This study examined the cerebral response during a metacognitive task, appraisal of the self on trait adjectives. We used this task in people at risk for AD because converging research has indicated that the regions normally responsive on this task 30–32
appear to overlap with brain regions affected by AD. Our analyses indicated differences in task-related activation associated with FH as well as regions where APOE and FH risk factors interacted. Parental FH of AD had the effect of diminishing the cerebral response in the ventral posterior cingulate and the left mesial temporal lobe. Although there were no main effects of APOE4, this risk factor interacted with FH in left dorsolateral prefrontal cortex, AMPFC, and retrosplenial posterior cingulate; plots indicated that e4 carriers who were −FH exhibited greater signal change to the task. The observed effects were not due to gray matter atrophy, nor global cognitive function.
The medial parietal cortex has been implicated in memory retrieval and recognition22, 41, 42
as well as metacognitive appraisals.19, 31, 32, 43–46
Several recent studies report medial parietal hypometabolism47
in individuals with Mild Cognitive Impairment (MCI), a diagnosis that confers considerable risk for developing AD. Longitudinal studies also indicate that posterior cingulate metabolism and regional blood flow discriminate between individuals with MCI who soon develop AD and those MCI patients who remain stable.49–51
Reiman and colleagues 4, 24
found that the medial parietal lobe including the posterior cingulate (PCC) and precuneus were hypometabolic for glucose in cognitively normal APOE4 carriers relative to noncarriers (the effect of FH was not tested in these earlier studies). The medial parietal findings observed in the present study during a cognitive challenge appear to be generally consistent with these prior results, and suggest that this region may be beginning to exhibit dysfunction in these asymptomatic middle-aged adults at risk for AD. As further evidence of this possibility, Ries et al studied amnestic MCI patients with the same paradigm reported here and with ratings of anosognosia. A significant positive correlation was found between insight and activation; MCI subjects who exhibit diminished insight for their cognitive impairment also exhibit diminished responses in the posterior cingulate and mesial frontal lobe.34
The data from Ries et al. and the present study suggest that risk factors for AD are influencing systems supporting metacognition, which may eventually become part of the symptom picture of AD.
Areas of the left MTL were also differentially active in −FH subjects on this task. In a young adult sample we have recently shown that this region of the hippocampus exhibits task-dependent functional connectivity with the anterior medial prefrontal cortex on this same task.30
The hippocampus and subiculum are densely connected to the medial frontal lobe 52, 53
in rhesus monkeys. Phillips et al21
include the hippocampus in the dorsal axis of an emotion appraisal model (also involving the dorsomedial and dorsolateral frontal lobe) that receives biasing self-relevant input from ventral structures including the amygdala, nucleus accumbens and ventral medial frontal lobe.17
Interestingly, amyloid burden in the mesial temporal lobe has been found to be related to the degree of anosognosia in patients with AD.54
The role of the hippocampus in affective and cognitive appraisal and how this might relate to the symptom picture of AD is not completely understood and deserving of much more study.
In this sample, APOE4 and FH interacted (), but there were no APOE4 main effects. The interaction was largely due to the finding that e4 positive, but FH negative subjects exhibited the greatest activation. An intriguing study by Mondadori et al55
points out several salutary affects of APOE4 on the brain in early life, and they present fMRI results with a memory encoding task indicating that young adult ε3/ε4 carriers exhibit hippocampal learning-related signal adaptation but young non-carriers do not. There is still much to learn about the effect of APOE4 across the lifespan, but in the context of the recent literature and the findings in the present report, it is likely that interactions are occurring between APOE4 and age and/or other AD risk factors which manifests as a putative salutary effect early in life, but a deleterious effect later in life.
The results in this report are consistent with a prior report of an episodic encoding task with most of these same subjects12
in which we found a robust effect of FH in the hippocampus and ventral temporal lobes during object encoding. In that prior report we also found that the −FH,+ ε4 group again exhibited the greatest cerebral response in the hippocampus, while +FH, +ε4 subjects had the least. A similar finding was observed when subjects possessing the ε2 allele were removed.15
It is noteworthy that at least two other recent studies have reported first-degree family history effects. In a behavioral experiment of odor identification it was found that siblings of AD patients exhibited reduced accuracy relative to controls. This effect was more pronounced in siblings who were APOE4 positive.56
With fMRI, Bassett et al7
examined first-degree family history and APOE in a large sample (n=195) and found FH affected brain activation during a paired-associate encoding task, whereas APOE did not.
There remains a fundamental issue regarding fMRI group differences in cognitively normal versus at-risk or cognitively impaired populations. Some studies have reported risk-associated 8, 57–59
and disease-associated 10, 60
increases in cerebral activity, while other studies report decreases in cerebral response with increased risk 12, 14, 55
or cognitive impairment.13, 61–63
Although there are many sources of noise and variability with fMRI, some possible reasons for these study differences may be: A) task difficulty. Increased difficulty has the effect of increasing fMRI activation;64, 65
B) choice of comparison condition from which BOLD signal change is measured. It has been shown that a resting low level baseline such as rest or cross hair fixation versus an active cognitively challenging baseline produce very different results;66, 67
; and/or C) choice of analysis methods and statistical model—for example spatially normalizing to a standard space versus native space,68
or counting of suprathreshold voxels within a region versus statistical parametric mapping.10
Given the variability across studies, researchers that develop fMRI tasks for use in clinical and at-risk populations should adopt a task-specific psychometric approach to measuring brain activation. Such an approach might include parametrically varying difficulty, comparison to normative data,55
and characterizing tasks across larger samples and across a range of demographic (e.g. age) and clinical parameters (e.g. genes, cognitive status61
In conclusion, these data suggest that first-degree family history of AD may influence brain function many years prior to typical disease onset. The genetic and environmental factors that embody family history are still largely unknown and further study is required. The results highlight the idea that factors beyond APOE contribute to AD and should be included when possible in studies of AD risk. Although memory dysfunction is a core feature of AD and is typically one of the first noticeable symptoms, these findings with a self-referential decision task suggest that brain areas underlying metacognitive functions may also show compromise in people at risk, and may correspond, in part, to the metacognitive deficits that are observed in symptomatic AD.