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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grant RF1AG059872 (Glymour, Graff, Wang), grant K99AG073454 (Ackley), and grant K99AG075317 (Hayes-Larson) from the National Institute on Aging. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of the North West Multi-centre Research Ethics Committee (MREC) gave ethical approval for the UK Biobank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online at https://www.ukbiobank.ac.uk/