ELSC Seminar Series

Alzheimer’s disease is a devastating neurodegenerative disease of advanced age that progresses slowly over 20 years. In this talk, I will present our current efforts to understand mechanisms of disease and to develop better therapeutic solutions to promote healthy brain aging. To effectively treat the disease there is a need to shift from correction therapies at late stages of the disease, to early detection and prevention therapies at the pre-symptomatic stage of the disease, before any signs of memory loss. Yet, for developing effective prevention therapies there is a need to elucidate the specific changes in brain cells throughout the course of the disease and to distinguish between disease and healthy brain aging. To address this, we are applying cutting edge molecular technologies and machine learning methods to define the cellular and molecular events underlying the processes of disease and aging in mouse models and Human brains. Specifically, I will describe several recent works in which we built detailed cellular maps of close to 500 human aged brain. Our maps identified specific sets of glial cells predicted as early drivers of the disease. Furthermore, we devised a new methodology to predict trajectories of cellular change in aging brains, which uncovered two distinct paths during aging with coordinated changes across brain cells. We showed that one of these paths leads to Alzheimer’s Disease-dementia while the other path leads to alternative brain aging. Moreover, we uncovered selective vulnerability of neuronal cells in Alzheimer’s disease and a link between microglia and neurons at early disease stages. This discovery overcame several major obstacles in the field, and uncovered molecular markers in the brain that distinguishes between disease and aging at an early pre-symptomatic stage of the disease and highlights the differences between the two processes. Our work provides a new perspective of Alzheimer’s Disease pathophysiology that could inform the development of new therapeutic interventions.

“The Road Not Taken” By Robert Frost
Two roads diverged in a yellow wood,
And sorry I could not travel both
And be one traveler, long I stood
And looked down one as far as I could

To where it bent in the undergrowth;
Then took the other, as just as fair,
And having perhaps the better claim,
Because it was grassy and wanted wear;
Though as for that the passing there

Had worn them really about the same,
And both that morning equally lay
In leaves no step had trodden black.
Oh, I kept the first for another day!
Yet knowing how way leads on to way,
I doubted if I should ever come back.

I shall be telling this with a sigh
Somewhere ages and ages hence:
Two roads diverged in a wood, and I—
I took the one less traveled by,
And that has made all the difference.