Longitudinal change in ATN biomarkers in cognitively normal individuals

Biomarkers for amyloid, tau, and neurodegeneration (ATN) have predictive value for clinical progression, but it is not clear how individuals move through these stages. We examined changes in ATN profiles over time, and investigated determinants of change in A status, in a sample of cognitively normal individuals presenting with subjective cognitive decline (SCD).

We included 92 individuals with SCD from the SCIENCe project with [¹⁸F]florbetapir PET (A) available at two time points (65 ± 8y, 42% female, MMSE 29 ± 1, follow-up 2.5 ± 0.7y). We additionally used [¹⁸F]flortaucipir PET for T and medial temporal atrophy score on MRI for N. Thirty-nine individuals had complete biomarker data at baseline and follow-up, enabling the construction of ATN profiles at two time points. All underwent extensive neuropsychological assessments (follow-up time 4.9 ± 2.8y, median number of visits n = 4). We investigated changes in biomarker status and ATN profiles over time. We assessed which factors predisposed for a change from A- to A+ using logistic regression. We additionally used linear mixed models to assess change from A- to A+, compared to the group that remained A- at follow-up, as predictor for cognitive decline.

At baseline, 62% had normal AD biomarkers (A-T-N- n = 24), 5% had non-AD pathologic change (A-T-N+ n = 2,) and 33% fell within the Alzheimer's continuum (A+T-N- n = 9, A+T+N- n = 3, A+T+N+ n = 1). Seventeen subjects (44%) changed to another ATN profile over time. Only 6/17 followed the Alzheimer's disease sequence of A → T → N, while 11/17 followed a different order (e.g., reverted back to negative biomarker status). APOE ε4 carriership inferred an increased risk of changing from A- to A+ (OR 5.2 (95% CI 1.2-22.8)). Individuals who changed from A- to A+, showed subtly steeper decline on Stroop I (β - 0.03 (SE 0.01)) and Stroop III (- 0.03 (0.01)), compared to individuals who remained A-.

We observed considerable variability in the order of ATN biomarkers becoming abnormal. Individuals who became A+ at follow-up showed subtle decline on tests for attention and executive functioning, confirming clinical relevance of amyloid positivity.