While both Primary Age-Related Tauopathy (PART) and Alzheimer's Disease (AD) involve the accumulation of hyperphosphorylated tau (pTau)-positive neurofibrillary tangles (NFTs) in the hippocampus, PART is distinguished by the absence of β-amyloid (Aβ) deposition and is generally associated with milder cognitive impairment than AD. To delineate cellular and molecular mechanisms that are common or uniquely linked to disease progression in PART and AD, we constructed a transcriptome-wide, high-resolution atlas of the human hippocampus using samples from six individuals spanning the aged control (AC), PART, and AD groups. Our results supported that PART represent a precursor stage of AD, as evidenced by the altered transcriptional profiles of excitatory neurons (Exc) in the PART group, which exhibited a markedly increased capacity to promote Aβ production compared to both AC and AD groups. While the microglia (Mic) were reactivated in the PART group, this response was reduced in AD samples despite the presence of Aβ deposition, and appeared to further induce NFTs formation as a loop consequently driving the progression from PART to AD. Furthermore, subregion interactions in the signalling pathways related to neuronal survival and the maintenance of blood-brain-barrier (BBB) integrity were decreasing in the PART and disrupted in the AD groups, compared to the AC group. Additionally, we found a P53 signalling-related gene, , was uniquely upregulated in astrocytes near large vessels in AD. This suggests a potential mechanism of vessel-induced neuronal apoptosis in AD, a feature absent in AC and PART. In summary, our study offers new insights into the relationship between PART and AD, along with the molecular mechanisms driving the transition from PART to AD. Furthermore, we identified key molecular pathways associated with BBB disruption and vascular-associated neuronal degradation in AD which were absent in PART. These findings deepen our understanding of AD pathogenesis and may inform the development of targeted therapeutic strategies.