Alzheimer Disease Pathology in Middle Age Reveals a Spatial-Temporal Disconnect Between Amyloid-β and Phosphorylated Tau

We studied the brain distribution of amyloid-β (Aβ) and phosphorylated tau (τ) in 20 consecutive autopsy cases between the ages of 51 and 65, with no history of neurologic disease during life. We note that early accumulations of Aβ and τ occur in distinct neuroanatomical distributions. In the locus ceruleus and medial temporal lobe allocortex τ often occurs in the absence of diffuse Aβ and that Aβ occurs in the neocortex in the absence of τ. In those cases with both Aβ and τ were present in the sections, there was no overlap at the microanatomical or cellular level. APOE genotype was also assessed, showing no specific relationship with the presence or distribution of Aβ and τ, although the numbers of cases were limited. These findings indicate that the early appearances of hallmark proteins of Alzheimer’s disease are disconnected both in time and in space, suggesting that both are reactive phenomena with no mechanistic relationship in aging or preclinical disease.