Background: Brain volume is associated with cognitive decline in later life, and cortical brain atrophy exceeding the normal range is related to inferior cognitive and behavioral outcomes in later life. Objective: To investigate the likelihood of cognitive decline, mild cognitive impairment (MCI), or dementia, when regional atrophy is present in participants’ magnetic resonance imaging (MRI). Methods: Multi-center MRI data of 2,545 adults were utilized to measure regional volumes using NEUROPHET AQUA. Four lobes (frontal, parietal, temporal, and occipital), four Alzheimer’s disease-related regions (entorhinal, fusiform, inferior temporal, and middle temporal area), and the hippocampus in the left and right hemispheres were measured and analyzed. The presence of regional atrophy from brain MRI was defined as ≤1.5 standard deviation (SD) compared to the age- and sex-matched cognitively normal population. The risk ratio for cognitive decline was investigated for participants with regional atrophy in contrast to those without regional atrophy. Results: The risk ratio for cognitive decline was significantly higher when hippocampal atrophy was present (MCI, 1.84, p < 0.001; dementia, 4.17, p < 0.001). Additionally, participants with joint atrophy in multiple regions showed a higher risk ratio for dementia, e.g., 9.6 risk ratio (95% confidence interval, 8.0–11.5), with atrophy identified in the frontal, temporal, and hippocampal gray matter, than those without atrophy. Conclusions: Our study showed that individuals with multiple regional atrophy (either lobar or AD-specific regions) have a higher likelihood of developing dementia compared to the age- and sex-matched population without atrophy. Thus, further consideration is needed when assessing MRI findings.