Sequence and trajectory of early Alzheimer’s disease-related tau inclusions in the hippocampal formation of cases without amyloid-β deposits

Abstract

Sporadic Alzheimer’s disease (AD) involves specific neuronal types and progresses in a systematic manner, permitting subdivision into six neuropathological stages. Neurofibrillary tangle (NFT) stages I–III display abnormal tau inclusions confined to subcortical nuclei and temporal allocortical regions, frequently without amyloid β (Aβ) deposition. We previously suggested a sequence of neuronal involvement in AD that could proceed from entorhinal pre-α cells to hippocampal prosubicular pyramidal cells and the CA1/CA2 sectors, from there to the thorny excrescences on mossy cells in CA3/CA4, and, finally, from the mossy cells to dentate fascia (Fd) granular cells. Here, we aimed to see if associations existed between the early NFT stages I–III, when Aβ deposits are frequently absent, and the following four categories: (1) anatomical regions and abnormal morphological tau changes in region-specific layers, (2) nerve cell loss, (3) APOE genotype, and (4) the trajectory (directionality) of tau progression in the hippocampal formation. To do so, we examined the transentorhinal/entorhinal regions and hippocampal formation using AT8-immunohistochemistry in 100 µm sections from N = 308 brains with tau inclusions lacking Aβ deposits between NFT stages I and III (average age at death 66.7 years for females, 66.4 years for males). Our results indicated a significantly (p < 0.001) ordered progression of abnormal tau in a direction opposite to currently known unidirectional intrahippocampal connections, thereby indirectly supporting the idea of transneuronal abnormal tau spreading, i.e., anterogradely, through the hippocampal formation. Tau-related neuronal loss was also significant (p < 0.001 for the transentorhinal/entorhinal regions and for sectors CA1/CA2 and p = 0.003 for CA3/CA4/Fd). These findings challenge the amyloid cascade and the PART hypotheses, corroborating the concept that early AD-related tau inclusions and tau-related neuronal loss occur independently of Aβ deposition.