Epidemiologic projections indicate that the incidence of Alzheimer’s disease (AD) will increase dramatically in the coming decades due largely to the demographics of the disease and our aging population. Associated cognitive and physical decline greatly contributes to disability in older adults and places considerable burden on the health system, patients, and caregivers. Bone health is an important issue in AD given that AD patients are at higher risk than cognitively healthy adults for osteoporosis, falls, bone fractures, and poor post-fracture outcomes [1
]. Bone mineral density (BMD) is a strong predictor of bone fractures and accounts for 60–70% of bone strength [3
]. We have previously demonstrated that BMD is reduced in both men and women in the earliest clinical stages of AD compared to non-demented older adults independent of habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. Moreover, low BMD was independently associated with lower whole brain volume and memory deficits, suggesting that degeneration of the central nervous system (CNS) may play a role in bone loss [4
]. However, it is unknown whether bone loss is related to volume loss in specific regions of the brain, such as the hypothalamus.
Bone mass is maintained locally by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Multiple factors modulate this servo system and perturbations of this system can result in bone loss. The most important and well-studied regulators of bone health are calcium and vitamin D availability, sex steroids, and mechanical usage. Recent work, however, indicates that the CNS directly regulates bone remodeling through the actions of the hypothalamus through two distinct pathways, the neurohumoral and neural arms [5
]. Briefly, the neurohumoral arm involves hypothalamic control of the anterior pituitary hormones, such as growth hormone (GH), thyroid stimulating hormone (TSH), and follicle-stimulating hormone (FSH) (see [7
] for a full review). GH executes its anabolic action on bone through insulin-like growth factor 1 (IGF-1). TSH and FSH receptors are present in bone cells and receptor activation stimulates bone resorption. The neural arm involves hypothalamic control of bone remodeling through sympathetic nervous system (SNS) output. SNS output from the leptin-ergic/peptidergic neurons in the ventral hypothalamus directly regulates bone remodeling through activation of beta-2 adreno-receptors on the osteoblasts, resulting in reduced bone formation [8
]. There is evidence that sympathetic output from the hypothalamus via the neural arm may be more important than actions of sex steroids in the regulation of bone remodeling [9
Clinical, neuropathological, and neuroimaging data together suggest that the hypothalamus is affected in AD and undergoes neuronal loss [11
], profound plaque and tangle formation [12
], and overall atrophy [14
]. However, there have been no studies to investigate whether neurodegeneration of CNS and the hypothalamus, specifically, is associated with bone loss. We hypothesized that atrophy of the hypothalamus and loss of hypothalamic neurons associated with AD may be one of the mechanisms of accelerated bone loss in AD. Thus, the aim of this cross-sectional study was to examine the underlying neural substrate of an association between BMD and brain volume and establish specific correlations of regional grey matter (GM) with bone loss in early AD and non-demented aging using voxel-based morphometry (VBM) analysis.