Initially implicated in the pathogenesis of amyotrophic lateral sclerosis/frontotemporal dementia (ALS-FTD), TDP-43 proteinopathy has been documented in 30-70% of subjects with Alzheimer’s disease (AD) neuropathology. Moreover, TDP-43 pathology has been shown to be significantly associated with cognitive impairment and brain atrophy in AD. Previously, we showed that TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients. It is not known whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons or how extensively such splicing defects occur in AD. Here, we report that cryptic exon incorporation occurs in all AD cases exhibiting TDP-43 pathology. Furthermore, in AD cases exhibiting both TDP-43 cytoplasmic inclusions and nuclear clearance in amygdala, but only nuclear clearance in the hippocampus, cryptic exon incorporation could still be detected in the hippocampus. These data support the notion that the depletion of nuclear TDP-43 precedes its cytoplasmic aggregation and is widespread in AD, offering important mechanistic and therapeutic implications for this devastating illness of the elderly.