Degeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer’s disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, p75^NTR, has been associated with the degeneration of BFCNs in AD. The senescence-accelerated mouse prone number 8 (SAMP8) is a well-accepted model of accelerated and pathological aging. To gain a better understanding of the role of p75^NTR in the basal forebrain during aging, we generated a new mouse line, the SAMP8-p75^{exonIII−/−}. Deletion of p75^NTR in the SAMP8 background induces an increase in the number of BFCNs at birth, followed by a rapid decline during aging compared to the C57/BL6 background. This decrease in the number of BFCNs correlates with a worsening in the Y-maze memory test at 6 months in the SAMP8-p75^{exonIII−/−}. We found that SAMP8-p75^{exonIII−/−} and C57/BL6-p75^{exonIII−/−} mice expressed constitutively a short isoform of p75^NTR that correlates with an upregulation of the protein levels of SREBP2 and its targets, HMGCR and LDLR, in the BF of both SAMP8-p75^{exonIII−/−} and C57/BL6-p75^{exonIII−/−} mice. As the neurodegeneration of the cholinergic system and the dysregulation of cholesterol metabolism are implicated in AD, we postulate that the generated SAMP8-p75^{exonIII−/−} mouse strain might constitute a good model to study long-term cholinergic neurodegeneration in the CNS. In addition, our results support the role of p75^NTR signaling in cholesterol biosynthesis regulation.