Medial temporal lobe atrophy is associated with age and pathologies, especially small vessel disease.

Visual assessment of medial temporal lobe atrophy (MTA) in the clinical workup of cognitive impairment is traditionally corrected for age since MTA increases with age. In addition, common pathologies in the elderly such as amyloid, tau, alpha-synuclein and TDP-43 accumulation as well as white matter hyperintensities representing small vessel disease may affect the association between MTA and age. We investigated this in 949 cognitively unimpaired (CU) and 854 cognitively impaired (CI) individuals focusing on amyloid, tau and alpha-synuclein that at present can be measured in vivo in plasma, CSF or using PET. MTA was associated with age also when these aforementioned pathologies were accounted for. WMH was the strongest and most consistent predictor and mediated 32-41% of the association between age and MTA. Secondly, an age-independent cut-off for distinguishing between Aβ- CU and Aβ + CI was derived from 195 CU participants with low levels of pathology. Accuracy, sensitivity and specificity were comparable for our age-independent and previously published age-adjusted cut-offs. In summary, age and WMH emerged as the most prominent factors associated with MTA. Our age-independent cut-off for MTA performed in line with the best performing age-adjusted cut-off, suggesting our more parsimonious proposal could be useful in a clinical setting.