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

MTA was associated with age even after accounting for amyloid, tau, and alpha-synuclein pathologies.

• Study included 949 cognitively unimpaired (CU) and 854 cognitively impaired (CI) individuals.
• Pathologies assessed included amyloid, tau, alpha-synuclein, and TDP-43 accumulation as well as white matter hyperintensities.
• The association between MTA and age persisted when these pathologies were statistically accounted for.
• Pathologies were measured in vivo using plasma, CSF, or PET imaging.

White matter hyperintensities (WMH) representing small vessel disease was the strongest and most consistent predictor of MTA.

• WMH mediated 32-41% of the association between age and MTA.
• WMH was described as 'the strongest and most consistent predictor' among the pathologies examined.
• This finding held across both cognitively unimpaired and cognitively impaired groups.
• WMH was assessed as a marker of small vessel disease.

An age-independent cut-off for MTA was derived to distinguish between amyloid-negative CU and amyloid-positive CI individuals.

• The age-independent cut-off was derived from 195 CU participants with low levels of pathology.
• The cut-off was designed to differentiate Aβ- cognitively unimpaired from Aβ+ cognitively impaired individuals.
• Accuracy, sensitivity, and specificity were comparable between the age-independent cut-off and previously published age-adjusted cut-offs.
• The authors describe their proposal as 'more parsimonious' and potentially useful in a clinical setting.

Visual assessment of MTA in clinical workup of cognitive impairment is traditionally corrected for age because MTA increases with age.

• The paper notes that age correction for MTA is standard clinical practice.
• Common pathologies in the elderly such as amyloid, tau, alpha-synuclein, and TDP-43 accumulation may affect the association between MTA and age.
• The study investigated whether these pathologies confound or mediate the age-MTA relationship.
• The traditional approach uses age-adjusted cut-offs for MTA scoring.

The age-independent MTA cut-off performed in line with the best performing age-adjusted cut-off.

• Accuracy, sensitivity, and specificity were described as 'comparable' for the age-independent versus age-adjusted cut-offs.
• The age-independent cut-off was suggested as a clinically useful alternative to age-adjusted cut-offs.
• The authors characterize the age-independent approach as 'more parsimonious.'
• The comparison was made against 'previously published age-adjusted cut-offs.'