The pathophysiological changes associated with the development of Alzheimer’s disease (AD) include the accumulation of toxic amyloid-β, hyperphosphorylation of tau protein, and development of neurofibrillary tangles, neurodegeneration, and dementia. Although much is known regarding the roles of amyloid and tau in the development of AD, several important questions remain unanswered.

We know that amyloid comes from APP, which is cleaved by α-secretase and γ-secretase. This gives you soluble APP-α, which is part of the normal cycle of physiology and is cleared. In AD, the cleavage mechanism changes from α-secretase to β-secretase, so you instead have the cleavage of APP by β-secretase and γ-secretase. This creates a 42-amino acid amyloid as opposed to a 40-amino acid amyloid. That 42-amino acid amyloid monomer then goes through a multistep process to become a dimer, an oligomer, a protofibril, a fibril, and a plaque. This process is considered the earliest seminal event that leads to downstream changes. Interestingly, the brain does not react to the presence of the amyloid monomer until it becomes an oligomeric species, which is considered the toxic species that triggers a response.

It is thought that amyloid triggers tau. In neurons, microtubules are held together with tau-stabilizing proteins. In the AD brain, tau becomes hyperphosphorylated. This ultimately leads to nonbinding of tau to the microtubules and the formation of paired helical filaments and neurofibrillary tangles. These hyperphosphorylated tau forms get released into the cellular milieu, and it is theorized that they may get taken up by adjacent neurons. The hyperphosphorylation of tau is important because we know that the tau spread correlates much better with the clinical progression of disease than the amyloid spread.

So, although amyloid is the earliest seminal event in the development of AD, it is the spread of tau that correlates with cognitive decline. Once amyloid is present, tau starts to spread. If tau is present without amyloid, you may have a neurodegenerative disease. It is just not AD. I like to call amyloid the “match” and tau the “fire.” You need amyloid, but that is not the main driver of disease once tau spreads.

We do have gaps in our knowledge of amyloid and tau. For example, how does amyloid trigger the hyperphosphorylation of tau? Second, how are we going from an α-secretase to a β-secretase pathway? We also think of AD as being a sequential disease (ie, amyloid followed by tau, followed by other things), but now we are beginning to consider that perhaps inflammation is an early event, which may lead us to rethink our whole approach.

AD is the diabetes and HIV of our time. We are on the cusp of being able to transform AD from a terminal disease to a chronic disease. We did it with diabetes. When I was in medical school, if a person had diabetes, it was just a matter of when—not if—they were going to be on dialysis, blind, and amputated. Now, people with diabetes are able to live normal lives, and we are going to achieve the same thing for people with AD.