Abstract
BackgroundNeuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.MethodsFourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2–3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2–4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.ResultsLongitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.ConclusionsOur results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.
Highlights
Neuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset
We previously reported that abnormally elevated medial temporal lobe (MTL) tau positron emission tomography (PET) was evident in Presenilin -1 (PSEN1) E280A carriers relative to non-carriers from the Colombian kindred as early as 6 years prior to expected onset of mild cognitive impairment (MCI), and the overall spatial pattern of tau PET in ADAD was similar to that seen in sporadic AD [18]
One of the youngest carriers in our sample (15–20 expected years to onset (EYO)) showed baseline Aβ burden comparable to non-carriers (1.09 neocortical distribution volume ratio (DVR), ~ 2 CL), but accumulated neocortical Aβ over 4 years at a faster rate compared to non-carriers (0.04 DVR/year ~ 2.7 CL/year; 3.5%/year), consistent with previous work suggesting that neocortical Aβ increases beginning more than a decade prior to symptom onset in carriers
Summary
Neuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. We previously reported that abnormally elevated MTL (entorhinal cortex, EC) tau PET was evident in PSEN1 E280A carriers relative to non-carriers from the Colombian kindred as early as 6 years prior to expected onset of mild cognitive impairment (MCI), and the overall spatial pattern of tau PET in ADAD was similar to that seen in sporadic AD [18]. Another ADAD study found that tau PET was elevated only among impaired individuals, and suggested that MTL tauopathy including EC may be less involved in ADAD compared to sporadic AD [19]
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