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White matter hyperintensities (WMH) are common radiological findings among older adults and strong predictors of age-related cognitive decline. Recent work has implicated WMH in the pathogenesis and symptom presentation of Alzheimer's disease (AD), which is characterized clinically primarily by a deficit in memory. The severity of WMH volume is typically quantified globally or by lobe, whereas white matter itself is organized by tracts and fiber classes. We derived WMH volumes within white matter tract classes, including association, projection, and commissural tracts, in 519 older adults and tested whether WMH volume within specific fiber classes is related to memory performance. We found that increased association and projection tract defined WMH volumes were related to worse memory function but not to a global cognition summary score that excluded memory. We conclude that macrostructural damage to association and projection tracts, manifesting as WMH, may result in memory decline among older adults. Keywords: White matter hyperintensities, White matter fiber tracts, Memory, Alzheimer's disease

Microstructural and macrostructural white matter damage occurs frequently with aging, is associated with negative health outcomes, and can be imaged non-invasively as fractional anisotropy (FA) and white matter hyperintensities (WMH), respectively. The extent to which diminished microstructure precedes or results from macrostructural white matter damage is poorly understood. This study evaluated the hypothesis that white matter areas with normatively lower microstructure in young adults are most susceptible to develop WMH in older adults. Forty-nine younger participants (age = 25.8 ± 2.8 years) underwent diffusion-weighted imaging (DWI), and 557 older participants (age = 73.9 ± 5.7 years) underwent DWI and T2-weighted magnetic resonance imaging (MRI). In older adults, WMH had a mostly periventricular distribution with higher frequency in frontal regions. We found lower FA in areas of frank WMH compared to normal-appearing white matter (NAWM) in older adults. Then, to determine if areas of normatively lower white matter microstructure spatially overlap with areas that frequently develop macrostructural damage in older age, we created a WMH frequency map in which each voxel represented the percentage of older adults with a WMH in that voxel. We found lower normative FA in young adults with regions frequently segmented as WMH in older adults. We conclude that low white matter microstructure is observed in areas of white matter macrostructural damage, but white matter microstructure is also normatively low (i.e., at ages 20–30) in regions with high WMH frequency, prior to white matter macrostructural damage.