Causes of Dementia

Understanding the cause(s) of Dementia of the Alzheimer’s Type (DAT) and other dementia’s has been elusive. The last drug approved for DAT treatment came on the market over 15 years ago. There have been over 200 studies without useable results. What we do know is summarized in this section. We start with the result of DAT which is the breakdown of protein material into tangles/knots of fibrils inside dead neurons. What kills the neurons is unknown, but for many years scientists have believed that toxic plaques that form between neurons play a role in their cell death, and that genetic mutations affect who and how much plaque is formed.

These neurofibrillary tangles and plaques were first seen by Dr. Alois Alzheimer in the early 1900s, when he used iodine to stain thin sections of brain tissue so he could see them with a newly developed powerful microscope. Certain regions in the brain appear more susceptible to DAT as more tangles are seen indicating earlier development of the disease; e.g., deep in the hippocampal area. The hippocampus plays an important role in short-term memory (STM) formation. Thus, the association of STM deficits and DAT was established and STM deficits have been the hallmark indicator of DAT for many decades.
Will We Ever Cure Alzheimer’s is an good NYT article (11/19) to consult.

Tangles
The result of DAT is damage to the cells (neurons) of the brain. You have billions of these tiny cells which are only clearly visible with electron microscopes. Unlike other cells in the body you are born with all the neurons you will even have, as they don’t heal or regenerate once damaged. These cells serve to help transmit electrical and chemical signals among each other, and produce their power (e.g., human thoughts, actions and behavior) when networks of millions of them operate together.

If killed, like when DAT advances, the proteins inside the nucleus of a cell die and deteriorate into a broken mess that looks like tangle, or knot. These proteins are shaped like threads (the shape of protein assemblies is an important concept) and are called tau. Tau has phosphate molecules which help it bind to essential structure in the nerves system called microtubules which help transport nutrients and remove waste, they also play a role in the transportation of the neurotransmitter acetylcholine in vesicles through the neuron. Acetylcholine is released at a synapse to chemically turn on other downstream neurons, and this forms the basis of how three of our four DAT medications work; i.e., the three Aricept-type drugs.

In Alzheimer’s disease, tau proteins have a larger then usual number of phosphate molecules attached (hyperphosphorylation) and this breaks down the microtubule support system, while in turn causes tau to die and break into threads or filaments that become tangled together. They are called fibrils because when these proteins become damaged, or die, they lose their shape and in this case they become folded and then stick together in stringy masses. No longer can they serve their purpose of helping one neuron communicate (trigger or be triggered by) millions of other neurons. The tangles are tiny, inside the nucleus, inside the neuronal cell–but can be seen with electron microscopy.

Seeing these tangles serves to make a “definite” diagnosis of DAT, which relies on an autopsy when a pathologist observes these tangles, when a slice of brain tissue is placed under the microscope. Since most people won’t submit to this invasive level of diagnosis (a brain tissue biopsy), instead we relie on neuropsychological tests which can yield a diagnosis of “probable” DAT when short-term memory and other cognitive problems are determined. A Probable DAT diagnosis is enough to start treatment. The takeaway here is that tangles of nucleic material (proteins) are the likely result of Alzheimer’s dementia and looking for them is the key method of definitely diagnosing dementia in research; either in mice or humans who agree to participate in studies like the CERAD program.

Plaques
Additionally, postmortem brain studies of DAT patients almost always show a semi-hard insoluble (i.e., won’t dissolve) clumps of gook. Dental plaque is a gooky film of bacteria that grows between your teeth as saliva washes it off the the smooth surfaces otherwise. The bacteria produce acids as they digest (ferment) sugars in your mouth, which then eat away at the enamel of teeth causing tooth decay and gum disease. Eventually, the bacteria die and the plaque and hardens into tartar or dental calculus which provides a rough surface for even more plaque to adhere to and form on.

In DAT globs of gooky stuff called plaques that forms between neurons. It looks like dissolved white bread, and we call this amyloid (the Greek word, amylon, for starch) plaques. Specifically, in DAT it is beta-amyloid which is made up of fragments of peptides (proteins) that have a toxic effect on the nearby brain cells between which they accumulate, somewhat like our above dental analogy. Proteins assemble in poly (multiple) peptide chains that take on distinct shapes and folds–when they are is sheet-like formation we call them
β-sheets as they look like pleated sheets, and this is what the beta-amyloid in DAT looks like. Most research on DAT has assumed a causal role in amyloid plaque in the disease, and has focused on finding ways to prevent amyloid aggregation is a disease called amyloidosis that appears to play a role in many degenerative diseases. Aside: some amyloids are, themselves, infectious and can cause other proteins to fold into weird, toxic shapes–think prion diseases like Mad Cow or Cruetzfeld-Jakob disease.

While an association plaques and DAT is evident, it is unknown if plaques are a cause or a result of DAT. People with DAT almost always show this damage; however, many people with advanced dementia don’t have much evidence of the damage on post-mortem microscopic examination of their brains.