How familial cases are helping us model a crippling brain disease when it counts

A neurology professor of mine once stated that “if you want to make a good diagnosis, choose neurology, but if you want to cure diseases, you may want to choose something else.”

Consider Alzheimer’s disease (AD), a crippling and ultimately fatal disease that try as we might we have not been able to cure, prevent or even treat effectively. Although mouse studies have shown promising results in ameliorating the disease clinical trials have ultimately failed to slow the progression of disease. Today, there is little that can be done for the 35 million people suffering with this horrible neurodegenerative disorder.

Some fault the transgenic animal models, which have typically been used to test new drug compounds preclinically. Transgenic models have been blamed because the treatment is usually given prophylactically, while clinical studies are conducted in AD patients with advanced disease.

There is no doubt that a discrepancy exists between the animal models and the clinical studies, but rather than blame one or the other let’s focus for a minute on the purpose of the models and the clinical studies that have tried unsuccessfully to replicate those outcomes.

Firstly, it’s important to understand that transgenic models are not complete representations of the disease. While they have been re-engineered to mimic some of the pathology of AD, they are not our genetic twin. Moreover, the typical mouse only lives around two years, a major challenge when studying diseases of aging. With that said, the prophylactic dosing regimen is in many cases justified because scientists are looking for proof-of-concept mechanisms and an optimal therapeutic window in AD models that have been adapted to accommodate the much shorter life-span of the mouse.

On the other hand clinical trials have generally focused on end-stage patients with severe neuron loss. The neurons responsible for memory and cognition are gone. Diagnosing Alzheimer can be challenging, too, and is usually only made after other forms of dementia have been ruled out. At this point the disease is already so far advanced there is nothing that can be done to arrest it or slow it down.

Where to go from here?

One could adapt the preclinical models to be more representative of the human condition, and thus treat transgenic mice with Alzheimer’s-like symptoms during the latter stages of disease. But this would limit the full potential of the models and the early therapeutic window they provide.

So instead of changing the Alzheimer’s models to meet the clinical situation, the clinical studies are changing to meet the models. And they are doing so with the help of a rare group of individuals whose specific genetic traits make them particularly vulnerable to AD.

Though Alzheimer’s is largely seen in the elderly, a number of clinical studies have been tracking a much younger cohort of individuals with familial i.e. inherited Alzheimer’s, a rare form of the disease that is found in less than 5% of people and is caused by different single-gene mutations on chromosomes 21, 14 and 1. Patients, some beginning in their 20s, have been receiving medical examinations and brain imaging tests every few years. The studies include individuals who carry the genetic allele that causes AD, and their siblings who do not have the mutation.

Based on these studies of familial AD, researchers and clinicians alike have gained a good understanding of how Alzheimer’s progresses over a period of up to 20 years. And one thing they have learned is that like any disease it’s better to hit early. With that in mind, researchers have begun treating familial cases of AD 10-15 years before the symptoms emerge—in other words prophylactically—using drugs that, ironically, didn’t work in studies of late-stage patients.

Will this hypothesis pay off? Well, this groundbreaking idea is exactly the paradigm most often used with preclinical models, where the treatment begins, relatively speaking, long before the first memory deficits appear and well before the formation of plaques in the brain.

In the end it does not really matter what is changing, the model or the outline of a clinical study. The important thing is that the gap between preclinical and clinical studies is being narrowed and new therapies have a chance to show their efficacy both preclinically and clinically.

Let’s hope this strategy brings some hope and fresh insights to AD patients and their families.


How to cite:

Ahtoniemi, T. Ancestry and Alzheimer’s. Eureka blog. Jun 22, 2015. Available: