BACKGROUND: The role of cognitive reserve (CR) to explain individual differences in cognitive functioning is unclear in memory clinic patients. OBJECTIVE: To examine the cross-sectional effect of CR on cognition in relation to levels of neurodegeneration in a large elderly single-center memory clinic population. METHODS: We included patients with subjective cognitive impairment (SCI, n = 481), mild cognitive impairment (MCI, n = 628) or Alzheimer's disease (AD, n = 1,099). Education was used as proxy for CR and visually rated medial temporal lobe atrophy (MTA) on CT was used as parameter of neurodegeneration. Relations between CR, cognition, and MTA were analyzed with multiple linear regression adjusted for age, sex, and cerebral atrophy. In addition, we examined if education affects the relation between MTA and cognition using an interaction variable. RESULTS: Education was significantly related to all measures of cognition including subtests with an explained variance of education as a determinant of cognition of 11%. More highly educated patients had more advanced levels of MTA at the same level of cognition. All these results were stronger or only present in demented compared to non-demented patients but appeared no longer significant in those with lowest overall cognition. The interaction effect was significant indicating that with more advanced MTA, less cognitive decline was shown in higher educated patients. CONCLUSION: Education is a very strong determinant of cognition in an elderly memory clinic population. The positive effect of education was stronger in demented than in non-demented patients but disappeared in those with the lowest cognitive scores indicating a "window of CR benefit".