Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Abstract

Alzheimer’s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

Trajectory of clinical symptoms in relation to amyloid chronicity

“…This finding has support from the neuropathology literature 22 . Furthermore, in agreement with recent studies, we found that passing the threshold of amyloid positivity at an older age was associated with a shorter period before the emergence of cognitive symtpoms 7,10 . PET tau sample sizes for susceptibility groups were insufficient to detect differences in tau positivity between groups.…”

“…Amyloid positivity was defined as the average cortical PiB distribution volume ratio (DVR) > 1.19 using a global composite region of interest comprising bilateral anterior and posterior cingulate cortex, the precuneus, the angular gyrus, supramarginal gyrus, middle and superior temporal gyrus, and medial orbital gyrus. The DVR A+ cutpoint was derived with reference to a visual rating 16 and corresponds to 22 centiloids 7 …”

“…Last, amyloid chronicity was calculated as the age at CDR assessment minus estimated amyloid onset age 6 . GBTM‐based chronicity estimates were replicated recently using two additional methods 7 …”

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

“…These findings are in accordance with the known role for APOE ε4 in amyloid aggregation and clearance, and consistent with an earlier age of amyloid and AD dementia onset among APOE ε4 carriers. 3 , 34 , 35 Interestingly, prior studies on the relationship of APOE ε4 to amyloid change have been mixed. Some studies among cognitively normal individuals have reported increased rates of amyloid accumulation among APOE ε4 carriers, 36 , 37 , 38 whereas others have reported faster changes only among APOE ε4 carriers with low amyloid burden (Burnham et al.…”

“…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 3–5 . Furthermore, we explored interactions with sex, because prior studies have reported sex‐related differences in AD biomarkers 6–8 and clinical outcomes 9–12 .…”