Thursday, November 21, 2024
11/21/2024
Project Summary 1) Objectives: We will define associations and pathways through which exposure to PM2.5 and metals contribute to dementia-associated neuropathology (DAN), incident dementia, and cognitive function. We will do so by leveraging resources from the Adult Changes in Thought (ACT) study, an ongoing, prospective cohort study of brain aging and dementia in older adults who are cognitively intact at enrollment. Every two years since 1994, ACT has collected vetted data on dementia, other brain health measures, physical health, lifestyle, medications, and residential history for over 5000 participants, following them until incident dementia or death. At each timepoint, ACT assesses dementia using the Cognitive Abilities Screening Instrument (CASI) and consensus diagnosis using DSM-IV criteria. AD is also assessed based on NINCDS criteria. For participants who consent to autopsy (~25%), ACT performs a neuropathological examination of their brains, including confirmation of dementia diagnoses. Our study will build on these data and resources to achieve 3 primary aims: (1) to characterize PM2.5 and metal concentrations within the olfactory bulb (OB), olfactory tract (OT), and brain tissues of ~140 human donors to establish whether the OB is a pathway through which air pollutants reach the brain; (2) to investigate the OB as a pathway for DAN within the OBs and brains of these donors; and (3) to assess the association of PM2.5, metals with incident dementia - including for pathologically-defined AD, μVBI, LBD, and mixed dementia – and cognitive function, controlling for key confounders and examining effect modification by sex, race/ethnicity, socio-economics, and health conditions and mediation by health conditions. 2) Approach: We will test our aims following a multi-disciplinary approach that relies on (1) our detailed analysis of brains and OB for particles, metals and DAN indicators for ACT participants who consented to autopsy and (2) our epidemiological analyses of the association of long-term ambient PM2.5 and metal exposures with incident dementia, AD, μVBI, and LBD for the entire ACT cohort and for the subset with neuropathology confirmed dementia diagnoses. For both, we will leverage ACT’s rich database of clinical and functional health measures, behaviors, and residential histories. We, for example, will use the residential histories to estimate long-term ambient PM2.5 and associated metal exposures for each ACT participant using novel spatio-temporal models. We will also use health and behavioral data to control for key confounders and predictors and health data to assess modification and mediation of the pollutant-dementia associations. 3) Expected Results: We will provide new evidence of the risks posed by airborne metals to incident dementia and of the pathways through which airborne metals cause damage. In so doing, results from our study will help identify targeted interventions to block pathways to dementia by type and mitigate the severe and growing burden of AD and other dementias.
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