Alzheimer’s Dementia: A Primer

Alzheimers Dementia A PrimerPlaques and Tangles, Amyloid deposits and Apo-E: Who can keep them straight? Unless you are a researcher, all you really need to know is how to diagnose dementia, and how to dose the acetylcholinesterase inhibitor du jour.

Nonetheless, being able to talk intelligently about current research is always a good thing for professionals, is certainly impressive to your patients, and may theoretically be entertaining for spouses during long road trips (but probably not).

Neuritic Plaques. On a slice of brain under the microscope, neuritic plaques look like ugly gobs of material crowding out neurons. But plaques begin their lives delicately, as a dance of scissor-like enzymes. At birth, all of our brains inherit a protein called amyloidprecursor protein (APP). APP’s function is not clear, but it is thought to do something useful in helping us to think our ways through life.

Eventually APP gets broken down by an enzyme called alpha secretase, with the residues dissolving harmlessly in the extracellular fluid, to be whisked away from the brain. But two evil enzymes, beta and gamma secretase, sometimes snip APP in the wrong places, leaving fragments that tend to clump together into beta-amyloid deposits, also known as “A-beta”. A-beta then forms itself into insoluble beta-pleated sheets in between neurons. These sheets are not only neurotoxic, but also, being foreign bodies, attract white blood cells. Eventually, a whole morass of amyloid, dead neurons, and inflammatory tissue congeals to form neuritic plaques.

Neurofibrillary tangles. Meanwhile, via an apparently unrelated, but equally gory process, the scaffolding of our neurons is collapsing. Tau is a protein that supports the microtubules that keep cells in good shape. In old age, tau gets hyperphosphorylated, peals away from its microtubules, and forms helical unions with neighboring tau proteins. These helical filaments aggregate with others, eventually forming the infamous neurofibrillary tangles.

Acetylcholine. At this point, we are left with a picture of a pretty botched brain. Surveying the extent of the slaughter, one might assume that any neurotransmitters left would be zinging around in mazes and slamming into dead ends. So why the particular focus on acetylcholine?

Anyone who has taken a course in pharmacology recalls how much lecture time is devoted to acetylcholine (ACh). There are ACh receptors all over the body, explaining the multiple pesky actions of anticholinergic drugs (tachycardia, blurred vision, constipation, dry mouth, cognitive impairment). In the brain, most of the cholinergic neurons are concentrated in one particular area, toward the front, and close to the base. This area is called the nucleus basalis of Meynert. Long axons extend from the cholinergic cell bodies here to reach the hippocampus, the amygdala, and the cortex.

This article originally appeared in The Carlat Psychiatry Report -- an unbiased monthly covering all things psychiatry.
Want more, plus easy CME credit?
Subscribe today!

In Alzheimer’s Disease (AD), plaques and tangles initially zero in on “Meynert,” raining havoc preferentially on cholinergic neurons, which explains why drugs that increase ACh levels at this early stage are so effective. As AD progresses, degeneration spreads throughout the brain, eventually affecting the entire population of neurons and neurotransmitters.

Apo-E. Patients may ask you if they should be tested for “Apo-E” in order to determine their risk of getting AD. The scoop here is that apolipoprotein-E in itself is not at all bad, being a good all-around transport protein in the body. One of its functions is to bind with evil beta amyloid and clear it from the brain, thereby preventing the formation of plaques. However, a genetic variant of Apo-E, called E-4, is ineffective at binding to amyloid.

There are three different genetic versions (alleles) of the Apo-E gene: E2, E3, and E4. We inherit one allelle from each parent, so there are 6 different variations possible in our genetic makeup. If you are lucky enough not to have inherited E4 from either of your parents, you have only a 20% chance of getting AD by the time you’re 80. If you are heterozygous for E4 (ie, you inherited E4 from only one parent), your risk goes up to 50%. If you are homozygous (E4 from both parents), you have, unfortunately, a 90% risk of AD by age 80. By the way, the Apo-E allele confers an even higher risk of AD if you are a woman.

So, should all your patients be offered Apo-E testing? A tricky issue. The test itself involves no more than a blood draw, and costs about $300 if paid privately, though some insurance companies cover it. However, most experts feel that the testing does more harm than good, because it causes such tremendous anxiety in patients who test positive, and there is little that can be offered to them in the way of preventing AD.

TCR VERDICT: Avoid Beta Amyloid; Don’t Phosphorylate your Tau !

Alzheimer’s Dementia: A Primer

This article originally appeared in:

The Carlat Psychiatry Report
Click on the image to learn more or subscribe today!

This article was published in print 10/2003 in Volume:Issue 1:10.

The Carlat Psychiatry Report

Carlat Publishing provides clear, authoritative, engaging, independent psychiatric education to make you look forward to learning, with the goal of helping you feel smarter, more competent, and more confident in your ability to help your patients become happy. We receive no corporate funding, which allows a clear-eyed evaluation of all available treatments. Learn more and subscribe to one of their newsletters here.


APA Reference
Psychiatry Report, T. (2013). Alzheimer’s Dementia: A Primer. Psych Central. Retrieved on October 27, 2020, from


Scientifically Reviewed
Last updated: 3 Apr 2013
Last reviewed: By John M. Grohol, Psy.D. on 3 Apr 2013
Published on All rights reserved.