Association of Cancer History with Structural Brain Aging Markers of Alzheimer’s Disease and Dementia Risk

Abstract

Background and Objectives: Cancer survivors are less likely than comparably-aged individuals without a cancer history to develop Alzheimer's disease and related dementias (ADRD). We investigated the association between cancer history and structural magnetic resonance imaging (MRI) markers for ADRD risk, using linear mixed-effects models to assess differences at the mean values of MRI markers and quantile regression to examine whether the association varies across the distribution of MRI markers of brain aging. Methods: Among UK Biobank participants with ≥1 brain MRI, we considered total gray matter volume, total brain volume, hippocampal volume, white matter hyperintensity volume, and mean cortical thickness in the Alzheimer's disease (AD) signature region. Cancer history was ascertained from national registry and self-report. We first specified linear mixed models with random intercepts to assess mean differences in MRI markers according to cancer history. Next, to examine whether effects of cancer history on these markers varies across the ADRD risk distribution, we specified quantile regression models to assess differences in quantile cut-points of the distribution of MRI markers according to cancer history. Models adjusted for demographics, APOE-ε4 status, and health behaviors. Results: The sample included 42,242 MRIs on 37,588 participants with no cancer history (mean age 64.1 years), and 6,073 MRIs on 5,514 participants with a cancer diagnosis prior to MRI (mean age 66.7 years). Cancer history was associated with smaller mean hippocampal volume (b=-19 mm3, 95% confidence interval [CI]=-36, -1) and lower mean cortical thickness in the AD signature region (b=-0.004 mm, 95% CI=-0.007, -0.000). Quantile regressions indicated cancer history had larger effects on high quantiles of white matter hyperintensities (10th percentile b=-49 mm3, 95% CI=-112, 19; 90th percentile b=552 mm3, 95% CI= 250, 1002) and low quantiles of cortical thickness (10th percentile b=-0.006 mm, 95% CI=-0.011, -0.000; 90th percentile b=0.003 mm3, 95% CI=-0.003, 0.007), indicating individuals most vulnerable to ADRD were more affected by cancer history. Discussion: We found no evidence that cancer history was associated with less ADRD-related neurodegeneration. To the contrary, adults with cancer history had worse MRI indicators of dementia risk. Adverse associations were largest in the highest-risk quantiles of neuroimaging markers.