First Comprehensive Mitochondrial DNA Brain Mutation Atlas for Alzheimer's Disease

Kuakini Medical Center, Honolulu HI

Investigators

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Abstract

ABSTRACT It is well established that mitochondria play multiple critical roles including providing cellular energy, regulating apoptosis, and maintaining oxidative balance. Mitochondrial dysfunction is a hallmark of aging, chronic disease, and neurodegeneration. Developing a comprehensive atlas of acquired mitochondrial DNA (mtDNA) mutations across multiple brain regions and in blood cells will advance the discovery of disease mechanisms related to early Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) diagnosis, neuropathology, and cognitive decline. The proposed study leverages brain autopsy samples, blood samples, and longitudinally collected clinical data from the 50+ year Kuakini Honolulu Heart Program/Kuakini Honolulu-Asia Aging Study (Kuakini HHP/Kuakini HAAS) cohort of American men of Japanese ancestry. We propose three study aims that will advance current knowledge regarding the role of acquired mtDNA mutations (heteroplasmy) in AD/ADRD onset, neuropathology, and longitudinal change in cognitive function. For the first aim, we will sequence mtDNA from 6 brain regions in 213 patients given a clinical diagnosis of ADRD (of which 165 have AD) and 247 controls to identify individual disease-related mutation patterns. For the second aim, we will examine associations between heteroplasmy and plaque and tangle burden within each of the brain regions at autopsy. For the third aim, we will sequence mtDNA and measure AD biomarkers from blood DNA collected at Exam 4 (1991-93) from the 460 participants with autopsies to identify prospective associations with AD/ADRD onset, progression, and cognitive function assessed via longitudinal cognitive tests. Additional analyses will examine how established risk and resilience factors impact associations between mtDNA heteroplasmy and AD/ADRD diagnosis, neuropathology, and cognitive decline. To date, studies of mtDNA mutations involving brain archives include datasets of small sample sizes, examine few brain regions, and only assess specific mtDNA variants or utilize low-coverage sequencing methods. The proposed study utilizing high coverage next-generation mtDNA sequencing will produce the largest, most comprehensive, deeply sequenced, and clinically relevant brain atlas in existence of mtDNA variation related to cognitive aging. The study team is comprised of experts in mtDNA sequencing, AD/ADRD diagnosis and assessment, neuropathology, cognitive aging, biostatistics and risk-factor modeling. This work will fill a major gap in the understating of brain and blood mtDNA mutations in AD/ADRD etiology and pathology along with the risk of cognitive decline, with the potential to revolutionize AD/ADRD risk assessment and identify future molecular targets for intervention.