Considering Common Mechanisms in Alzheimer's Disease and Osteoporosis

It has been observed that Alzheimer's disease and osteoporosis appear to be correlated to a larger degree than one would expect simply because both emerge, after a long chain of cause and effect, from the root causes of aging. That they are correlated in this way suggests that they share in common some parts of the middle of that long chain. Given that osteoporosis is a condition of the bones, a disruption of the balance between cells that create bone and cells that destroy bone, and Alzheimer's is a condition of the brain, in which aggregated proteins overwhelm cells, what could these two very different outcomes of aging have in common? This open access paper looks at some of the current evidence and hypotheses.

Accumulation of abnormally folded amyloid beta peptide (Aβ) in cerebral amyloid plaques is the pathologic hallmark of Alzheimer's disease (AD). Aβ originates from the amyloid precursor protein (APP), a membrane protein expressed in many tissues and synapses of neurons with unknown function. A group of specific enzymes named secretases cleave APP into distinct fragments. APP cleavage by β-secretase and then γ-secretase leads to pathological Aβ oligomers. Oligomers are the units which form protofibrils and later fibrils and plaques. Genetic models of AD are typically established by excessively expressing Aβ protein and the current hypothesis of AD etiology centers around amyloid plaques.

Unlike the complexity and controversy in AD, the pathogenesis of osteoporosis is known as an imbalance between bone formation and mineralization. Hyperparathyroidism, Vitamin D deficiency, and steroid use are common causes of osteoporosis. Osteoporosis is mostly asymptomatic until minor trauma or falls lead to fractures. Bone formation involves bone matrix production and mineralization, whereas bone resorption is a biological erosive process mediated by osteoclasts. When the balance leans toward bone resorption, bone mineral density (BMD) decreases and osteoporosis develops.

Bone resorption is driven by the receptor activator nuclear factor-kappa B ligand (RANKL) / receptor activator nuclear factor-kappa B (RANK) signaling network, a signaling complex with multiple downstream pathways. The binding of RANKL to RANK triggers the cascade. Amyloid deposition in the brain and RANKL signaling are two seemingly independent pathways leading to AD and osteoporosis. The possible linkage between these two pathways has been investigated by measuring osteoclast activities in a transgenic mice model of AD. Both in vitro and in vivo examinations showed enhanced Aβ expression in bone, together with increased adipose tissue formation in the marrow space, analogous to osteoporotic bones. The abnormally expressed amyloid deposition appears to interfere with the RANKL signaling cascade and in turn the balance between bone formation and bone resorption. Similar findings extend to human studies.

Previous observational studies have reported the increased frequency of comorbid osteoporosis in AD. The relationship between these two diseases is more likely one of shared etiology than one condition causing the other. The overexpression of Aβ may take place in both brain and bone, interfering with the RANKL signaling cascade, enhancing osteoclast activities, and leading to osteoporosis. There is a growing body of evidence from in vitro and in vivo studies that the AD pathology in the brain can be reflected by examining the bone. Future investigation will focus on assessing biomarkers of cognitive aging in patients with osteoporosis and looking into the bone microstructure of patients with AD.


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