Purpose/Aim: Alzheimer's disease (AD), the primary cause of dementia in the elderly, is one of the leading age-related neurodegenerative diseases worldwide. While AD is notorious for destroying memory and cognition, dementia patients also experience greater incidence of bone loss and skeletal fracture than age-matched neurotypical individuals, greatly impacting their quality of life. Despite the significance of this comorbidity, there is no solid understanding of the mechanisms driving early bone loss in AD. Here, we review studies that have evaluated many of the obvious risk factors shared by dementia and osteoporosis, and illuminate emerging work investigating covert pathophysiological mechanisms shared between the disorders that may have potential as new risk biomarkers or therapeutic targets in AD.Conclusions: Skeletal deficits emerge very early in clinical Alzheimer's progression, and cannot be explained by coincident factors such as aging, female sex, mobility status, falls, or genetics. While research in this area is still in its infancy, studies implicate several potential mechanisms in disrupting skeletal homeostasis that include direct effects of amyloid-beta pathology on bone cells, neurofibrillary tau-induced damage to neural centers regulating skeletal remodeling, and/or systemic Wnt/Beta-catenin signaling deficits. Data from an increasing number of studies substantiate a role for the newly discovered "exercise hormone" irisin and its protein precursor FNDC5 in bone loss and AD-associated neurodegeneration. We conclude that the current status of research on bone loss in AD is insufficient and merits critical attention because this work could uncover novel diagnostic and therapeutic opportunities desperately needed to address AD.

中文翻译：

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阿尔茨海默病骨质流失的机制复杂性：综述。

目的：阿尔茨海默病 (AD) 是导致老年人痴呆的主要原因，是全球主要的与年龄相关的神经退行性疾病之一。虽然 AD 以破坏记忆和认知而臭名昭著，但痴呆患者的骨质流失和骨骼骨折发生率也高于年龄匹配的神经典型个体，这极大地影响了他们的生活质量。尽管这种合并症很重要，但对 AD 早期骨丢失的驱动机制还没有深入的了解。在这里，我们回顾了评估痴呆症和骨质疏松症共有的许多明显风险因素的研究，并阐明了调查疾病之间共有的隐蔽病理生理机制的新兴工作，这些疾病可能有潜力作为 AD 的新风险生物标志物或治疗靶点。 结论：骨骼缺陷在临床阿尔茨海默病进展的早期就出现，并且不能用诸如衰老、女性、活动状态、跌倒或遗传等巧合因素来解释。虽然该领域的研究仍处于起步阶段，但研究表明了破坏骨骼稳态的几种潜在机制，包括淀粉样蛋白 β 病理对骨细胞的直接影响、神经原纤维 tau 对调节骨骼重塑的神经中枢的损伤和/或全身 Wnt /β-连环蛋白信号缺陷。越来越多的研究数据证实了新发现的“运动激素”鸢尾素及其蛋白前体 FNDC5 在骨质流失和 AD 相关神经变性中的作用。