Alzheimer’s Disease: A Tough Nut To Crack

Alzheimer’s disease: A tough nut to crack

September 21 is World Alzheimer’s Day, a day focused on raising awareness of Alzheimer’s disease (AD). This week and next, we’ll review what is known about AD, and summarize novel treatments in development.

Alzheimer’s disease (AD) ranks as one of the toughest nuts to crack within drug discovery and development. Current treatments merely manage symptoms, so finding a better solution becomes more and more urgent as the aging population grows.

Approximately 70 percent of dementia cases are caused by AD. It is a neurodegenerative disorder which means neurons progressively lose structure and function. As the disease continues and more neurons are damaged and die, symptoms get worse. Neurons in the hippocampal region of the brain associated with memory formation are among the first affected. By 2025, the number of people age 65 and older with AD is projected to reach 7.1 million—a 40 percent increase from the 5.1 million affected in 2015 (Alzheimer’s Association).

A number of different companies are working to develop treatments, with several already in clinical trials. These drug candidates include a few that target the familiar amyloid-beta (Aβ) plaques and tau tangles, and several others that represent an entirely new approach to the disease. With no clear winner in sight, all-comers are welcome in the attempt to defeat this devastating disease.

PLAQUES AND TANGLES

Plaques

Alzheimer’s disease is associated with the build-up of amyloid-beta (Aβ) plaques in patients’ brains. But what, exactly, are Aβ plaques? Aβ plaques derive from the cleavage of a protein called the amyloid precursor protein, which is thought to play a role in the formation of synapses. Individual Aβ molecules clump together to form the plaques associated with Alzheimer’s.

Until recently, the mechanism by which Aβ plaques might cause Alzheimer’s was not known. Recent research from Stanford University suggests the plaques bind to a receptor on nerve cells, disrupting their function. However, there is no absolute consensus on whether these clumps of protein are the origins of AD or a symptom of the underlying cause.

Tangles

Another brain protein associated with Alzheimer’s is tau, which is concentrated in the neurons and is primarily understood as a component in stabilizing nerve cell structure. Abnormal aggregates of tau form “tangles” within nerve cells. These tangles are correlated with the onset of Alzheimer’s along with the characteristic plaque formations.

GENETICS PLAYS A ROLE

About 70% of Alzheimer’s cases are thought to have at least some genetic association, with different genes being implicated depending on the type of Alzheimer’s.

A gene found on chromosome 19 called the apolipoprotein E gene (APOE) influences the development of late-onset Alzheimer’s. Individuals with different variants of the APOE gene have different risk profiles:

• Variant ε2 (APOE2) is rare and possibly lessens or delays Alzheimer’s onset
• Variant ε3 (APOE3) is neutral
• Variant ε4 (APOE4) is associated with a significantly increased risk of Alzheimer’s

The APOE proteins plays a role in clearing Aβ from the brain, with APOE4 carrying out this function less efficiently than the other variants. There is also some evidence that APOE4 contributes to the breakdown of the blood-brain barrier seen in patients, resulting in increased brain inflammation—another marker of Alzheimer’s. A better understanding of APOE4’s role in Alzheimer’s onset may lead to the development of a whole new class of drug. (Article continues below)

IF AT FIRST YOU DON’T SUCCEED…

A number of drug developers have attempted to use monoclonal antibodies (mAbs) to disrupt the formation of the AD-associated Aβ plaques. Unfortunately, this approach has yet to experience clinical success. However, this doesn’t mean that the approach is not viable—different mAbs attach to different parts of Aβ, meaning that the outcome of one mAb trial does not necessarily predict the outcome of another. Roche (Basel, Switzerland) has an mAb therapy, gantenerumab, targeting Aβ plaques in Phase III clinical development. In earlier phase studies, this mA showed the most promise in patients with less advanced forms of the disease.

The prevention of Aβ plaques is also the focus of growing interest in creating an AD vaccine. Leading this effort is Novartis (Basel, Switzerland), whose CAD106 vaccine contains fragments of the Aβ protein and has been shown to be safe in Phase I trials. The goal of the vaccine is to activate an immune response against Aβ, thereby reducing its accumulation and potential to form plaques in the brain. CAD106 is currently in Phase II studies of efficacy, in which the vaccine is being tested in cognitively normal individuals between the ages of 60 and 70 who are at high risk of developing the disease based on their APOE4 status.

UNTANGLING TAU 

AbbVie (North Chicago, IL) is targeting tau, the other major protein associated with AD. The company currently has an anti-tau mAb therapy, ABBV-8E12, in Phase II clinical testing, and has also announced a partnership with Voyager Therapeutics (Cambridge, MA) to develop a gene therapy treatment that targets tau. The treatment will deliver a gene encoding an anti-tau antibody directly to cells in patients’ brains, enabling those cells to make the antibody. If successful, this would bypass altogether the blood-brain barrier that makes it difficult for some drugs to even enter the brain.

Ionis Pharmaceuticals (Carlsbad, CA) is in Phase I/IIA clinical studies of their tau-targeting drug, IONIS-MAPT. This antisense drug targets the source of the tangles associated with AD. Like other antisense drugs, IONIS-MAPT destroys tau mRNA, thereby diminishing tau protein production.

Amyloid-beta and tau remain tantalizing targets for AD drug development because of their close association with the disease. However, new approaches are springing up as frustration over the lack of progress in treating this devastating disease grows. Next week, we’ll examine some of these alternative strategies.