Abstract. This study presents the simulated response of regional climate and the oxygen isotopic composition of precipitation (δ18Op) to different along-strike topographic evolution scenarios. These simulations are conducted to determine if the previously hypothesized diachronous surface uplift in the Western and Eastern Alps would produce δ18Op signals in the geologic record that are sufficiently large and distinct to be detected using stable isotope paleoaltimetry. We present a series of topographic sensitivity experiments conducted with the water-isotope-tracking atmospheric general circulation model (GCM) ECHAM5-wiso. The topographic scenarios are created from the variation of two free parameters, (1) the elevation of the Western–Central Alps and (2) the elevation of the Eastern Alps. The results indicate Δδ18Op values (i.e., the difference between δ18Op values at the low- and high-elevation sites) of up to −8 ‰ along the strike of the Alps for the diachronous uplift scenarios, primarily due to changes in orographic precipitation and adiabatic lapse rate driven localized changes in near-surface variables. These simulated magnitudes of Δδ18Op values suggest that the expected isotopic signal would be significant enough to be preserved and measured in geologic archives. Moreover, the simulated slight δ18Op differences of 1 ‰–2 ‰ across the low-elevation sites support the use of the δ–δ paleoaltimetry approach and highlight the importance of sampling far-field low-elevation sites to differentiate between the different surface uplift scenarios. The elevation-dependent rate of change in δ18Op (“isotopic lapse rate”) varies depending on the topographic configuration and the extent of the surface uplift. Most of the changes are significant (e.g., −1.04 ‰ km−1 change with slope error of ±0.09 ‰ km−1), while others were within the range of the statistical uncertainties (e.g., −0.15 ‰ km−1 change with slope error of ±0.13 ‰ km−1). The results also highlight the plausible changes in atmospheric circulation patterns and associated changes in moisture transport pathways in response to changes in the topography of the Alps. These large-scale atmospheric dynamics changes can complicate the underlying assumption of stable isotope paleoaltimetry and therefore require integration with paleoclimate modeling to ensure accurate reconstruction of the paleoelevation of the Alps.