# Estimated onset age of CSF amyloid and tau accumulation and relationship to clinical outcomes

## TL;DR

This study estimates when Alzheimer's disease biomarkers start accumulating in midlife and finds they precede symptoms by decades.

## Contribution

It identifies the estimated onset ages of CSF amyloid and tau accumulation and links them to later cognitive decline.

## Key findings

- CSF amyloid and tau biomarker accumulation begins in midlife, about 24 years before MCI symptoms.
- APOE-ε4 carriers show biomarker changes about 6 years earlier than non-carriers.
- Older estimated onset ages of biomarker accumulation correlate with faster progression to MCI symptoms.

## Abstract

Neuropathological studies indicate AD pathology is present in midlife. Few studies, however, have examined the onset of AD biomarker changes, simultaneously for amyloid and tau, starting in midlife. Using data from initially cognitively unimpaired, primarily middle‐aged participants, we evaluated: 1) the ‘change point’ that marks accelerated accumulation of CSF AB42/AB40 and p‐tau181 and estimated onset ages of biomarker accumulation (EABA); 2) factors impacting EABA variability, and 3) association of EABA with risk of progression to MCI clinical symptoms.

Analyses evaluated CSF AB42/AB40 and p‐tau181 (Fujirebio Lumipulse G1200 assays) in N = 384 cognitively unimpaired BIOCARD Study participants (M baseline age=58.4y, 58% female; M = 3.2 CSF measures collected over 8.6y). Biomarker ‘change points’ were identified (in the 62% with ≥2 CSF measures) and EABA calculated for AB42/AB40 and p‐tau181 using methods previously applied to amyloid PET (Schindler et al., 2021).

The mean EABA for AB42/AB40 was 49.3 years vs. 51.6 for p‐tau181; EABAs were ∼6y earlier for APOE‐e4 carriers vs. non‐carriers (Table 1, Figure 1). Participants with an EABA demonstrated steeper CSF biomarker changes over time, compared to participants without an EABA (Figure 2). In Cox regression models, APOE‐e4 carriers had a shorter time to EABA for both AB42/AB40 (HR=3.65, p <0.01) and p‐tau181 (HR=2.00, p <0.01). In Cox models including the subset of participants with EABAs, older EABAs (but not APOE‐e4, sex, or education) were associated with a shorter time to MCI symptom onset (AB40/AB40 HR=2.12, p <0.01; p‐tau181 HR=3.34, p <0.01); additionally, for AB40/AB40, the association of EABA with symptom onset accelerated (became increasingly shorter) at older EABAs (HR for EABA2=1.35, p <0.01). EABA preceded MCI symptom onset by 24 years, on average (SD=8‐11).

Results indicate that AD CSF biomarker changes begin in midlife, decades before MCI clinical symptom onset. They are consistent with the view that both amyloid and tau onset occurs earlier in APOE‐e4 carriers, with additional analyses needed to evaluate whether APOE‐e4‐related changes in p‐tau181 are due to APOE‐e4‐related AB42/AB40 changes. Lastly, the shorter time to symptom onset with older EABAs suggest that co‐pathologies (which are greater at older ages) may reduce the time from biomarker accumulation to symptom onset.