Active Brain & Nervous System Genetics & Molecular Biology

The Mechanisms Of The Cellular Phase Of Alzheimer's Disease

Funder MRC (part of UKRI)
Recipient organisation University College London Source-published name: University College London
Funding £5.2M
Period May 2023 — Mar 2028

In plain English

AI plain-English summary

Alzheimer’s disease begins decades before memory fails, as every cell type in the brain scrambles to contain damage from accumulating amyloid protein. This project argues that current treatments—which either clear amyloid plaques or try to rescue already-demented brains—miss the critical window when the brain’s own resilience mechanisms are still working. The problem is that most Alzheimer’s research has focused on two narrow targets: the sticky amyloid clumps and the tangled tau proteins inside neurons. But genetic studies show that 58–79% of the risk for sporadic Alzheimer’s comes from genes active in immune cells, blood-vessel lining cells, and other non-neuronal brain cells. That means the real action happens in what the researchers call the “cellular phase”—a long period when the whole brain ecosystem reacts to amyloid but keeps itself stable. Understanding why that stability eventually fails could reveal entirely new treatment targets. If successful, this work would provide a cellular theory of Alzheimer’s progression, identifying the specific steps where the brain’s natural defences break down. That could shift drug development away from late-stage rescue and toward therapies that bolster the brain’s own resilience—potentially preventing dementia rather than treating its end-stage symptoms. This is fundamental science: it will not produce a drug tomorrow, but it redefines where to look for one.

View original technical description
Alzheimer's disease (AD) remains one of the areas of greatest unmet medical need. AD is a slow process evolving over decades, with a long prodromal phase before clinical symptoms appear. This, together with the complex genetic architecture of sporadic AD, made it necessary to revise the reductionist models for AD pathogenesis. We defined the concept of "the cellular phase of AD", discussing how all cell types of the brain react to amyloid pathology yet maintain the brain for a long time in homeostasis. It is only in the end phase of the disease that the brain functionally collapses giving rise to the clinical phase. In addition, the high heritability (58-79%) of sporadic AD suggests that genetic risk is an important determinant of these cellular reactions. A large part of genetic risk of AD is in genes that are expressed in cells other than neurons, reinforcing the concept that the cellular phase is crucial to understand the progression of AD towards dementia. In the current project we focus on our chimeric mouse models and how they can be used to capture polygenic risk in human cellular models of disease with the aim of understanding mechanisms. The overall aim of the work is to provide a cellular theory for AD and to identify critical steps in the pathological process. In contrast to current therapies that focus on blocking the appearance of the biochemical hallmarks of AD or attempting to treat end-stage dementia (Long and Holtzman 2019), therapies that engage the natural resilience mechanisms of AD promise a new and possibly more effective path to a cure.

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Researchers

Bart De Strooper (Principal Investigator)Irma Arancibia-Carcamo (Co-Investigator)

Related Research

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Original classification

Research Grant

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