Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder, which currently affects the lives of one in every eight people worldwide. Little knowledge regarding its pathogenesis makes it difficult to prevent and treat. The amyloid precursor protein (APP), is cleaved to produce the neurotoxic amyloid beta (Aβ) peptide that accumulates into plaques and destroys neuronal axons in the brain. Bone loss with ageing is a major problem, predisposing to falls and fracture in the elderly. We have previously shown expression of the App gene and protein by the osteocyte. In this study, we investigated the effects of a mouse knock-in model that mimics AD, AppNL-G-F, where three humanised mutations believed to cause Alzheimer’s disease were introduced into the mouse App gene. Microcomputed tomography analysis of trabecular bone in the midpoint region of 16-week-old APPNL-G-F female mice demonstrated a 27% decrease in femoral BV/TV (p<0.05) and a 19% reduction in trabecular number (Tb.N) (p= 0.0572). Investigation into the 29 week male cohort also revealed significant 33% reduction in BV/TV% (p=0.0027), a 31% reduction in Tb.N (p=0.0042). The dramatic reductions in these parameters all point to an age related bone loss phenotype. These highly novel findings suggest that an abundance of Aβ peptides formed as a result of the knock-in model may not only impact negatively on the brain, but may also have pathophysiological roles in the bone as we age. This significant reduction in BV/TV% seen across both genders with ageing suggests a bone resorption phenotype occurring at an accelerated rate when compared to age-matched wild-types. Since bone remodelling increases in peri-/post-menopausal women predisposing to osteoarthritis and osteoporosis, this evidence for pleiotropy introduces the possibility that bone-derived APP could be a source of soluble Aβ peptides, providing a possible link between the bone and the brain in the development of AD.