The major findings of this study are: 1) an abnormally low baseline CSF Aβ level, suggestive of underlying Alzheimer’s pathology, predicted 1-year change in hippocampal volumes in all groups; 2) APOE4 carriers demonstrate greater hippocampal volume loss only in the NC and MCI groups; 3) APOE4 and low CSF Aβ are synergistic risk factors, such that APOE4 carrier status amplifies the predicted 1-year volume loss beyond that predicted by a low CSF Aβ alone.
The finding that an abnormally low CSF Aβ predicted 1-year hippocampal volume loss is consistent with the predominantly cross-sectional literature, which describes an association between amyloid pathology and hippocampal atrophy [1
]. Some have postulated that the large extracellular amyloid plaques disrupt cortico-hippocampal pathways, leading to neurodegeneration [2
]. Another hypothesis is that insoluble plaques detected in cerebrospinal fluid are an indirect marker of soluble Aβ oligomers, which may be the inciting agent in Alzheimer’s disease, by disrupting hippocampal synapses and promoting volume loss [34
The second finding that APOE4 is associated with greater longitudinal hippocampal volume loss in the NC and MCI groups is also compatible with prior literature. Numerous studies suggest that APOE4 carriers demonstrate increased vulnerability to developing AD, which is manifested through neurodegeneration [36
]. A reason for the lack of increase volume loss among APOE4 carriers in the AD group may be that, although APOE4 carriers develop AD at an earlier age [13
], once the disease is clinically apparent in an individual, APOE4 no longer alters the course of the disease. The lack of a significant difference in hippocampal volumes among APOE4 carriers and noncarriers with AD has also been reported in prior studies [40
Finally, the finding that the presence of a genetic risk factor, APOE4, amplifies the association between CSF Aβ and progressive hippocampal volume loss in MCI is novel. One possible explanation for this is that the APOE4 carriers with low CSF Aβ are more likely to have Alzheimer’s pathology. Although an abnormally low CSF Aβ is highly sensitive for detecting brain amyloid associated with AD, it is not an entirely specific for AD [28
]. Some of the participants with low CSF Aβ may have frontotemporal dementia and would not demonstrate the same degree of hippocampus-specific volume loss as prodromal Alzheimer’s patients [42
]. However, this argument would also be true among NC subjects, in which no interaction was demonstrated.
A second explanation for the APOE4-CSF Aβ interaction in MCI could be explained by a temporal progression of pathological mechanisms resulting from the APOE4 genotype. Early on when subjects demonstrate normal cognition, the predominant effect of APOE4 appears to be to increase brain amyloid deposition, as reported by numerous prior studies [15
]. Since, both APOE4 carrier status and a low CSF Aβ, as defined by our cutoff value, reflect greater brain amyloid, no interaction is seen in our NC group. However, once cognitive impairment is evident clinically, as in the MCI group, the effects of Aβ and APOE4 on pathogenesis of Alzheimer’s disease may diverge, thus resulting in disproportionately greater volume loss in those with both risk factors. Indeed, APOE4 has been found to be associated with an inability to repair synaptic damage, more rapid promotion of other neurotoxic species, such as tau, susceptibility to oxidative stress, and promotion of inflammatory cascades [17
], beyond simply increasing levels of brain amyloid. Further work examining this interaction is warranted.
A third possible explanation is that both APOE4 and a low CSF Aβ are markers of disease progression. According to the literature, only 10-15% of individuals with MCI will convert to AD each year [43
]. The other 85-95% of stable MCI individuals may be more likely have higher levels of CSF Aβ and be APOE4-negative, thus resulting in slower hippocampal volume loss.
Several study limitations deserve mention. First, the ADNI was designed to mimic a trial population, so participants were more educated, more Caucasian, and had fewer comorbidities than a community-based cohort [22
]. The generalizability of our conclusions is thus controversial, and the length of follow-up was short. Second, this was a secondary analysis of the cohort, so there were different proportions of APOE4 carriers individuals at each clinical stage. Overall, the NC and AD groups had about half the number of participants as the MCI group, resulting in reduced power to detect differences. Rather than take a sample with balanced proportions, we wanted to include all available data. Furthermore, an allelic dose-dependent effect of APOE4 could not be explored, since only two NC were homozygous for APOE4, and the MCI and AD had imbalanced proportions of heterozygotes and homozygotes. Third, we only included hippocampal volumes as a marker of structural change to limit the number of comparisons. Inclusion of other limbic or whole brain markers would potentially detect more APOE4 effects not described in our analysis. Further prospective studies are needed to validate our findings.
In summary, we demonstrated that baseline CSF levels of Aβ are predictive of near-term hippocampal volume loss. The strengths of this study include the recruitment of participant from multiple centers, longitudinal follow-up, and consideration of all 3 clinical stages. We further raised the possibility of an APOE4-CSF Aβ interaction on longitudinal hippocampal atrophy among MCI participants. As interest grows in using hippocampal atrophy as an outcome in clinical trials, it will be important to consider how varying risk factors and biomarkers interact and influence the progression of neurodegeneration.