PROJECT SUMMARY The proposed supplement is directly related to the parent U01 and will provide the exploratory clinical evidence needed for a larger fully powered study to determine if blood Nfl values might serve as a prognostic biomarker and as a clinical trial enrichment tool in our post U01 planned clinical trials to treat and hopefully prevent the development of VCID in at-risk heart failure (HF) patients. In our U01 TPP, we planned our first patient population to include an at-risk VCID population that include Heart Failure Class II/IV patients with decreased ejection fraction and evidence of mild cognitive impairment. We believe that NfL may serve as a clinical trial enrichment tool in our planned Phase 1b/2a clinical trial to treat and hopefully prevent the development of VCID in ADRD at-risk HF patients. The timing of proposed study in this administrative supplement will position our team in an excellent position to deploy Nfl as a biomarker for enrollment enrichment for clinical trial eligibility criteria to identify which HF patients who are more likely to develop VCID/ ADRD. In the clinic, VCID diagnosis and disease monitoring is generally achieved by magnetic resonance imaging (MRI) scans and the presence of white matter hyperintensities (WMH) that are typically interpreted as a surrogate of cerebral small vessel disease (SVD). However, the assessment and diagnosis of VCID using MRI most often occurs after the development of significant clinically measured cognitive dysfunction. Neurofilament light protein (NfL), a neurofilament found in blood and cerebral spinal fluid, has been shown to increase following axonal damage and neurodegeneration and is tightly correlated with increased cognitive impairment and has been observed to be elevated in subjects with neurodegenerative diseases, hypoxic brain injury, and cardiac disease and related surgeries. It is unclear if NfL can be used to detect neuronal damage in individuals at risk for VCID such as those withs chronic inflammatory disease such as coronary heart disease or HF. Ideally, if we can predict the presence of neurological and cognitive complications in individuals with heart disease, we will be able to identify those at-risk VCID patients who would benefit from therapeutic treatment. Our proposed Context of Use is that NfL might serve as a Prognostic Biomarker in blood that can help predict clinical progression in early at-risk VCID with stage II/IV heart failure (HF). Our ultimate goal will be to use levels of Nfl in blood as an enrollment enrichment factor for our planned post U01 clinical trial to identify individuals with HF who are more likely to develop VCID or ADRD. Specific Aim: Establish a baseline and 12-month longitudinal Nfl values in HF patients at risk for VCID and determine the association between absolute levels of Nfl with measures cognitive function and MRI in subjects with stage I/II and III-IV HF patients.