Abstract
BackgroundModels of Alzheimer’s disease (AD) pathophysiology posit that amyloidosis [A] precedes and accelerates tau pathology [T] that leads to neurodegeneration [N]. Besides this A-T-N sequence, other biomarker sequences are possible. This current work investigates and compares the longitudinal trajectories of Alzheimer’s ATN biomarker profiles in non-demented elderly adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodsBased on the ATN classification system, 262 individuals were identified before dementia diagnosis and accompanied by baseline and follow-up data of ATN biomarkers (CSF Aβ42, p-tau, and FDG-PET). We recorded the conversion processes in ATN biomarkers during follow-up, then analyzed the possible longitudinal trajectories and estimated the conversion rate and temporal evolution of biomarker changes. To evaluate how biomarkers changed over time, we used linear mixed-effects models.ResultsDuring a 6–120-month follow-up period, there were four patterns of longitudinal changes in Alzheimer’s ATN biomarker profiles, from all negative to positive through the course of the disease. The most common pattern is that A pathology biomarker first emerges. As well as the classical A-T-N sequence, other “A-first,” “T-first,” and “N-first” biomarker pathways were found. The N-A-T sequence had the fastest rate of pathological progression (mean 65.00 months), followed by A-T-N (mean 67.07 months), T-A-N (mean 68.85 months), and A-N-T sequences (mean 98.14 months).ConclusionsOur current work presents a comprehensive analysis of longitudinal trajectories of Alzheimer’s ATN biomarkers in non-demented elderly adults. Stratifying disease into subtypes depending on the temporal evolution of biomarkers will benefit the early recognition and treatment.
Highlights
Models of Alzheimer’s disease (AD) pathophysiology posit that amyloidosis [A] precedes and accelerates tau pathology [T] that leads to neurodegeneration [N]
Models of AD pathophysiology theorize a temporal sequence in which amyloidosis [A] initiates a biological cascade, followed by pathologic tau aggregation [T] that leads to neurodegeneration [N] [7, 8]
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) was established to test whether serial MRI, Positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early AD
Summary
Models of Alzheimer’s disease (AD) pathophysiology posit that amyloidosis [A] precedes and accelerates tau pathology [T] that leads to neurodegeneration [N] Besides this A-T-N sequence, other biomarker sequences are possible. The length of the preclinical phase has encouraged efforts to identify in vivo biomarkers to aid disease diagnosis and prognosis [3] During this period, biomarkers derived from biofluids and brain imaging vary in continuous pathological processes that begin before the onset of symptoms [1, 4, 5]. Models of AD pathophysiology theorize a temporal sequence in which amyloidosis [A] initiates a biological cascade, followed by pathologic tau aggregation [T] that leads to neurodegeneration [N] [7, 8] Besides this classic A-T-N sequence, other biomarker sequences are possible [6]. A current challenge in AD research is to identify the sequence of pathologic changes that occurs during the preclinical stages of disease by in vivo longitudinal study [9]
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