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Longitudinal CSF Alzheimer's disease biomarker changes from middle age to late adulthood

Abstract Introduction We examined longitudinal cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker changes among cognitively normal individuals with 10.7 years follow‐up, on average. Methods Analyses included 278 participants (M age = 57.5 years); 94 have progressed from normal cognition to mild cognitive impairment (MCI). Amyloid beta (Aβ)42/Aβ40, phosphorylated tau181 (p‐tau181), and total tau (t‐tau) were measured using automated electrochemiluminescence assays. Results Apolipoprotein E (APOE) ε4 carriers had lower baseline Aβ42/Aβ40, but longitudinal Aβ42/Aβ40 decreases did not differ by APOE ε4 after accounting for Aβ42/Aβ40 positivity. Lower baseline Aβ42/Aβ40 was associated with greater increases in tau (more strongly in males), and APOE ε4 genotype was associated with greater tau increases after reaching Aβ42/Aβ40 positivity. Participants who progressed to MCI had more abnormal biomarker levels and greater tau increases prior to MCI symptom onset. Biomarkers were more abnormal among older adults, but unrelated to sex or education. Discussion Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations.

This study's aim was to characterize longitudinal AD biomarker trajectories spanning an average of 10.7 years (max = 23 years) in 278 cognitively normal, primarily middle-aged individuals (M baseline age = 57.5 years). AD biomarkers were measured by cerebrospinal fluid (CSF) amyloid beta (Aβ) 42 /Aβ 40 , phosphorylated tau 181 (p-tau 181 ), and total tau (t-tau). We examined the impact of demographics (age, sex, education) and apolipoprotein E (APOE) ε4 genotype on biomarker trajectories. We also examined associations among the biomarker measures, and tested the hypothesis that APOE ε4-related differences in biomarker trajectories are due to differences in amyloid positivity between APOE ε4 carriers and non-carriers, given APOE ε4 carriers accumulate amyloid earlier than non-carriers. [3][4][5] Furthermore, we explored interactions with sex, because prior studies have reported sex-related differences in AD biomarkers [6][7][8] and clinical outcomes. [9][10][11][12] Finally, given the sizeable number of individuals who progressed to mild cognitive impairment (MCI) or dementia (n = 94) during followup, we examined whether CSF biomarker trajectories differed with respect to clinical outcomes. The focus on middle-aged individuals is particularly important because AD pathology begins to develop in midlife, 5,13 and abnormal midlife levels of CSF amyloid and tau are associated with poorer cognitive outcomes. 11,14,15

Study design and participant selection
Data were derived from the BIOCARD study, which was designed to identify variables among cognitively normal individuals that predict subsequent development of cognitive decline and dementia. As described previously, 16

Statistical analyses
Group differences in descriptive statistics were compared using t tests or chi-square tests, as appropriate. Rates of change in the CSF biomarkers over time were analyzed with li mixed effects models that included random intercepts and slopes with unstructured covariance. CSF measures were standardized (z-scored) separately for CSF collected at NIH versus JHU using the first available measure at each site, so that model coefficients reflected z-scores while simultaneously accounting for potential differences due to collection site. Time was modeled in the unit of years (since baseline).
The primary analyses evaluated the relationship of demographics and APOE ε4 genotype to levels and rates of change in CSF biomarkers. Model predictors included: baseline age (centered), sex, years of education (centered), APOE ε4 genotype, time, the interaction (cross-product) of each predictor with time, and time 2 for evaluating non-linear (quadratic) trajectories. Models also included a "collection site" indicator, reflecting the location of CSF collection (NIH vs. JHU) to control for potential systematic site differences. To examine the robustness of our primary findings, models using chronological age (in years) as the timescale are also presented (excluding terms for baseline age).
The first set of follow-up models evaluated associations between (1a) baseline tau biomarkers (p-tau 181 or t-tau) and change in Analyses were run in Stata (v17.0). Estimates and 95% confidence intervals are reported with p-values ≤0.05 considered significant.

CSF biomarker changes and impact of demographics, APOE ε4 genotype
In the primary analyses (Table 2, Figure 1 were similar, except that the quadratic effect of time (i.e., age 2 ) was TA B L E 1 Baseline characteristics for participants included in the analyses, for the full sample and stratified by follow-up diagnosis 2)* * p < 0.05 and ** p < 0.001 for significant differences between remain normal versus progress to MCI/dementia. Of the 94 participants who progressed from normal cognition to MCI/dementia, n = 86 and n = 8 had a diagnosis of MCI and dementia, respectively, at their last (i.e., most recent) visit. Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; p-tau, phosphorylated tau; SD, standard deviation; t-tau, total tau. significant for Aβ 42 /Aβ 40 (p = 0.006; Table 2). Similar effects were found for the tau/(Aβ 42 /Aβ 40 ) ratios (Text S3), and in models excluding extreme participant age groups (i.e., <40 and >85 years; Text S4 in supporting information).

Associations between CSF biomarkers
For the models that examined baseline levels of p-tau 181 or t-tau in relationship to change in Aβ 42 /Aβ 40 , there were main effects of tau but no tau x time interactions (Table 3)

CSF biomarker changes and follow-up diagnosis
There were significant main effects of follow-up diagnosis for  (Table 4; Figure 2). Further exploratory analyses examining CSF biomarker change before versus after MCI symptom onset indicated greater increases in tau prior to MCI clinical symptom onset, compared to those who remained cognitively normal (Text S6).

CSF biomarker changes: interactions among sex and age, APOE, and baseline biomarker levels
There were no significant interactions between sex and age or APOE ε4 genotype with respect to change in Aβ 42 /Aβ 40 , p-tau 181 , or t-tau over time (all p > 0.11; data not shown).  Note: Different models were estimated for each CSF measure. Models were also adjusted for all variables indicated in Table 2.
Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; CI, confidence interval; CSF, cerebrospinal fluid; p-tau, phosphorylated tau; t-tau, total tau.  Note: Different models were estimated for each CSF measure. Models were also adjusted for all variables indicated in Table 2.

F I G U R E 2
Abbreviations: Aβ, amyloid beta; APOE, apolipoprotein E; CI, confidence interval; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; p-tau, phosphorylated tau; t-tau, total tau. In contrast, the rate of change in CSF Aβ 42 /Aβ 40 did not differ between those who remained normal versus progressed to MCI/dementia. Given there were baseline differences between these groups, it is likely that the greatest Aβ 42 /Aβ 40 change occurred prior to the observation period (particularly for individuals who progressed to MCI more proximally to baseline), which in turn initiated increases in tau prior to symptom onset. For example, it has been suggested that CSF Aβ 42 plateaus at least 9 years before dementia onset, 29 with studies in ADAD reporting similar CSF Aβ 42 plateaus relative to the estimated age of symptom onset. 30 3 they may also be more likely to show amyloid-related increases in tau during the observation period. Consistent with this, a prior study estimated that the effect of APOE ε4 genotype on neurofibrillary tangle pathology is mainly mediated by amyloid pathology. 43 However, APOE ε4 genotype was associated with changes in p-tau 181 and t-tau independent of baseline Aβ 42 /Aβ 40 levels (Table 3), which may suggest some amyloid-independent effects of APOE ε4 on tau accumulation. 44 To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up. These findings advance our understanding of early AD-related biomarker changes by further highlighting the important role of amyloid in the acceleration of tau, as well as the importance of studying longitudinal AD biomarker changes during middle age. Dr. Albert is an advisor to Eli Lilly. Dr. Moghekar receives research support to JHU (but no direct or indirect salary support) from Fujirebio Diagnostics to analyze CSF preanalytics.