By Paul Aisen, M.D.

Director, Alzheimer’s Disease Cooperative Study
Professor of Neurosciences, University of California San Diego

There has been much discussion in the news lately as to whether the amyloid hypothesis is the correct path for research. The amyloid hypothesis is supported by a huge body of evidence, but to my thinking the most convincing support is based on genetically determined Alzheimer’s disease (AD).

Mutations of three different genes can cause familial autosomal dominant (FAD) AD in affected families. In such families, the mutated gene is causative, that is each child who inherits the mutated gene (each child of an affected parent has a 50% chance of inheriting the mutated gene) will definitely develop the disease, often within a narrow age range (e.g. between ages 38 and 41).

A gene codes a single protein. When a gene causes a disease, it means that the protein coded by that gene causes the disease. So we know that AD can be caused by the proteins coded by the mutated genes for three different proteins. These proteins must be sufficient to cause familial AD.

And what are these proteins? APP (the amyloid precursor protein), PS1 (presenilin 1) and PS2. What do these mutated proteins have in common? The proteins are each directly involved in generating the amyloid peptide. The mutations of APP associated with FAD each alter one of the cleavage sites of APP in a way that leads to excess generation of the amyloid peptide. PS1 and PS2 are components of the gamma secretase complex.

Gamma secretase is one of the two enzymes required for generating the amyloid peptide, and the causative mutations increase the generation of the most toxic form of the peptide. So each of the mutations does the same thing: increases generation of toxic amyloid peptide. The only reasonable conclusion is that this peptide causes FAD.

Now, almost all cases of AD are sporadic; FAD is rare. But though there are variations to the presentation of FAD, it really only differs from sporadic AD in terms of age of onset and inheritance. This very strongly indicates that sporadic AD is also triggered by amyloid peptide.

Why is there too much amyloid peptide in sporadic AD, that is, in the absence of the mutations that cause FAD? There are likely multiple factors, both genetic (e.g. APO E genotype), biological (e.g. aging) and environmental (head trauma, lifestyle) that alter amyloid generation. These factors together determine susceptibility to sporadic AD.