A primer on amyloid, tau and PET scans

In retrospect, my first symptom of Alzheimer’s disease occurred in 2006 when I first noticed a decrease in my sense of smell.  About a year later I started having illusory odors that were always the same but which were not the result of any real olfactory stimulus.  Over the next few years my sense of smell disappeared entirely.  In 2012 I accidently discovered that I have two copies of the APOE-4 allele, a genetic combination that greatly increased my chances of developing Alzheimer’s disease. At that time, I had no symptoms of cognitive impairment, but I knew that I was at risk. In 2015 I first noticed some subtle memory problems, but when I underwent cognitive testing I passed with flying colors.

Soon after, I was invited to join a longitudinal research study to track people at risk for Alzheimer’s disease using in-depth cognitive testing, high resolution MRI scans, and amyloid- and tau-PET scans.

Amyloid (also called beta-amyloid, amyloid-beta, and Aβ) is a protein that forms tiny clumps in the brain called amyloid plaques.  These plaques occur in the spaces between nerve cells, and they start to form up to 20 years before any cognitive signs of Alzheimer’s disease occur.  Up to 30% of people found to have amyloid in their brain after death have not yet developed Alzheimer’s, but everyone with Alzheimer’s has amyloid plaques.

Abnormal tau protein forms spiral clumps within nerve cells called neurofibrillary tangles.  These neurofibrillary tangles start to occur near the onset of cognitive impairment or even a few years before.  The combination of amyloid plaques and neurofibrillary tangles is required for a neuropathological diagnosis of Alzheimer’s disease.

When I first began practicing neurology in 1989, the official diagnosis I would give a patient who, based on clinical presentation, appeared to have Alzheimer’s disease would be “senile dementia of the Alzheimer’s type” (SDAT).  At that time there was no way to conclusively make a diagnosis of Alzheimer’s until examining the brain after death and finding the obligate amyloid plaques and neurofibrillary tangles.  Other forms of dementia including dementia with Lewy bodies, Parkinson’s disease, frontotemporal dementia, and vascular dementia often looked different, but there was a lot of overlap, and many patients ended up having more than one type of dementia pathology at autopsy.  I would get a CT or MRI scan of the brain and some lab tests to rule out treatable mimics of dementia such as certain strokes or brain tumors, normal pressure hydrocephalus, hypothyroidism and vitamin B12 deficiency, but that was about all I had to work with in 1989. Within a decade, spinal fluid tests for amyloid and tau could provide extra information, first in research studies and later in the clinic. But they required scrupulous collection techniques, were uncomfortable for the patient and sometimes unreliable. 

PET scans (Positron Emission Tomography) have offered a diagnostic leap forward.  In a brain PET scan, chemicals that bind to either amyloid or tau in the brain are labeled with a very tiny amount of radioactivity and then injected into a vein.  The subject’s head is then scanned in a machine a little like a CT scanner that detects the radiation given off by the injected chemical after it has bound to its target in the brain.  The scanner and a computer then construct an image showing the location of amyloid or tau in the brain. Areas with high amounts of amyloid (or tau in a tau-PET scan) will show up as yellow, orange or red with red representing the greatest concentration. For example, this amyloid PET scan of two horizontal slices through my brain in 2015, a time when I my cognitive tests were still normal, shows a moderate amount of amyloid in my prefrontal cortex, a part of the brain involved with executive functions such as making plans, as well as in the piriform cortex and medial orbitofrontal cortex, both centers for processing olfactory information. This seemed to be a pretty cool correlation at the time between specific changes in my brain and my nearly 10 years of progressive olfactory impairment.

Amyloid and tau PET scans are now FDA approved for clinical use, but they are very expensive and not always covered by insurance. There is no controversy about their use in research studies to confirm that subjects for a drug trial do indeed have Alzheimer’s disease.  But there is a lot of controversy about using these scans clinically, especially in people who have no symptoms yet of dementia.  This is an evolving discussion that I will return to in later posts.