Shared mechanisms: osteoporosis and Alzheimer’s disease?

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 [1]. 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 [2]. In fact, studies have used 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 [3]. This is not to say that every adult with osteoporosis will develop AD, however, the fact that over half of AD patients do experience bone deficits merits further consideration as skeletal fracture can detrimentally impact quality of life and diminish life expectancy of this already-vulnerable population. 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 (i.e. APPswe, APP/PS1ΔE9, and htau mice) 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 among these three models 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 Aβ dominant APPswe and APP/PS1ΔE9 models support a bone-cell-autonomous role for Aβ in damaging bone tissue, with evidence that Aβ interfaced Editorial