Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers

Abstract

Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.

Keywords: Alzheimer’s; FDG; MRI; amyloid; flortaucipir.

Figure 1

Visualization of pathology across the cohort. Spatial renderings in mutation non-carriers, asymptomatic mutation carriers, and symptomatic mutation carriers for amyloid-β deposition measured with PiB PET, glucose metabolism measured with FDG PET, neurofibrillary tau pathology measured with AV1451, and cortical thickness measured with MRI. PET values represent SUVRs relative to the cerebellar cortex and cortical thickness values are in millimetres. For convenience, data are shown for the inflated left hemisphere.

Figure 2

Biomarker values across the three groups. Box and whisker plots showing (A) precuneus PiB PET, (B) precuneus FDG PET, (C) tau PET in the precuneus, (D) tau PET in the inferior temporal lobe, (E) cortical thickness in the precuneus from MRI, and (F) scores on the cognitive composite for mutation non-carriers, asymptomatic mutation carriers, and symptomatic mutation carriers. Aβ = amyloid-β.

Figure 3

All regions where pathology was significantly different in symptomatic mutation carriers relative to non-carriers. The colour scale represents the difference between groups in the units of that measurement (SUVRs for PET, and mm for thickness). Data were for the averaged left and right regions of interest, but are presented here on the left hemisphere for visualization.

Figure 4

Scatter plots showing biomarker values as a function of disease severity. Biomarkers plotted by estimated years to symptom onset (EYO) for mutation non-carriers (green circles), asymptomatic carriers (orange triangles), and symptomatic carriers (red squares) for (A) precuneus PiB PET, (B) FDG PET, (C) cortical thickness from MRI, and (D) tau PET. The dashed line shows the model fit for mutation carriers and the solid line is for non-carriers. Aβ = amyloid-β.

Figure 5

Cross-modal relationships between biomarkers. The relationship between precuneus tau PET binding in the precuneus and (A) precuneus PiB binding, (B) precuneus FDG uptake, and (C) precuneus cortical thickness and the (D) cognitive composite for mutation non-carriers (green circles), asymptomatic carriers (orange triangles), and symptomatic carriers (red squares).

Figure 6

Comparison of tau PET binding in symptomatic mutation carriers (left) and older adults with sporadic Alzheimer’s disease (right) with cognitive impairment. Values represent SUVRs relative to the cerebellar cortex. AD = Alzheimer’s disease.

Figure 7

Tauopathy in the frontal lobe of a DIAN participant. N = neurofibrillary tangle; P = a neuritic plaque; arrows = neuropil threads. Phosphorylated tau (PHF1) immunohistochemistry. Scale bar = 50 mm.