We investigated the effect of APOE ε4 status on brain amyloid load (measured by CSF Aβ1–42 levels), neuronal injury (measured by CSF t-tau), and neurodegeneration (measured by atrophy on MRI) across the cognitive continuum. The major findings regarding the effect of APOE genotype on biomarkers were: (1) CSF Aβ1–42 is closely linked to APOE genotype, but is less strongly associated with cognitive impairment; (2) in contrast, MRI atrophy is closely linked with cognitive impairment, whereas its association with APOE ε4 is weaker; and (3) of all the biomarkers, MRI retains the strongest relationship with cognitive impairment in the later stages. The other main conclusion from this paper was support for a model where the biomarker for Aβ amyloid deposition (CSF Aβ1–42) is the earliest of the 3 biomarkers examined to become abnormal.
We regard imaging and CSF biomarkers as in vivo indicators of specific pathologies in AD. Low CSF Aβ1–42
is a marker of Aβ amyloid plaque load, and CSF Aβ1–42
levels correlate inversely with total Aβ load in the brain.5,31
In this study, we found that Aβ amyloid deposition was significantly greater among ε4 carriers within each clinical group, which is consistent with earlier CSF14,15,32
and PET amyloid imaging33
studies. Increased CSF t-tau is a marker of neuronal injury, which correlates well with neurofibrillary tangle (NFT) stage and NFT load.5,34
Our results indicate that t-tau does not significantly differ by APOE genotype among CN or AD, which is in agreement with a majority of CSF t-tau studies.14,32
Atrophy on structural MRI is a biomarker of neurodegeneration, and it too correlates with Braak NFT stage and quantitative NFT burden.35–40
However, the most proximate histological correlate of MRI volume loss is loss of synapses and neurons.7,41
Our finding of no association of neurodegeneration (as measured by MRI) and APOE genotype among CN or AD subjects is also consistent with some earlier MRI studies.18,19,42–44
Observed Relationships between APOE, Biomarkers, and Baseline Clinical Status
is low in APOE ε4 carriers in all clinical groups, and therefore our data support the hypothesis that the primary pathological effect of APOE ε4 is to increase Aβ amyloid plaque formation by any of several potential mechanisms, including reducing the efficiency of Aβ clearance.45
A plausible model of the development of AD posits that amyloid deposition occurs early in the process but by itself does not directly cause clinical symptoms.46–48
Impaired cognitive performance is largely driven by neurodegeneration, which may be mediated by tau pathology. Based on this evidence, it has been hypothesized that AD pathological cascade is a 2-stage process where amyloidosis and neuronal pathology (tauopathy, neuronal injury, and neurodegeneration) are largely sequential rather than simultaneous processes.47,49
Our data show that MRI correlates more closely with cognitive status than with APOE genotype. Also, there is some evidence that t-tau correlates better with cognitive status than with APOE genotype. Thus, whereas we see significant differences between the CSF Aβ1–42
levels of ε4 carriers and noncarriers in all clinical groups, t-tau and MRI values do not differ significantly between ε4 carriers and noncarriers among CN or AD subjects. In patients with clinically diagnosed AD, the influence of APOE genotype on cognitive decline appears most consistently present in milder patients, and less evident or absent when patients with more advanced cognitive decline are examined.50
This is not to say that APOE ε4 is unrelated to indicators of neuronal pathology. When all subjects are combined, APOE ε4 clearly increases the odds that any individual will be more impaired clinically, and have higher t-tau and a higher STAND score. APOE ε4 is not deterministic, in the sense that there are many ε4 carriers who are not demented and many ε4 noncarriers who are demented. In contrast, subjects with highly abnormal STAND values are almost invariably demented, and those with normal STAND are almost invariably cognitively normal regardless of APOE genotype.
There was evidence of lower median age in aMCI ε4 carriers when compared with ε4 noncarriers, which suggests that ε4 carriers might have slightly more cognitive reserve (brain reserve, ie, less age-related atrophy and brain resiliency) when compared with noncarriers. This possibly explains why STAND was worse in aMCI ε4 carriers when compared with ε4 noncarriers, that is, more atrophy in younger subjects brought them to the same cognitive level of less atrophy in older subjects. This along with evidence that MRI atrophy does not differ by APOE ε4 status in CN and AD subjects strengthens the argument that MRI as a marker of the actual stage of neurodegeneration is more closely related to the present clinical status.
Effect of APOE on the Biomarkers across the Alzheimer's Disease Continuum
EFFECT OF APOE ON CSF Aβ1–42
Age of clinical AD onset is lowered by 5 to 10 years in ε4 carriers relative to noncarriers.1,51,52
This is supported in our data by the fact that among both AD and aMCI subjects ε4 carriers are younger than noncarriers; that is, carriers reach the same clinical disease stage at a younger age. Our data show that CSF Aβ1–42
is lower in ε4 carrier CN subjects relative to noncarriers, and does not differ noticeably between AD/aMCI ε4 carriers and CN ε4 carriers. This can be interpreted to indicate that CSF Aβ1–42
has reached a nadir while APOE 4 carrier subjects are still cognitively normal, whereas Aβ1–42
falls progressively in ε4 noncarriers from CN to aMCI to AD.
The observed effect of APOE ε4 is to cause a plateau in the CSF Aβ1–42
levels early in the clinical disease progression, such that worsening MMSE is not accompanied by worsening CSF Aβ1–42
. In contrast, in ε4 noncarriers the relationship between CSF Aβ1–42
and MMSE remains roughly linear into lower levels of MMSE performance. Both these relationships can be observed in . We do acknowledge that the assumption here that APOE ε4 carriers who are currently cognitively normal had normal CSF Aβ1–42
at an earlier time in life cannot be proven by our data. However, a recent nonselected all-age autopsy series53
convincingly demonstrates that APOE ε4 does shift the onset of Aβ accumulation to an earlier age relative to noncarriers, with the greatest difference in the plaque load as a function of APOE genotype occurring in the 50-to 59-year age group.
EFFECT OF APOE ON CSF T-TAU
There was no cross-sectional difference in t-tau between aMCI and AD in ε4 carriers presumably with more advanced disease, but t-tau does differ between aMCI and AD in ε4 noncarriers (see ). These data can be interpreted to mean that t-tau increases may have plateaued by the aMCI stage in the more advanced ε4 aMCI carriers, but not in the less advanced ε4 noncarriers. This argument is strengthened by .
EFFECT OF APOE ON MRI ATROPHY
There were cross-sectional differences on MRI between aMCI and AD in both ε4 carriers and noncarriers (see ), and the variability in STAND scores is largely driven by cognitive status and less by APOE genotype (see ). These data can be interpreted to indicate that, unlike t-tau, brain atrophy does not plateau by the aMCI stage even in the more advanced ε4 carriers, and hence MRI retains its close relationship with clinical status later into the clinical disease progression than t-tau. The evidence for this can also be seen in , where the relationship between MMSE and STAND scores remains linear across the cognitive spectrum in both ε4 carriers and noncarriers.
TEMPORAL ORDERING OF BIOMARKERS
Although biomarker assessments were obtained only at baseline in this study, we found evidence for a temporally ordered sequencing of CSF Aβ1–42
, CSF t-tau, and MRI. The specific findings in this study support the comprehensive model of AD proposed earlier.47,54
The main observed effect of APOE genotype was to shift the entire AD biomarker cascade toward younger age, which results in an earlier onset of AD in ε4 carriers.
An important point is that the aMCI group is heterogeneous. Based on prior studies, some of these individuals simply have poor memory performance and will never progress to dementia, whereas others will go on to develop clinical AD. Some (particularly ε4 noncarriers) likely have substrates for cognitive impairment other than AD, for example, vascular disease or Lewy body disease. Many likely have a mixture of pathologies including but not confined to AD.55,56
There are some limitations to the study. First, the ADNI cohort is not a population-based cohort. The recruitment mechanisms were those used for clinical trials in AD, and included memory clinics, patient registries, public media campaigns, and other forms of public advertisements. Consequently inferences about the diagnostic sensitivity and specificity of biomarkers in the general population cannot be drawn from ADNI data. However, biologically based conclusions concerning the effect of APOE genotype on AD biomarkers are valid.