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Alzheimer's Disease Analysis Leads to Potential Epigenetic Signatures

NEW YORK – A team from the US and China has identified a set of cytosine methylation marks in neuronal cells that show apparent ties to Alzheimer's disease (AD) development and progression in both familial and sporadic AD cases.

As they reported online today in Science Advances, the researcher used oxidative bisulfite deep sequencing (OXBS-seq) and methylase-assisted deep sequencing (MAB-seq) to profile 5-methyl cytosine, 5-hydroxymethyl cytosine, and 5-formyl/carboxyl cytosine marks at the base level in induced pluripotent stem cells from unaffected individuals or individuals with mutations linked to early- or late-onset AD, which had been coaxed to become cortical neurons. They also profiled the methylation marks in frontal lobe brain tissues from individuals with or without AD.

The team's comparisons of these profiles unearthed more than two dozen regions with distinct methylation patterns in AD cells, along with 39 site-specific cytosine methylation signatures spanning various epigenetic marks and forms of AD. The signatures were subsequently verified with array-based methylation profiles for 371 AD cases and 163 unaffected controls from a clinical cohort.

"These signatures are AD-specific and age independent, which were further validated in a large clinical cohort," co-senior authors Yujiang Shi, an endocrinology, diabetes, and hypertension researcher at BWH and Harvard, and Feizhen Wu, an epigenetics researcher affiliated with Shanghai Medical College of Fudan University and the Dana-Farber Cancer Institute, and their colleagues wrote. "Notably, a major group of the signatures occur on the genes implicated in AD or AD-related pathways, or on genomic regions that are critical for proper neurodevelopment."

Along with notorious AD contributors such as APOE4 alleles contributing to late-onset AD, the team noted that past research has uncovered single gene mutations behind some autosomal dominant forms of the disease, as well as common genetic variants that might mark disease onset or progression. Still, the group explained, the full collection of genetic and epigenetic features that determine when the disease hits and how fast it moves are still largely unknown, particularly in sporadic AD.

Given proposed roles for DNA methylation in AD and other neuronal conditions, the researchers reasoned that it might be possible to focus in on AD-related epigenetic features by mapping 5mC, 5hmC, and 5fC/5caC in neural precursor cells and neurons, starting with iPSC cells from a healthy individual; individuals with early-onset AD-related mutations in PSEN1 or PSEN2 mutations; and an individual with homozygous version of APOE4 that is linked to late-onset AD.

"To ensure generalizability of the epigenetic features and signatures of healthy controls and AD-associated epigenetic alterations found in cell culture models, we extended our epigenomic studies to post-mortem brain tissues of a normal donor and sporadic AD cases," the authors explained, noting that the study "provides the first comprehensive and comparative reference maps of genome-wide distribution of all three DNA methylation states at base resolution during neural differentiation from iPSCs to mature neurons and in post-mortem brain tissues."

Compared to the initial iPSCs, the team saw levels of 5mC creep up in both the neural precursor cells and neurons, while 5hmC showed the opposite trajectory. The levels of 5fC/caC also appeared to decline as iPSCs became neurons, though the neural precursor cells showed a spike in that epigenetic mark.

When they dug into potential 5mC methylation, 5hmC, or 5fC/5caC differences in the cells produced from individuals with early- or late-onset AD, meanwhile, the researchers saw several epigenetic dynamic changes, and uncovered 27 differentially methylated parts of the genome in AD. They also narrowed in on 39 epigenetic signatures that varied by AD type and cytosine modification features.

The team confirmed the signatures in available clinical samples spanning familial and sporadic cases, and saw hints that such signatures might eventually help to refine AD detection and diagnostic strategies. 

"We found that the observed epigenetic features in normal cells were dysregulated in AD cell models, suggesting that precise regulation, proper establishment, and maintenance of these epigenetic features likely play important roles in regulation of neural lineage commitment, maturation, and function," the authors wrote. Even so, they warned that "future investigations … in larger cohorts are warranted to ultimately turn these into even more reliable, reproducible, and verifiable signatures."

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