Jun 16, 2022 / Neuroscience

What a tangled web it weaves: Untangling the complex biology of dementia at the ADRD Symposium

Josh Azevedo

According to the World Health Organization, 55 million people globally have been diagnosed with Alzheimer’s disease (AD) or a related dementia. AD is the seventh leading cause of death. A new case is diagnosed every three seconds. It is responsible for more than half of all dementia cases. These numbers, which are expected to accelerate, are punctuated by a smaller one: there are zero known disease-modifying therapies.

AD is not only debilitating, it is also highly complex. But researchers are working tirelessly to uncover the mechanisms of disease and novel therapeutic targets. We showcased some of their accomplishments at our recent Alzheimer’s Disease and Related Dementias Symposium and, in honor of Alzheimer’s and Brain Awareness Month, we want to highlight how they’re untangling the complexities of AD, neuron by neuron.

Familial and sporadic: Examining the cellular bases of AD subtypes

From a genetic perspective, AD can be sorted into two categories: autosomal dominant (ADAD, typically caused by mutations in APP, PSEN1, or PSEN2) or sporadic (sAD), which is more genetically complex. While clinically similar, the underlying cellular mechanisms of these AD subtypes may vary substantially. To address this, Oscar Harari, PhD, (Assistant Professor, Washington University in St. Louis) performed single nuclei sequencing of 9 control, 16 ADAD, and 31 sAD cases.

Emphasizing the complexity of AD, Dr. Harari identified multiple subclusters for each cell type. While similar differential gene expression trends were found in both ADAD and sAD (e.g., microglia and astrocytes tended to exhibit upregulated and downregulated genes, respectively), these trends tended to be stronger in ADAD.

In addition to multiple cell (sub)types, Dr. Harari and colleagues found a variety of transcriptional cell states. Multiple AD-associated cell states, including a damage-associated astrocyte and stress-gene-enriched microglial subtype, were also seen in 5xFAD mice (a model of Alzheimer’s where mice carry three mutations in amyloid precursor protein and two in presenilin 1). Speaking to the strength of their findings, they were able to replicate their results in an independent cohort of human nuclei. Watch Dr. Harari’s full on-demand webinar to see what else they found.

When aging goes wrong: Characterizing CSF in health and neurodegenerative disease

While inflammation has been established as a central hallmark of AD, our understanding of how the adaptive immune response plays a role is less clear. In his talk at the symposium, David Gate, PhD, (Assistant Professor, Northwestern University) examined adaptive immunity in the cerebrospinal fluid (CSF) of AD patients and controls.

Dr. Gate initially characterized a signature of increased CD8+ T cells in CSF that correlated with cognition and AD status, and were also expanded in AD and Parkinson’s disease (PD) patients. Using single cell T-cell receptor sequencing (scTCR-seq), his group demonstrated that, while only 10% of healthy controls showed this expansion, 66% of AD and 33% of PD patients had high expansion of antigen-specific, cytotoxic, and proinflammatory CD8+ T cells. Watch Dr. Gate’s full webinar on demand to learn more about his findings.

Unraveling dementia’s tangled web

Alzheimer’s disease and related dementias are devastating, intricate, and complex illnesses—but they are not unsolvable. We’d like to thank all the presenters who showcased their work untangling the complex biology of dementias, as well as the attendees who joined us. Your enthusiasm made the 2022 ADRD a resounding success, and we look forward to seeing you next year! In the meantime, discover a little more about some of the technologies our presenters used, and see what they can do for your research.