We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer’s Disease Neuroimaging Initiative data; n = 1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p < 0.04 in two separately analyzed groups), but not in Alzheimer’s disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.
|Number of pages||18|
|State||Published - Dec 1 2016|
Bibliographical noteFunding Information:
We are extremely grateful to the research volunteers, clinicians, data repositories, and researchers that contributed to this work. Funding included the National Institutes of Health Grants for Alzheimer’s Disease Genetics Consortium (ADGC; U01 AG032984 and RC2AG036528), National Alzheimer’s Disease Coordinating Center (NACC; U01 AG016976), the National Cell Repository for Alzheimer’s Disease (NCRAD, which received support through a cooperative agreement Grant, U24 AG21886), and additional Grants K25 AG043546, R21 AG050146, UL1TR000117, and the UK-ADC P30 AG028383. Phospho-TDP-43 clone 1D3 antibody was graciously provided by Dr. Manuela Neumann. Special thanks to Ms. Ela Patel and Ms. Sonya Anderson for technical assistance. For additional acknowledgments, including funding support information, see Supplemental Material.
© 2016, Springer-Verlag Berlin Heidelberg.
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience