Tracking the origin of tau spread in the brain

Abstract

AbstractBackgroundAutopsy studies report that the locus coeruleus (LC) is the first site to accumulate tau, after which it spreads topographically to the entorhinal cortex (EC) and limbic regions. Once tau has reached the cortex, its spread is assumed to occur via connectivity and to be facilitated by Aβ. We aimed to examine whether lower LC integrity is related to tau accumulation in the EC, followed by spreading of tau to cingulate regions. In addition, we examined whether Aβ facilitates tau accumulation beyond these initial regions.MethodOne‐hundred‐and‐five individuals (Figure 1) from the Harvard Aging Brain Study underwent 3T‐MRI (including LC imaging),Aβ and tau‐PET imaging and neuropsychological assessments. Assessments up to 8 years prior to LC‐imaging were included (median:5.02 years). LC intensity (normalized to pontine tegmentum) was regressed onto each vertex of the cortical mantle of the PET data. Robust regressions and mediation analyses related LC intensity to tau, Aβ and cognition (composites and subtests). LME models examined interactions between LC intensity and Aβ on cognitive changes. Covariates were age, sex and education. Results were compared to LME models of tau spread via connectivity in a previously examined extended sample (n=252).ResultLC intensity was associated with medial and lateral temporal tau (peak:EC (t=4.69)). These associations became more widespread with increasing Aβ (Figure 2). This is consistent with results in the extended sample showing that spread from the EC to the posterior cingulate cortex via structural connections was greater in individuals with elevated Aβ (Figure 3). LC intensity was specifically positively associated with cross‐sectional memory (p=0.024) (Figure 4A‐B) and this was mediated by entorhinal tau (mediation: p=0.007, Figure 4C‐D). Finally, lower LC intensity predicted Aβ‐associated retrospective memory decline (Figure 5, p=0.0009). In the extended sample, lower connectivity and higher downstream‐connected tau accrual was associated with greater prospective memory decline in elevated Aβ persons (Figure 3).ConclusionLC intensity measures are associated with initial cortical Alzheimer’s disease (AD) pathology. Elevated Aβ facilitates tau spread to regions outside the medial temporal lobe and accelerates AD‐related cognitive decline. These results mimic autopsy findings of the anatomy of tau spreading and can advance early detection.