This study examined four principal classes of biomarkers for AD in normal middle-aged subjects, including reduced FDG-PET CMRglc, amyloid beta, and tau pathology and cellular oxidative damage and their associations in relationship to the ApoE genotype and the presence of SMC. The ApoE E4 allele is known to increase the risk for AD in cognitively normal individuals, possibly because of less effective neural protection and repair mechanisms as compared with the other allelic variants (1
). Subjective memory complaints are very common in the elderly, with prevalence estimates of 25% to 50%, and may represent preclinical signs of incipient dementia (35
), although their predictive value remains to be validated (35
). Our data show that the relationship between AD-related CSF and CMRglc measures differs in normal subjects as a function of the ApoE genotype and is further modulated by the presence of SMC.
There are no prior reports of an association between FDG-PET and CSF measures in normal subjects. Of the two published FDG-PET and CSF studies, one reported an association between reduced CMRglc and increased P-Tau levels in MCI (20
) and the other a relationship between CMRglc and CSF Aβ42 levels, but no relationship with T-Tau, in a group of patients with AD and other dementing disorders (19
). However, an [123
IMP) single photon emission computed tomography (SPECT) study by the same authors showed an association between cerebral perfusion and CSF T-Tau, which predicted decline from MCI to AD (37
Our E4 carriers showed significantly higher levels of CSF IP, P-Tau, T-Tau, and P-Tau/Aβ42 as compared with the noncarriers. The groups were comparable for clinical and demographic characteristics and showed a similar performance on neuropsychological testing. These findings are consistent with previous reports of significantly higher CSF IP levels in AD patients carrying the E4 allele as compared with noncarriers (13
). There are no previous studies of P-Tau and P-Tau/Aβ42 measures in E4 carriers.
Although CSF measures were not different between SMC groups, there was a significant interaction between ApoE and SMC status, which was driven by the E4 carriers with SMC who had significantly higher IP, P-Tau, and P-Tau/Aβ42 as compared with the noncarriers. Previous studies showed that CSF IP and P-Tau are increased in AD and MCI patients (38
), and P-Tau181
/Aβ42 measures increase in nondemented adults prior to developing dementia (16
). Our study shows that P-Tau231
/Aβ42 measures are significantly higher in NL E4 carriers and even more in those with SMC. Among different possible P-Tau epitopes, P-Tau231
levels are thought to be specific for AD (12
). Although oxidative stress is common in most neurodegenerative diseases, there is also evidence that IP levels distinguish AD from other dementias (44
No differences were found for CSF Aβ40 and Aβ42 between ApoE and SMC groups. A previous study showed that Aβ42 levels are decreased in NL elderly E4 carriers as compared with noncarriers in an E4 allele dose-dependent fashion (17
). Although limited by the small number of subjects, we also found progressively reduced Aβ42 levels: noncarriers (1305 ± 504 pg/mL) > E4 heterozygotes (1191 ± 450 pg/mL) > E4 homozygotes (883 ± 272 pg/mL). The 40 amino acid form of β-amyloid (Aβ40) showed a similar trend. Since Aβ effects were reported in normal E4 carriers (17
), MCI, and AD (46
), the present lack of group differences may depend on the small sample size. Alternatively, P-Tau and IP levels were significantly different between groups, suggesting that alterations in these biomarkers may be detectable in the CSF of normal E4 carriers prior to Aβ changes. Longitudinal examination of our study subjects as well as other studies with larger samples are needed to replicate these findings and to address questions related to potential pathophysiological models of AD (49
Our E4 carriers showed CMRglc reductions in the parieto-temporal, occipital, and frontal cortices; fusiform gyrus; and thalamus as compared with the noncarriers. These results are consistent with previous FDG-PET studies showing that CMRglc abnormalities in middle-aged and young normal E4 carriers involve brain regions typically affected in AD (e.g., parieto-temporal cortices) and also extend to other regions that decline metabolically with aging, like the frontal and occipital regions and thalamus (3
). Although the functional significance of progressive CMRglc reductions in aging-related regions remains to be established, they may reflect an interaction between the E4 allele and aging rather than a static trait (3
). On the other hand, we did not find CMRglc deficits in the posterior cingulate cortex (PCC) of our E4 carriers, which was found in some FDG-PET ApoE studies (3
) but not in others (6
). Since PCC hypometabolism appears to be an early sign of AD (7
), possibly associated with the onset of episodic memory deficits (10
), it remains to be established whether our subjects will also develop PCC CMRglc abnormalities.
Subjects with SMC showed hypometabolism in the PHG, parieto-temporal, and frontal cortices as compared with subjects without SMC. There are no previous FDG-PET studies directly comparing NL subjects with and without SMC. Our data are in agreement with MRI studies showing that SMC in subjects without cognitive impairment is associated with greater medial temporal lobes (MTL) atrophy, including the PHG, and neocortical regions (50
). Parahippocampal gyrus CMRglc abnormalities in subjects with SMC may have an impact on subjects’ awareness of memory decline.
Moreover, CMRglc reductions in the E4 carriers with SMC were exacerbated in the PHG and its functionally associated temporal and occipital regions and thalamus (52
). The PHG region mainly included the entorhinal cortex, an MTL key brain region for memory (53
). The E4 carriers with SMC had three to four times greater risk of having reduced PHG CMRglc and increased IP and P-Tau/Aβ42 levels as compared with all other subgroups. These findings suggest that the E4 genotype and the presence of SMC may confer risk for cognitive impairment in an incremental fashion, as reflected not only in more severe and extended CMRglc reductions but also elevated CSF markers for AD pathology.
Amyloid and neurofibrillary tangles (NFT) PET imaging (54
) may provide more regionally specific information about the underlying distribution of AD pathology. Nonetheless, the association between PHG hypometabolism and increased CSF IP and P-Tau is consistent with the expected effects of progressive AD pathology resulting in MTL NFT, neuronal loss, and volume reductions (56
). Consistently with our findings, MTL CMRglc and perfusion were shown to correlate with regional densities of NFT but not senile plaques (59
Our determination of SMC is vulnerable to error. There are no established criteria for SMC, SMC do not presently constitute a universally accepted clinical entity, and the association between SMC and AD remains to be established (35
). To reduce potential for misclassification, all our subjects were carefully screened for conditions potentially related to reporting memory complaints, such as depression, and uniform structured procedures were used in all clinical exams. Nonetheless, our SMC cohort may have included subjects with a tendency to underestimate their level of cognitive functioning, and some of the subjects without SMC may be denying perceived deficits. In either case, this would lead to erroneous distribution of subjects across groups, with the effect of conservatively reducing group differences. Our results suggest that individuals with SMC possess some insight into their level of functioning, which may be related to CMRglc changes in memory-related brain regions.
The E4 genotype is also a risk factor for vascular disease (61
). None of the subjects in the present study had significant cerebrovascular disease or showed evidence for cortical or lacunar infarcts or extensive white matter disease. It is unlikely that small vessel disease, which usually is a subcortical phenomenon, may have impacted the FDG-PET results.
The present cross-sectional results need to be replicated with larger samples and longitudinal follow-ups to assess whether the CMRglc and CSF abnormalities are predictive of cognitive decline.