20.500.12556/DiRROS-31454 Beyond amyloid systemic and brain frailty as determinants of response to anti-amyloid therapy in Alzheimer’s disease a conceptual review Anti-amyloid therapy (AAT) with monoclonal antibodies (mAbs) modestly slow cognitive and functional decline in early Alzheimer’s disease (AD). However, both the magnitude of clinical benefit and the risk of treatment-related complications vary substantially even among patients with similar biomarker profiles. Frailty, both brain and systemic, is highly prevalent in older adults with AD and affects a large proportion of those considered for AAT. Despite this, it has been largely absent from current decision frameworks. Brain frailty, defined by structural and microvascular damage (e.g., small-vessel disease, microbleeds, and atrophy), limits the clinical benefit of amyloid clearance and increases susceptibility to amyloid-related imaging abnormalities. In contrast, systemic frailty, reflecting reduced physiological reserve, mainly affects treatment tolerance and recovery from adverse events. In this narrative, conceptual review, we synthesize evidence that both forms of frailty act as biologically grounded modifiers of AAT efficacy and safety and may limit the clinical benefit while increasing susceptibility to complications and decompensation. Importantly, the precise empirical thresholds at which frailty begins to exert harmful effects remain unknown. We further outline how MRI-based markers of brain frailty, combined with brief systemic frailty measures, could support risk stratification, patient selection, monitoring intensity, and shared decision-making, including deferring treatment when the benefit–risk balance is unfavorable, while avoiding exclusion of patients who may still benefit. Taken together, we propose that future studies should incorporate frailty measures and perform precise assessments of both brain and systemic frailty, as this may improve patient stratification and better characterize the effects of AAT. Alzheimer’s disease frailty brain frailty systemic frailty monoclonal antibodies amyloid-related imaging abnormalities (ARIA) precision medicine cerebral small vessel disease risk-benefit stratification amiloid zdravljenje krhkost Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Neznano 2026-08-03 10:08:29 2026-08-03 10:08:29 2026-08-04 03:53:11 0000-00-00 00:00:00 2026 0 0 Nasl. z nasl. zaslona; Opis vira z dne 3. 8. 2026; str. 1-16 issue 8, [article no.] 1489 Vol. 62 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.8 1648-9144 10.3390/medicina62081489 286702083 RAZ_Rus_Prelog_Polona_2026.pdf RAZ_Rus_Prelog_Polona_2026.pdf 1 AE9962B6BB9DFD83B1283256A1093BA9 e510be4f494018da4d96415972469a040d82fda07a890528ecb080515aae416f 9d32c238-8f12-11f1-a7fa-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=48725 https://www.mdpi.com/1648-9144/62/8/1489 1 84315e53-8f12-11f1-a7fa-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=48724 Univerzitetni klinični center Ljubljana 0 0 0