The Shared Mechanisms of Osteoporosis and Alzheimer's Disease
Aging is at root a matter of accumulated cell and tissue damage. There are a comparatively small number of such forms of damage at the lowest level, the origins of aging. In that sense, all age-related diseases share their mechanisms. When researchers talk about shared mechanisms of age-related disease, they are usually considering processes further downstream from the sort of damage considered in the SENS rejuvenation research proposals, however. In this short commentary, the authors consider what is shared between osteoporosis and Alzheimer's disease, which, on the face it, might not be expected to have much in common at all once one passes beyond the fundamental damage of aging. One is a condition of the bones, and the other a condition of the brain, and the proximate causes in each case just don't seem to have much to do with one another. Nonetheless, read on.
Bone loss and Alzheimer's disease make an unexpected, but increasingly common combination in the aging population. The vastly different clinical presentations of these conditions made it hard to envision that a complex brain disease known for destroying our most advanced cognitive abilities could also impact the fundamental framework of the human body. This bias has likely contributed to the dearth of investigation into mechanisms of bone loss in Alzheimer's disease (AD) - which presents as a very real and unique problem for these patients.
Osteoporosis and bone fracture are estimated to occur in AD patients at over twice the rate as similarly-aged neurotypical adults. Occurring across international demographics and in both sexes, skeletal problems in AD patients are not a coincidence of aging, nor are they the result of disease-related immobility, as they often precede AD diagnosis. In fact, studies have used bone mineral density (BMD) to stratify neurotypical subjects 65 years and older into groups at greatest risk for developing dementia - with those exhibiting the lowest bone densities most likely to receive an AD diagnosis within 5-10 years.
The little empirical evidence that does exist on this subject makes a compelling case that the neuropathophysiological features of AD may also drive bone loss. To date, three genetic mouse models of AD have been characterized with a "pre-clinical" low BMD; however, there are possibly many more among the 150+ available AD models that have not been investigated for bone loss. What has been found is a low bone mass phenotype at ages just preceding the onset of significant hallmark brain pathology and detectable across models representing each hallmark pathology of AD: amyloid beta (Aβ) and phosphorylated tau (ptau) - with data implicating separate mechanisms by which each pathology disrupts skeletal homeostasis.
Data from amyloid-β mouse models support a bone-cell-autonomous role for Aβ in damaging bone tissue, with evidence that Aβ interfaced directly with bone cells to enhance the bone-resorbing activity of osteoclasts and inhibit the bone-building function of osteoblasts. Data obtained from studies with mouse models which selectively develop ptau and neurofibrillary tangle brain pathology showed that ptau - which is largely relegated to the neuronal cytoskeleton - damages the serotonergic dorsal raphe nucleus (DRN) of the brainstem. Serotonergic inputs from the DRN to the hypothalamus form a circuit that is essential for maintaining healthy bone mass in adult mammals; hence these findings suggest this circuit is compromised by ptau pathology.