Despite the prevalence and impact of Alzheimer’s disease (AD), there is no effective treatment due to the lack of a clear understanding of the root cause of its neuropathology. DNA damage has been implicated as a potential driver of numerous neurodegenerative diseases, including AD, but remains poorly studied. Perhaps the most compelling evidence for DNA damage playing a causal role in neurodegenerative diseases like AD comes from patients with genome instability disorders, which almost invariably experience early onset dementia. In particular, defects in nucleotide excision repair (NER) can lead to dementia with profound cerebral atrophy. Also, numerous studies provide evidence of increased DNA damage in brains from AD patients. However, these studies establish correlation rather than causation. More mechanistic studies in mice established that cellular senescence, a key cellular response to environmental and endogenous genotoxic stress, drives aging and many age-related diseases, including AD. In fact, very recently, three groups demonstrated that ablation of senescent cells (either with genetic tools or senolytic drugs) attenuates AD pathology and progression in models of tauopathy. Collectively, these findings open the possibility of novel treatment options for AD, but first it is imperative to establish if DNA damage and senescence play a causal role in human AD, which will be addressed by this supplement. Here, we capitalize on two existing clinical trials of AD in which participants are rigorously screened for clinical manifestations of subjective cognitive impairment and mild cognitive impairment due to AD, and the effects of aerobic exercise and cognitive training are evaluated for their ability slow the progression of AD. The parent grant focuses on developing and implementing an assay to measure NER capacity in human populations. Absence of NER causes a profound increase in risk of skin cancer caused by an inability to repair UV-induced DNA damage as well as neurodegeneration and premature dementia. In the parent grant, the assay is used to test the hypothesis that reduced (but not absent) NER increases the risk of skin cancer. In the supplement, we will test the hypothesis that reduced NER correlates with increased risk of AD and related dementias. It is estimated that 2-3% of genes in the human genome contribute to DNA repair. Sequence variants in many of these might affect NER capacity. To define the extent of variability in NER capacity in the human population (the goal of the original RFA), it is logical to start with extremes: 1) skin cancer patients vs. controls (parent U01) and 2) AD patients vs. controls (supplement). We propose to measure NER in peripheral blood mononuclear cells from persons enrolled in two existing clinical trials of AD and compare them to age/sex- matched individuals without a diagnosis of cognitive impairment. This will yield novel information as to whether DNA repair defects correlate with dementia, sup...