Plasma ptau231 predicts locus coeruleus integrity earlier in life than other Alzheimer’s disease plasma markers: a 7T MRI study across the adult lifespan

Abstract

AbstractBackgroundAutopsy studies indicated that the locus coeruleus (LC) is one of the first regions to accumulate pretangle material, and imaging work demonstrated that the LC MRI‐signal correlates with entorhinal tau in cognitively normal individuals. Recently developed phosphor‐tau (ptau) blood‐based biomarkers correlated well with cortical tau‐PET and have been suggested as early markers of aberrant tau phosphorylation. Here we evaluated the relationship between LC‐MRI signal intensity and plasma markers of tau (ptau231, ptau217, ptau181), neurodegenerative processes (total tau (t‐tau), neurofilament light (NfL)) and amyloidosis (Aβ42/40).Method99 cognitively normal individuals across the lifespan (30‐85 years, n=52 female) underwent dedicated 7T LC‐imaging and fasting blood draw. A sample‐specific template for the LC was generated and transformed into a surface. All plasma markers were quantified in duplicate using Single molecule array methods (Simoa, Quanterix) or Meso‐Scale Discovery. Voxel‐wise robust regressions associated LC intensity values with plasma markers, adjusted for age and sex (or Aβ42/40). Interactions between Aβ42/40 and ptau, t‐tau or NfL were also tested. Multiple comparisons were corrected using Threshold‐Free‐Cluster‐Enhancement (p<0.001). Bootstrapped sliding window analyses determined the age‐window of significant plasma marker–LC intensity associations.ResultOlder age was associated with higher ptau181, NfL and lower Aβ42/40 (Figure 1). Higher ptau231 was associated with lower LC intensity in bilateral dorso‐rostral clusters. Ptau181, ptau217 and t‐tau correlated negatively with LC intensity in right dorso‐rostral clusters. Small clusters of negative associations between LC intensity and NfL were distributed across the length of the LC. LC intensity was not associated with Aβ42/40 (Figure 2). Adjusting for Aβ42/40 did not change these results. We did not find interactions between Aβ42/40 and ptau, t‐tau or NfL. The association between LC intensity and ptau231 became significant from age 55.5 years, and for ptau181 and ptau217 from age 60 years (Figure 3).ConclusionPlasma ptau231 showed robust and earlier relationships with LC intensity compared to ptau217 or ptau181 in asymptomatic individuals across the lifespan. Given that tau phosphorylation at threonine 231 is one of the earliest events in the phosphorylation cascade hindering tubulin assembly, these findings suggest that LC intensity may reflect processes related to early tau aggregation.