cerebral blood flow occur in the anterior cingulate in established AD and decreased resting cerebral blood flow to the anterior cingulate has been described in presymptomatic PSEN1
MCs (Johnson et al. 2001
). The relatively increased signal seen in NCs during blocks of novel stimuli in the anterior cingulate was more related to decreased activation during novel blocks in MCs than to decreased deactivation during repeated trials (data not shown). As there were minimal true rest periods during this task, it is not possible to address the integrity of the intrinsic connectivity networks in this study.
A PET study using the amyloid-binding ligand Pittsburgh Compound B (PIB) in persons with established variant FAD due to a deletion in exon 9 of PSEN1
that features spastic paraparesis found increased signal in the striatum and anterior cingulate (Koivunen et al. 2008
). Some persons carrying the A431E substitution in PSEN1
also develop spastic paraparesis (Murrell et al. 2006
), and carriers of this mutation made up 43% of our study population. A PET investigation of presymptomatic PSEN1
MCs using PIB demonstrated high signal in the striatum early in the presymptomatic period, presumably reflecting amyloid pathology there (Klunk et al. 2007
). In this study, some asymptomatic subjects showing this pattern were more than 10 years younger than the age at which they would be expected to begin to show cognitive decline, an age comparable to that of the subjects in our study. We did not observe any differences in BOLD signal in the striatum in FAD MCs though this area did not tend to be activated during the task we employed. The nucleus accumbens of the striatum has indirect connections with the anterior cingulate via frontal-subcortical circuits (Cummings 1995
). Therefore, possible explanations for our finding of decreased anterior cingulate activation include involvement of the cingulate gyrus with amyloid or diaschisis secondary to striatal pathology. Obtaining both fMRI and amyloid imaging in the same subjects would be required to directly address this question.
Multiple prior fMRI studies have found increased focal fMRI response during various activation tasks in carriers of the APOE
ϵ4 allele (Bookheimer et al. 2000
; Dickerson et al. 2004
; Bondi et al. 2005
; Fleisher et al. 2005
; Johnson et al. 2006
; Yassa et al. 2008
). As this allele is the principal genetic susceptibility locus for late-onset AD, such findings have been interpreted as representing an increase in focal brain activity to compensate for or differentiation of the BOLD signal due to subclinical AD pathology. Familial AD, in which alterations in PSEN1
), are fully penetrant and cause the onset of AD at a young and somewhat predictable age (Fox et al. 1997
; Murrell et al. 2006
) provide an alternative genetic model in which to test this hypothesis. A prior fMRI study of 2 persons inheriting the C410Y PSEN1
mutation found increased activation in multiple brain areas during learning and retrieval of faces in the young (20 years of age) but not the older (45 years of age) preclinical carrier (Mondadori et al. 2006
). As the age of onset of symptoms in this family tended to be around age 48, the authors interpreted this as possibly representing increased focal cerebral blood flow 30 years prior to the development of symptoms. In our larger study, we were unable to demonstrate a similar effect in similarly -aged presymptomatic FAD MCs.
Though at least one fMRI study suggested that having a family history of AD was associated with increased fMRI activity independently of APOE
genotype (Bassett et al. 2006
), most fMRI findings in persons susceptible to AD due to APOE
genotype are equally compatible with an effect of APOE
on activation-related blood flow that is at least somewhat independent of AD pathology. Johnson et al. (2006)
, using an activation task similar to ours, found increased activation in the medial temporal lobes in response to novel items in APOE
ϵ4 carriers but decreased activation in nondemented persons with a family history who did not carry the ϵ4 genotype. This study and ours are consistent with APOE
genotype exerting a direct effect on activation-related BOLD signal. This latter interpretation is further supported by a recent study, also employing a novelty encoding paradigm, that found increased activation in the hippocampi and cerebellum in 18 APOE
ϵ4 carriers relative to 18 NCs who were between 20 and 35 (mean 28.5) years of age (Filippini et al. 2009
). As this age is before the age at which AD pathology would be expected to appear, even in APOE
ϵ4 carriers, it is consistent with our findings in which APOE
had an effect on focal fMRI activity in relatively young persons that was greater that that of fully penetrant autosomal dominant FAD mutations.
A limitation of our study is the small number of subjects in the APOE ϵ3/4 (n = 4) genotype subgroup. It is possible that our findings are random effects of interindividual variability in fMRI BOLD signal. Unfortunately, the absolute number of subjects eligible to participate in studies such as this is low due to the rarity of FAD mutations, and therefore, the number of subjects at-risk for FAD of various APOE genotypes is serendipitous. Because of the small numbers, we included one APOE ϵ3/4 carrier that was of an outlying age (55 years) compared with the remainder of the cohort. Exclusion of this subject did not change the fMRI results substantively.
Our study population was comprised of persons of varying FAD and APOE
genotypes from a limited number of Mexican or Mexican American families. This raises issues regarding the validity of cognitive testing and generalizability of our findings to other ethnic groups. As we employed neuropsychological measures that have demonstrated utility in Latinos living in the United States, the norms for comparison were derived from the nonmutation carrying family members, and we also independently administered a widely used global clinical measure (the Clinical Dementia Rating scale), the determination of clinical status of our subjects should be valid. The use of fMRI as an outcome measure has advantages with regard to the applicability of our findings to other populations. Prior studies of neuropsychological scores, clinical diagnosis, and structural MRI measures among African-Americans, Caucasians, and Hispanics (DeCarli et al. 2008
; Mungas et al. 2009
) showed only subtle interethnic differences with the main relationships among these variables being consistent between groups. We are unaware, however, of any studies of interethnic differences in BOLD activation or its relationship to cognition. Nonetheless, the novelty encoding activation task employed in our study, which was essentially nonlinguistic, is unlikely to be influenced by cultural or educational factors and therefore has promise as an endophenotype of utility across diverse ethnic groups.
In conclusion, we found that the AD risk–conferring APOE ϵ4 genotype was associated with increased BOLD signal during a novelty encoding task in multiple brain areas of asymptomatic persons, whereas no such increase was observable in presymptomatic persons carrying FAD mutations. A parsimonious explanation is that APOE ϵ4 exerts an effect on activation-related focal cerebral blood flow that is at least partly independent of AD risk and parenchymal AD pathology. Increases in BOLD signal seen in APOE ϵ4 carriers may not then be related to cognitive compensation or reserve but instead to an unidentified effect of the allelic variant on cerebral vascular reactivity.