Alzheimer’s disease (AD) is increasingly acknowledged not only as a neurological disorder but also as a condition modulated by systemic factors. While amyloid-β (Aβ) peptides are classically associated with brain pathology, compelling evidence suggests that significant Aβ production and metabolism also occur in peripheral organs and tissues. This review synthesizes the current understanding of systemic Aβ metabolic processes and their critical role in the pathogenesis of AD. We detail the biogenesis of Aβ in both the central nervous system (CNS) and periphery, establishing the existence of interconnected central and peripheral Aβ pools. Crucially, we examine the multiple pathways mediating Aβ clearance from the brain into the periphery, including transport across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), clearance via the glymphatic and meningeal lymphatic systems, and drainage along intramural periarterial pathways and arachnoid granule pathways. Once in the periphery, brain-derived Aβ is cleared by various mechanisms involving blood components (monocytes, enzymes, erythrocytes), the liver (primary site of degradation), kidneys (filtration and excretion), spleen (phagocytosis by macrophages), and potentially other organs like the skin and gut. Importantly, a range of systemic diseases – including metabolic disorders (diabetes and dyslipidemia), immune dysfunction, cardiovascular disease, hepatic/renal dysfunction, sleep/respiratory disorders, gut microbiome disturbances, blood abnormalities, infections, systemic inflammation, and bone diseases – are linked to impaired peripheral Aβ clearance and an increased risk of AD. These systemic abnormalities often form bidirectional feedback loops with AD brain pathology. The emerging understanding of the intricate cross-talk between central and peripheral Aβ pools suggests that peripheral Aβ clearance dysfunction is a major contributor to Aβ accumulation in sporadic AD. Consequently, targeting systemic Aβ metabolism and improving peripheral clearance represent promising therapeutic strategies for AD, complementing current brain-centric approaches like anti-Aβ antibodies. Future research should prioritize comprehensive therapeutic approaches and the control of comorbid systemic conditions to enhance prevention and treatment approaches for AD.