Alzheimer’s disease – “This is something that has just never been undertaken before.”

Researchers have delved into the gene expression and epigenomic shifts seen in Alzheimer’s, pinpointing potential cellular routes for future drug developments.

Over 6 million individuals in the U.S. grapple with Alzheimer’s, yet very few FDA-endorsed treatments are available to halt its advance.

Aiming to unveil potential therapeutic targets, a team from MIT undertook a comprehensive study of the changes in genomics, epigenomics, and transcriptomics across all cell types in Alzheimer’s-affected brains.

Leveraging data from over 2 million cells and 400-plus postmortem brain specimens, the team studied the disturbances in gene expression during the course of Alzheimer’s. Additionally, they monitored alterations in epigenomic modifications, which play a pivotal role in dictating gene activity in specific cells. This combined methodology provides an unparalleled insight into Alzheimer’s genetic and molecular foundations.

This groundbreaking research, documented in four articles in the journal Cell, was led by Li-Huei Tsai of MIT’s Picower Institute for Learning and Memory and Manolis Kellis from MIT’s CSAIL, who is also affiliated with the Broad Institute of MIT and Harvard.

Kellis commented, “What we set out to do was blend together our computational and our biological expertise and take an unbiased look at Alzheimer’s at an unprecedented scale across hundreds of individuals — something that has just never been undertaken before.”

The research suggests that a dynamic interaction between genetic and epigenetic variations propels the disease’s pathological characteristics.

Tsai added, “It’s a multifactorial process. These papers together use different approaches that point to a converging picture of Alzheimer’s disease where the affected neurons have defects in their 3D genome, and that is causal to a lot of the disease phenotypes we see.”

Navigating Complex Interactions

While many therapeutic endeavors against Alzheimer’s have primarily targeted the amyloid plaques seen in afflicted brains, the MIT group sought to discover alternative strategies. They delved into the molecular propellors of the disease, identifying the most susceptible cell types and the core biological channels fueling neurodegeneration.

For the study, the team deployed transcriptomic and epigenomic evaluations on 427 brain samples from the Religious Orders Study/Memory and Aging Project (ROSMAP). This long-term project has documented age-associated transformations, like memory and motor changes, in seniors since 1994. The assessed samples spanned individuals across the cognitive spectrum: 146 cognitively intact, 102 with mild cognitive shifts, and 144 with Alzheimer’s-related dementia.

In their first Cell article, which spotlighted alterations in gene expression, the team applied single-cell RNA sequencing on 54 distinct brain cell categories from the gathered samples. Their study revealed the cellular functionalities most compromised in Alzheimer’s patients. Notably, there were disruptions in genes crucial for mitochondrial operations, synaptic communication, and protein assemblies vital for safeguarding genome structural coherence.

This gene-centric research, steered by ex-MIT postdoctoral fellow Hansruedi Mathys alongside students Zhuyu (Verna) Peng and Carles Boix, also identified significant disturbances in lipid metabolism-linked genetic pathways. Previous work by the Tsai and Kellis teams in Nature demonstrated that the foremost genetic susceptibility for Alzheimer’s, termed APOE4, disrupts regular lipid processing, culminating in assorted cellular malfunctions.

In the Mathys-led study, they also analyzed gene expression patterns in patients with cognitive deficits and those who did not, including those who maintained their mental sharpness while having some amyloid accumulation in the brain, a trait known as cognitive resilience. According to that investigation, there were greater populations of two subgroups of inhibitory neurons in the prefrontal cortex in cognitively robust individuals. These cells seem to be more susceptible to neurodegeneration and cell death in persons with dementia associated with Alzheimer’s disease.

Mathys commented, “This revelation suggests that specific inhibitory neuron populations might hold the key to maintaining cognitive function even in the presence of Alzheimer’s pathology.

“Our study pinpoints these specific inhibitory neuron subtypes as a crucial target for future research and has the potential to facilitate the development of therapeutic interventions aimed at preserving cognitive abilities in aging populations.”

Epigenetic Insights

In the subsequent study published in Cell, spearheaded by Xushen Xiong, a former MIT postdoc, alongside graduate student Benjamin James and alumnus Carles Boix PhD ’22, the team delved into the epigenetic shifts observed in 92 participants, encompassing 48 without cognitive decline and 44 manifesting early to advanced Alzheimer’s symptoms. Epigenetic shifts refer to modifications in DNA’s chemical makeup or its structural packaging, influencing the activity levels of specific genes within cells.

Utilizing a method named ATAC-Seq, they gauged the accessibility of genomic sites at an individual cell level. When integrated with data from single-cell RNA-sequencing, it offered insights into the correlation between the expression levels of genes and their accessibility. This also paved the way to categorize genes into regulatory networks governing critical cellular activities, like synaptic transmission, which is pivotal for neuronal communication.

Through this methodology, the team pinpointed alterations in both gene expression and epigenetic accessibility linked to Alzheimer’s-associated genes. Moreover, they discerned the cell types primarily associated with the expression of these genes, discovering a notable prevalence in microglia – the brain’s immune cells tasked with debris removal.

The investigation further unveiled that as Alzheimer’s advances, all brain cell types experience what’s termed ‘epigenetic erosion.’ This suggests that the usual configuration of accessible genomic regions within cells diminishes, leading to a weakened cellular identity.

Microglia’s Function Explored

In another publication, spearheaded by MIT’s Na Sun, a graduate student, and Matheus Victor, a research scientist, attention was centered on microglia. These cells constitute between 5 to 10 percent of the brain’s cells. Beyond their role in debris clearance, these immune cells are crucial for neural communication and are actively involved in responding to injuries or infections.

Building on a 2015 research by Tsai and Kellis, it was highlighted that numerous genetic variants linked with Alzheimer’s, as identified in genome-wide association studies (GWAS), were notably more active in immune cells like microglia than in neurons or other brain cell variants.

In the recent paper, RNA sequencing was employed to categorize microglia into 12 distinct phases, determined by the varying expression levels of hundreds of genes in each phase. The study found that as Alzheimer’s intensifies, an increasing number of microglia transition into inflammatory phases. Earlier research from the Tsai team has indicated that heightened inflammation in the brain correlates with a deteriorating blood-brain barrier and compromised neuronal interactions.

Conversely, fewer microglia in Alzheimer’s-affected brains are found in a balanced, homeostatic phase essential for optimal brain functionality. The study identified specific gene regulators responsible for maintaining microglia in this balanced state. Currently, the Tsai research group is probing methods to stimulate these regulators, with the aspiration to treat Alzheimer’s by prompting the inflammatory microglia to revert to a balanced condition.

DNA Deterioration Insights

In another research, under the leadership of Boix and MIT’s Vishnu Dileep, the team delved into the role of DNA degradation in Alzheimer’s disease progression. Previous studies from the Tsai group highlighted that DNA deterioration in neurons can manifest well before any overt Alzheimer’s symptoms emerge. One contributing factor is that during memory consolidation, neurons often induce numerous double-stranded DNA ruptures. Although these are typically mended rapidly, the repair mechanism can falter as neurons age.

The new study revealed that accumulating DNA damage makes repair increasingly challenging for neurons, resulting in genomic reconfigurations and three-dimensional structural anomalies.

Dileep describes the process saying, “When you have a lot of DNA damage in neurons, the cells, in their attempt to put the genome back together, make mistakes that cause rearrangements.”

“The analogy that I like to use is if you have one crack in an image, you can easily put it back together, but if you shatter an image and try to piece it back together, you’re going to make mistakes.”

Such reconstruction errors also give rise to gene fusions. Here, gene rearrangements can lead to gene regulatory disruptions. Combined with the structural defects, these alterations seem to mainly affect genes tied to synaptic functions, which is possibly a significant contributor to the mental decline observed in Alzheimer’s patients.

These insights hint at the potential of fortifying the DNA repair mechanism in neurons as a strategy to decelerate Alzheimer’s progression.

Furthermore, the Kellis team is eager to harness cutting-edge AI tools, including protein linguistic models, graph neural networks, and expansive linguistic models, to unearth drugs that could target the pivotal genes pinpointed in their research.

Emphasizing the collaborative spirit of science, Kellis remarked, “We want the world to use this data.

“We’ve created online repositories where people can interact with the data, can access it, visualize it, and conduct analyses on the fly.”

Source: 10.1016/j.cell.2023.08.037

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