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Impact of EOFAD on Alzheimer's research

An exploration into the impact EOFAD has had on the greater Alzheimer's disease research field

The predictability of EOFAD has given researchers the ability to better understand, detect, and identify Alzheimer’s disease, contributing to breakthroughs now and in the future that will someday allow us to treat and prevent the disease. EOFAD’s hereditary nature holds an inordinate amount of power — knowing ahead of time who is at risk and who is going to develop Alzheimer’s disease due to a mutation and the information that those mutations have provided to the field of Alzheimer’s disease research cannot be overstated. And because EOFAD’s pathology (amyloid plaques and tau tangles) and progression is similar in many aspects to the more common forms of Alzheimer’s disease, many of the discoveries that have come out of harnessing the power of EOFAD mutations can be and have been applied to all forms of Alzheimer’s disease.

Why are Alzheimer’s researchers so interested in EOFAD?

In the early 1990s, scientists discovered mutations in families that have a dominantly inherited form of Alzheimer’s disease and demonstrated that those mutations cause the disease. From that molecular understanding, that a single genetic mutation in the DNA code causes Alzheimer’s disease, came a molecular revolution in the field of Alzheimer’s disease research. Mutations could be taken and put into cells in a lab dish or in animals to help conduct experiments and understand how Alzheimer’s disease starts, forms, and progresses into dementia. These experiments, made possible by the discovery of EOFAD mutations, opened up the possibility that once you understood how Alzheimer’s could start and progress, researchers could ask the question: what methods do we have and can we develop to detect, and ultimately, stop the disease in people?

EOFAD mutations powered research in a variety of labs all around the world in the quest of developing a cure for Alzheimer’s disease. From those mutations, the first specific treatments (that targeted the pathology of Alzheimer’s disease - amyloid plaques and tau tangles) were developed. Labs figured out they could immunize mice against amyloid-beta proteins and protect them from getting amyloid plaque pathology. From those immunizations, the mice created antibodies to protect them against amyloid-beta accumulation in their brains. Almost all of the current treatments now in clinical trials that we hear come from discoveries made from those immunization studies, including the monoclonal antibodies gantenerumab and aducanumab (a controversial drug marketed as Aduhelm and recently granted accelerated approval by the FDA). These experimental treatments have essentially all been developed from the initial findings of how to counteract amyloid plaques caused by EOFAD mutations. It’s an example of just how powerful and influential the discovery of EOFAD mutations has been on the field.

What is the history of the discoveries in science and Alzheimer’s research that have been made due to EOFAD mutations?

In the past decade, thanks to the DIAN/DIAN-TU researchers and participants, researchers have come to understand how Alzheimer’s disease progresses in an individual diagnosed with Alzheimer’s disease. One of the biggest findings of the DIAN Observational study was that in individuals with an EOFAD mutation, amyloid plaques start developing in the brain about 20 years before an individual starts to show any signs of memory loss. That was the first confirmatory data in the field that showed this disease involves a long process of (previously undetectable) changes in the body and brain.

In the image below, you can see the different biomarker changes (represented by different lines) that occur in early onset familial Alzheimer’s disease research participants with disease-causing mutations. For example, beta-amyloid (Aß) deposition begins to increase in the brain around 20 years prior to symptom onset, whereas tau (seen here as CSF tau) changes occur later in the disease. We know now that tau protein accumulation in the brain correlates with memory loss symptoms (reflected as CDR-SOB), meaning that when tau shows up in the brain symptoms are likely to occur in a few years. Once tau accumulation and disease onset occurs, brain cells begin to decline (reflected as hippocampal volume).

The discovery that amyloid changes occur in people with EOFAD mutations before symptoms develop gave strong rationale for prevention trials, particularly those that target amyloid. Primary prevention trials (see image below) seek to treat individuals before symptoms occur to prevent or delay the disease from happening. Scientists wondered: can we treat people before they have memory loss? Is there a way to stop the process before it starts? The scientific understanding and trajectory of research developed from the discovery of EOFAD mutations, and the generous contributions of research volunteers from EOFAD families (who contribute their time and bodies into investigations into their biofluids, such as blood and cerebrospinal fluid, brain scans, cognitive testing, and response to investigational drugs), have been instrumental. EOFAD mutations and families have allowed the Alzheimer’s field to gain a better understanding of Alzheimer’s disease, how it progresses, and how to develop effective therapies against it.

The next big focus in the field of Alzheimer’s disease therapeutics is tau. Again, studies in EOFAD patients illuminated the strong correlation of tau tangles to memory impairment, and highlighted the potential of targeting tau in disease prevention (in this case Secondary Prevention – see below).

It is important to say that many Alzheimer’s researchers have been and are still looking to the EOFAD families and their contributions to best understand the disease and develop the most effective therapies against it. As many EOFAD patients say: our greatest weakness is our greatest strength.

Figure: Timing of AD prevention trials related to core pathology and symptom onset

The powerful contribution EOFAD research participants have made to the field of Alzheimer’s disease

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