



Greater than 90% of all Alzheimer’s disease (AD) cases are sporadic, meaning there are few hereditary risk factors for developing the disease. Although certain genetic variants increase the risk of AD, age is the strongest known risk factor. Yet, understanding how the underlying molecular mechanisms of aging predispose individuals to AD has remained elusive. Now, a team of researchers from the Perelman School of Medicine at the University of Pennsylvania have discovered what they believe are changes to the normal epigenetic landscape that lead to the onset of Alzheimer’s.

Findings from the new study—published recently in Nature Neuroscience in an article entitled “Dysregulation of the Epigenetic Landscape of Normal Aging in Alzheimer’s Disease”—profile the epigenomic landscape of AD brains, specifically in one of the regions affected early in AD, the lateral temporal lobe. They compared these findings to both younger and elderly cognitively normal control subjects. The team described the genome-wide enrichment of a chemical modification of histone proteins that regulate the compaction of chromosomes in the nucleus (called acetylation of lysine 16 on histone H4, or H4K16ac for short). Changes to the way H4K16ac is modified along the genome in disease versus normal aging brains may signify locations for future drug development.





“This is the first time that we have been able to look at these relationships in human tissue by using donated postmortem brain tissue from the Penn Brain Bank,” explained senior study investigator Shelley Berger, Ph.D., a professor of cell and developmental biology in the Perelman School of Medicine and a professor of biology in the School of Arts and Sciences.

H4K16ac is a key modification in human health because it regulates cellular responses to stress and DNA damage. The team found that, while normal aging leads to increasing H4K16ac in new positions along the genome and an increase in where it is already present, in great contrast, AD entails losses of H4K16ac in the proximity of genes linked to aging and AD. In addition, the team discovered an association between the location of H4K16ac changes and genetic variants identified in prior AD genome-wide association studies.

“Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls,” the authors wrote. “We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles.”

The three-way comparison of younger, older, and AD brain tissue revealed a specific class of H4K16ac changes in AD compared to normal age-established changes in the brain. This finding indicates that certain normal aging changes in the epigenome may actually protect against AD and when these go awry, a person may become predisposed to AD.

“These analyses point to a new model of AD,” noted lead study investigator Raffaella Nativio, Ph.D., a postdoctoral fellow in Dr. Berger's lab. “Specifically, it appears that AD is not simply an advanced state of normal aging, but rather dysregulated aging that may induce disease-specific changes to the structure of chromatin—the combination of histone proteins and DNA.”

The accumulation of intercellular amyloid plaques and neurofibrillary tangles are the two hallmarks of AD that drive the death of neurons and the corresponding loss of cognitive abilities. However, expression of plaques and tangles is very late in the development of AD, while epigenomic alterations might occur much earlier and represent targets to attack with medications.

The authors emphasized that this study does not suggest a cure for AD, but rather the possibility of finding ways to prevent nerve cell death and enhance the quality of aging. Their upcoming experiments aim to discover the physiological changes that cause the decrease of H4K16ac specifically in AD brains, but not in normal-aged brains.

“…we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD,” the authors concluded.























