As disease-modifying therapies for AD are being developed, there is great need to identify biomarkers that will serve as surrogates of underlying disease pathology. In the eventual clinical setting, such biomarkers might be used to improve the accuracy of clinical diagnosis and to track disease progression. As an immediate application, biomarkers may be useful in the design and evaluation of clinical trials; for example, to assess the effect of a therapy on its intended target in early phase studies, to optimize patient enrollment in prevention trials (to increase homogeneity, decrease sample size and shorten trial duration), and to track disease progression (by providing quantifiable, pathology-related endpoints). Results of the present study suggest that alterations in Aβ42 metabolism, likely reflecting Aβ aggregation in the brain, are associated with brain atrophy in the “preclinical” phase of AD (as well as the very early CDR 0.5 stage), whereas alterations in tau and ptau181 are later events in the disease that correlate with further structural damage and occur with clinical (i.e., dementia) progression. Thus, CSF Aβ42 may be considered a useful biomarker for the presence of amyloid plaques regardless of clinical status, whereas CSF tau measures may have more utility in tracking disease progression once clinical symptoms and signs have appeared.
The correlations we observed between levels of CSF tau (and ptau181), but not Aβ42, and whole brain volume in DAT are consistent with histopathologic findings of associations between atrophy measures and NFT burden or Braak NFT stage35-38
but not Aβ plaque load.37, 38
In addition, studies suggest that by the time individuals become cognitively impaired due to AD, cortical amyloid deposition is close to reaching its maximal extent.39, 40
A recent antemortem study reported a positive correlation between whole brain atrophy and cortical amyloid as detected by PET PIB in a small number of demented subjects (n=9);41
however, evaluation of the robustness of this finding awaits further study in larger subject groups. Previous results regarding the relationship between CSF measures and atrophy in DAT (or MCI) have been mixed,42-47
likely due to the small number of subjects evaluated and the differences in subject characteristics and methodologies between the studies.
To our knowledge, only one study has investigated the relationship between CSF and volumetric measures in non-demented controls, and no associations between any CSF marker and hippocampal atrophy were found in that very small cohort (n=9)42
, consistent with our hippocampal analyses. It is possible that many of the CDR 0 subjects who have brain amyloid and low CSF Aβ42 still have many years before they convert to dementia . During this period, lasting possibly a decade or more, amyloid is depositing in several brain regions, including cortical regions that have recently been shown to exhibit thinning during this presymptomatic stage.48
The hippocampus proper is not a region with prominent early amyloid deposition so hippocampal volume may not be expected to strongly correlate with CSF Aβ42 in the presymptomatic stage, even though volume may be reduced in this stage. Reduction in hippocampal volume in the presymptomatic stage may relate to processes taking place in addition to amyloid deposition, especially tangle formation. Consistent with this hypothesis, we did observe a non-significant trend for an association between hippocampal volume and CSF tau (p=0.1030) in non-demented controls.
The present study is the first to characterize the relationship between CSF and volumetric measures in a large cohort (n=69) of well-characterized, cognitively normal controls. The positive correlation we observe between CSF Aβ42 and whole brain volume in this cohort may reflect the death of neurons in the preclinical stage of AD. However, cell death is not a fundamental feature of preclinical AD, 1, 49
and the lack of relationship between CSF Aβ40 and brain volume also argues against this hypothesis. Alternatively, because individuals with brain amyloid, as detected by PET PIB, have low levels of CSF Aβ42, 12, 34
the association between low CSF Aβ42 and small brain volume in this non-demented cohort may reflect underlying Aβ aggregation and deposition and consequent and/or concomitant axonal and synaptic degeneration leading to measurable atrophy in the preclinical phase. Reductions in CSF Aβ42 reflect the presence of amyloid plaques but perhaps also diffuse (non-fibrillar) plaques and/or concomitant Aβ oligomer formation, both of which could contribute to neurotoxicity (neuritic and/or cellular) and consequent volume loss, but would not be visualized with PET PIB. In support of this hypothesis, we have recently observed low CSF Aβ42 in the absence of cortical PIB binding in a subject later found to exhibit an abundance of diffuse, but not neuritic, plaques at autopsy two years after LP and PIB testing (N. Cairns, A. Fagan, M. Mintun, D. Holtzman, J. Morris, unpublished observations). Since the present data demonstrate that CSF Aβ42 and tau measures correlate with meaningful structural change in the preclinical and clinical stages of AD, respectively, and that the CSF tau/Aβ42 ratio predicts future cognitive decline in cognitively normal elders 34, 50
and individuals with MCI,51
we propose that CSF Aβ42, either alone or in combination with tau measures, may be especially useful for the selection of presymptomatic individuals with known preclinical AD pathology for enrollment in prevention
trials of disease-modifying therapies. As robust changes in CSF tau (and ptau) and further volumetric loss appear to occur later in the disease process, these biomarkers may be useful for evaluating the effects of a given treatment on disease progression.