In this study, we examined the relationship of two sets of CSF profiles to three outcome measures: (i) rate of decline on a composite cognitive measure, (ii) rate of disease progression (based on change in CDR-SB scores), and (iii) risk of converting to AD dementia.
Within the four groups formed by cross-tabulating t-tau and Aβ42, we found that, compared to MCI patients with normal–t-tauAβ42, (i) those with either abnormal–Aβ42 or abnormal–t-tauAβ42 had a steeper rate of decline on the composite cognitive measure whereas those with abnormal–t-tau did not; (ii) those with abnormal–Aβ42 or abnormal–t-tauAβ42 experienced a significant worsening of disease whereas those with abnormal–t-tau did not; and (iii) those with abnormal–Aβ42 or abnormal–t-tauAβ42 were at increased risk of converting to AD dementia whereas those with abnormal–t-tau were not any more likely to convert to AD dementia. In summary, these analyses showed that MCI patients with abnormal Aβ42, whether t-tau was normal or not, had worse outcomes, whereas MCI patients with normal Aβ42, even when t-tau was abnormal, had comparatively better outcomes. Similar findings were made when the analyses were repeated within the four groups formed by p-tau181 and Aβ42.
Our manner of creating the CSF subgroups examined in this study is noteworthy. Recent studies have suggested that biomarker ratios may be more sensitive to incipient AD compared to absolute biomarker levels.3, 21
However, by virtue of being ratios, such measures obscure an important distinction between individuals who have “normal tau but abnormal Aβ42” and those who have “abnormal tau but normal Aβ42.” For instance, exploratory analyses in this study found that the abnormal–t-tau group (mean ± SD = .51 ± .09) and the abnormal–Aβ42 group (mean ± SD = .54 ± .23) did not differ on the t-tau/Aβ42 ratio (p= .789). Similarly, the abnormal–p-tau181 group (mean ± SD = .14 ± .04) did not differ from the abnormal–Aβ42 group (mean ± SD = .14 ± .07) on the p-tau181/Aβ42 ratio (p= .771). In contrast with the apparent similarity of these two classes of MCI patients (i.e., those with only abnormal tau and those with only abnormal Aβ42) on the biomarker ratios, our analyses showed that their prospective course and outcome are quite different.22
The overall finding from this study is that, of the two types of CSF abnormalities commonly observed in patients with MCI (i.e., increased t-tau or p-tau181 and decreased Aβ42), abnormally low Aβ42 appears to be the one most closely associated with cognitive decline, disease progression, and risk of converting to AD dementia. This is consistent with prior investigations that found that CSF Aβ42 concentrations are predictive of future conversion to AD dementia among MCI patients whereas tau concentrations are not.6, 19, 23
Because abnormally low CSF Aβ42 is presumed to be due to β-amyloid aggregation in the brain,24
our findings are in accord with the amyloid cascade hypothesis which, in brief, argues that deposition of β-amyloid in the brain is an early event in AD pathogenesis.25
However, we note that the tenets of the amyloid cascade hypothesis remain controversial.26
Indeed, there is some evidence that elevated CSF t-tau or p-tau, but not decreased Aβ42, predict progression from MCI to AD dementia.20
The reasons for these seemingly conflicting findings are not fully understood, and suggest the need for continued investigation of these important questions.2, 27
It is also important to note that although our findings suggest that Aβ42 abnormities are prominently associated with risk of progression to dementia, all models tested in this study consistently demonstrated that persons with combined tau and Aβ42 abnormalities had the worst outcomes.3
This study contributes to the ongoing attempts to identify subgroups of MCI subjects at increased risk of progressing to AD dementia3, 4
by demonstrating that MCI patients with abnormal Aβ42 have an elevated risk of cognitive decline and eventual conversion to AD dementia, even when tau is normal. The ability to detect incipient dementia in patients with MCI has obvious implications for clinical trials. One reason why MCI trials have experienced little success to date is the relatively slow disease progression among some study enrollees, which affects the ability of these trials to test key hypotheses. Enrolling MCI patients who are more likely to convert to AD dementia could shorten the time to attain the primary milestones, reduce the sample size needed for adequate power, and increase the ability to detect treatment effects.28
In addition, the finding that abnormal Aβ42 is comparatively more strongly associated with progressive decline and eventual conversion to AD is that the ability to abrogate the accumulation of Aβ peptides in the brain and/or restore Aβ42 levels in CSF might be a valid outcome for MCI drug trials, especially those in the phase II, proof-of-concept, stage.29
An important caveat is that, in this ADNI cohort, subjects with abnormal Aβ42 were also more likely to be APOE ε4 positive; and, there is some evidence that APOE ε4 carriers might have differential therapeutic response or higher risk of treatment-related toxicity.30
At the present time, no medications have been shown to delay the onset of dementia in patients with MCI.31
However, novel and promising AD therapeutics are currently being tested in clinical trials.2, 32
If these drugs prove therapeutic, there would be a viable role for biomarkers of incipient AD dementia in MCI patients as these drugs are presumably more effective if administered early in the disease process.2
Our findings would suggest that MCI patients with abnormal CSF Aβ42 might be ideal candidates for such therapies because of their comparatively elevated risk of transitioning to AD dementia. In general, because CSF biomarkers putatively reflect biochemical processes in the brain,5, 33
it is foreseeable that they could be used for matching patients to treatment approach (e.g., CSF Aβ42 levels may be used to assign patients to treatments that target β-amyloid plaques).33
A potential limitation of this study is the very small sample size of the group of MCI patients with abnormal–t-tau which resulted in an inability to reliably conduct some significance tests in this study. However, we note that the findings in the p-tau181—Aβ42 tetrad (where the distribution of the groups was relatively more proportional) closely mirrored the findings in the t-tau—Aβ42 models, thus, lending credibility to the observations made in the t-tau—Aβ42 groups. It would be of great interest to see whether this study's key finding—that abnormal Aβ42 is deleterious even when tau is normal—is replicable in other well-characterized and prospectively monitored cohorts of patients with amnestic MCI.