PROJECT SUMMARY Alzheimer?s disease (AD) presents heterogeneously with regional brain structures demonstrating distinct susceptibility to pathology and disease progression resulting in disease course temporal variation. Our prior NIH sponsored work demonstrated that the HFEH63D single nucleotide polymorphism (SNP) heterogeneously alters brain integrity. This missense mutation is one of the most widespread in the human genome; with nearly 16% of the world?s population as carriers. The HFE gene is intricately involved in systemic iron homeostasis and is hypothesized to be involved in AD; however, inconsistent findings have not determined directionality or the relationship of HFE SNPs to AD etiology. Our exciting recent preliminary data brings to light a negative relationship between HFEH63D-AD carriers and biomarkers of disease status, specifically demonstrating an apparent decrease in late-myelinating white matter integrity and increased susceptibility to disease pathology. It is unknown why late- myelinating white matter integrity is reduced during early AD pathogenesis. The HFEH63D genotype presents a unique opportunity to understand the mechanism wherein AD pathology and disease course are regionally exacerbated, as well as inform procedures that may alter disease progression. Finding factors that modulate AD is highly significant, particularly ones that are as common as this HFE polymorphism. Genetic factors involved in AD have largely been established based on familial early onset and pathology induction. Sporadic AD appears to have both environmental and genetic factors that synergistically culminate into disease. Data suggest a heterogeneous convergence towards the clinical manifestation of AD, forming a disease spectrum along domains of age of onset and time of progression. There exists a gap in understanding how the brain is modified during AD course and in normal aging, our work aims to specifically address this knowledge gap. This research will impact future work on dynamic brain and cognitive changes altered in AD and natural age-related brain senesce. The H63D genotype presents a unique opportunity to interrogate the relationship between regional AD pathology and disease course, as well as inform future procedures that may alter disease progression. The central hypothesis for this proposal is that the HFE genotype reduces brain integrity, increases pathology, and accelerates Alzheimer?s trajectory. We propose to: 1) characterize the longitudinal progression of late-myelinating white matter integrity in HFEH63D Alzheimer?s disease carriers, 2) determine the trajectory of cognitive status and brain integrity in mild-cognitive impairment and age-matched controls to establish if the HFEH63D SNP alters onset of cognitive loss, and 3) characterize the longitudinal progression of amyloid-beta deposition and brain metabolism in HFEH63D Alzheimer?s, MCI, and age-matched controls.
|Effective start/end date||6/1/21 → 5/31/22|
- National Institute on Aging: $199,689.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.