PET tau imaging in BLSA and GESTALT as an Early Marker of Alzheimer's Disease

National Institute On Aging

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Abstract

PET imaging with the Tau radioligand AV-1451 was introduced into the BLSA study in 2016. In combination with PET amyloid imaging and MRI measures, these studies will provide information on the preclinical stages of Alzheimer's Disease. Through March, 2020, more than 110 BLSA participants had at least one PET Tau scan, and of these, more than half had 2 or more scans. Due to COVID-19, PET imaging was suspended through May 2021 but has resumed at a reduced rate due to the diminished numbers of BLSA participant visits in the parent BLSA study and the continuing COVID19 pandemic. Several manuscripts have been published over the last year. One manuscript reported the absence of associations between vascular risk scores and amyloid or tau burden measured by PET in 87 cognitively normal individuals with median age of 77 years (Bilgel et al., 2021). As expected, amyloid positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG), and 10-year cardiovascular risk was positively correlated with white matter lesion burden, providing a validation of the measures used. Despite these predicted relationships, our data suggest that concurrently assessed vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia. In a second recently published manuscript (Bilgel et al, 2022), we conducted causal mediation analyses to investigate the relative contributions of amyloid-beta and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: our sample from the Baltimore Longitudinal Study of Aging (N = 103, age range 57-96) and the Alzheimer's Disease Neuroimaging Initiative (N = 122, age range 56-92). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid-beta moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology. In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau. Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, suggesting tau is the primary driver of neurodegeneration. Our findings suggest targeting amyloid or medial temporal lobe tau might slow neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes. In collaboration with Antonio Terracciano, we extended our investigation of the relationship between personality dimensions and AD. In previous studies, we had found that higher scores on Neuroticism and lower scores on Conscientiousness were associated with greater risk for AD, even when personality was measured many years earlier. More recently (Terracciano et al., 2022), we investigated the association between Neuroticism and Conscientiousness and AD biomarkers of amyloid and tau. Among cognitively normal BLSA participants, Higher Neuroticism was associated with higher cortical amyloid burden measured by PET (odds ratio 1.68, 95% CI 1.20-2.34), and higher Conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% CI 0.44-0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE 4. Similar associations were found with tau in the entorhinal cortex. These associations were confirmed in meta-analyses of 12 studies for amyloid deposition and 8 studies for tau. The associations in the meta-analysis were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and AD pathologies are not phenomena that emerge with neuropsychiatric clinical symptoms. These findings suggest that low Neuroticism and high Consciousness may contribute to resistance against amyloid and tau neuropathology. In addition to the study of PET biomarkers, we are investigating plasma biomarkers of AD pathology and neurodegeneration in the sample of individuals who have underg2one PET amyloid and tau studies. These assays have been performed in the laboratories of our collaborators, Dr. Abhay Moghekar at Johns Hopkins, and Drs. Drs. Zetterberg, Blennow and Ashton at Gothenburg University, and analyses are ongoing.