Over 95% of all Alzheimer’s is of the sporadic form that can afflict anyone

During the ageing process, many individuals experience a progressive build-up of insoluble and soluble lumps of a peptide denoted Aβ42 in the brain. The soluble lumps, or “oligomers”, can attach to nerve cells and cause synapse dysfunction. Eventually, this process leads to cell death which, ultimately, will kill the individual.

Positron emission tomography (PET) imaging of Aβ plaques using the PiB tracer. Alzheimer brain (top) and normal brain (bottom). Image courtesy of Prof A. Nordberg, KI, Sweden.

The Story

What causes Alzheimer’s?

Alzheimer’s disease is a disease of the brain. Disease often starts with mild symptoms and ends with severe brain damage and death.

Neuropathological hallmarks found in deceased patients include synaptic loss, neurodegeneration, the extracellular deposition of insoluble fibrillar amyloid aggregates of the amyloid-β (Aβ) peptide in neuritic plaques, and the intracellular deposition of insoluble aggregates of the protein “tau” in neurofibrillary tangles (NFTs).

The deposition of especially one form of Aβ, denoted Aβ42 and which typically constitutes 10% of all Aβ, into plaques is the earliest neuropathological sign of disease. This process can start decades before memory symptoms appear. The Aβ peptide is generated throughout most of the body as the transmembrane amyloid-β precursor protein (APP) is proteolytically processed (cleaved into fragments by other proteins) during normal cell functioning.

Although the Aβ42 peptide has been identified as the main culprit in the disease, the mechanistic aspect of Aβ pathology has been elusive. In fact, it is now understood that the association between neurodegeneration and plaque load in patients is not as clear as originally believed, as plaques are commonly found in healthy individuals and their correlation with cognitive impairment is not convincing.

Instead, it is the soluble aggregated forms of Aβ42 (or “oligomers”) that are found to be particularly neurotoxic when compared to non-aggregated and fibrillar forms of the same peptide. These oligomers are therefore very attractive therapeutic targets. But targeting the oligomer form of Aβ with therapeutics has historically been extremely challenging. It is a lot like targeting a “needle in a haystack” as other much less toxic (or even non-toxic) forms of the same peptide dominate within the brain (as fibril deposits and non-aggregated peptides) and also in the circulatory system (non-aggregated forms).

It is therefore likely that true specificity for the oligomer is required for effective therapeutic engagement of the target across the blood-brain barrier. Previous attempts at removing toxic Aβ using immunotherapy have lacked this critical feature. As a result, an indirect effect on the disease process was probably only achieved, resulting in complicating side effects and either a complete lack of therapeutic efficacy or a very marginal one.

Alzinova’s lead candidate vaccine ALZ-101, and the monoclonal antibody ALZ-201, are both designed to minimize redundant cross-reactivity with generic Aβ, to provide increased specificity towards toxic oligomers.

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