Selective neuronal vulnerability in Alzheimer's disease: mechanisms, biomarkers, and therapeutic implications

Alzheimer's disease (AD) is characterized by marked heterogeneity in the timing and extent of neuronal dysfunction and degeneration. Specific neuronal populations, including entorhinal cortex layer II stellate cells, hippocampal CA1 pyramidal neurons, basal forebrain cholinergic neurons, locus coeruleus noradrenergic neurons, and prefrontal parvalbumin interneurons, show different combinations of functional, pathological, and degenerative vulnerability during disease progression. The strength and nature of this evidence, however, vary across neuronal populations and between human studies and experimental models. Selective vulnerability is therefore unlikely to reflect a single cell-type-specific mechanism. Instead, pathological stress in AD interacts with intrinsic cellular properties, circuit organization, and the local microenvironment. Metabolic stress, axonal transport impairment, excitotoxicity and Ca²⁺ dysregulation, neuroinflammation, lipid dysregulation and ferroptotic stress, and proteostasis failure may consequently produce distinct functional and degenerative outcomes across neuronal populations. Advances in transcriptomics, neuropathology, multimodal imaging, and circuit-level analyses are also identifying molecular, regional, and functional measures associated with early involvement of vulnerable neuronal systems, although validated cell-type-specific biomarkers remain limited. In this Review, we integrate these findings to examine the evidence for selective neuronal vulnerability, the mechanisms that may modify neuronal susceptibility, and their implications for biomarker development and therapy. We further consider how vulnerability-informed strategies could complement pathology-directed therapies by aligning therapeutic mechanisms with prominent cellular or circuit dysfunction and disease stage. This perspective may help explain the spatial and temporal heterogeneity of AD and guide more biologically informed approaches to early detection and intervention.