Stafford Hill logo
Staying Informed,  
with Stafford Hill
 
Donald Marks, MD
 By: Donald Marks, MD
 
What is Alzheimer's Disease?
 
This is not a simple question... and neither is the answer. Of greater importance, to effectively treat any disease requires we understand its cause. The truth is, to this day we can describe much about Alzheimer's symptoms and progression but still do not fully understand what causes it at the cellular and molecular levels. For both those with this disease as well as their families, it is important to separate what we do know and what we do not. Expectations about current therapies and those under development need to be realistic.
 
First, it is probably inaccurate to think of Alzheimer's as a single disease.  In fact most chronic human degenerative diseases are multifactorial and complex. For Alzheimer's, many genes contribute (to varying degrees, mixed uniquely in each affected individual) to the molecular changes leading to what we refer to as Alzheimer's disease. Variations in lifestyle choices (most notably diet; e.g. lower risk of Alzheimer's with an Indian diet, higher risk with repetitive head injury) contribute, but probably more so years before symptoms occur, and to a far lesser degree than our genetic risk. All of these variations cause different ages of onset, variations in affected behaviors (based on slightly different parts of brain involvement), different rates of progression, different patterns of inheritance risk, and quite possibly, variations in response to medications.
 
As an editorial aside, we live in a culture in which we wish to believe we have more control over our biological destinies than we really do. Baby boomers (of which I am one) are starting to get Alzheimer's and have lived through a greater awareness (over the last 20 years) of Alzheimer's in their parents. While detrimental life choices may magnify a bad outcome, good choices may not prevent what is genetically destined. Where hope is limited, many will peddle hope, or promote false conclusions from limited information. When it comes to Alzheimer's, I believe the evidence strongly favors "nature over nurture". While I encourage all patients with Alzheimer's to work on both mental and physical fitness, it is inaccurate to suggest these measures have a major impact on progression of disease, especially once one is showing symptoms of dementia. 
 
By the way, dementia is a generic term for progressive global cognitive decline. The "technical term" for Alzheimer's (when it occurs > 60 years of age) is SDAT (senile dementia, Alzheimer's type).  Senile is just a synonym for old. For at least 70-75% of individuals with dementia in the US, the cause is Alzheimer's.  Before the 1980's, "hardening of the arteries", "senility", "senile dementia" were all more or less interchangeable terms.  "Oh it's just normal aging," still prevails in our attempts to minimize what we don't want to see. It is not normal, just prevalent (e.g. an ear infection in a 6 year old is common, but not normal). At age 65, ~1/30 people in the US population has Alzheimer's, 1/4 at age 80, 1/3 at age 85 and ½ at 90.
 
So, what is Alzheimer's? In the early 1900's when Alois Alzheimer first described it (he lived in Alsace on the French-German border and actually described an individual with early onset disease starting in her late 40's/early50's) his only technical tools were autopsy, microscope and tissue stains. Amyloid plaques were simply the microscopic tissue areas made visible by a staining technique to highlight them. It wasn't until the late 1970's that we even began to know the molecular chemistry of amyloid plaque. Amyloid plaque mostly consists of a-beta, derived from APP - amyloid precursor protein, which is molecularly "cut" to produce a-beta (Aβ) protein fragments. Most Alzheimer's research over the past 20 years has focused on this "Amyloid Hypothesis".
 
We are still locked in discussions and experiments to determine how amyloid relates to the causes of brain cell death in Alzheimer's. Amyloid plaques may yet turn out to only be a marker of other causes, or even a response to the real causes. That is, amyloid may be a tombstone. Or, as I believe much data suggests, amyloid pathways (especially combinations of 3-12 Aβ units, referred to as oligomeric Aβ) likely have some effects on the functioning of nerve cell connections (synapses), with resulting symptomatic deficits... but are not directly involved in cells' death. Along with >200 sites in the US and abroad, I am involved in the first "safe" clinical drug trial designed to test the "Amyloid Hypothesis", using an antibody ("vaccine") designed to remove amyloid from the brain of individuals with mild-moderate stage Alzheimer's.  At least 5 other pharmaceutical companies are in various stages of development of similar vaccines.
 
The anti-amyloid vaccines may have no effect, a symptomatic benefit, or actually alter disease progression. It may well be the vaccines will work, but only before people develop symptoms of dementia. Perhaps the vaccines will work on amyloid outside the cells, when it is amyloid inside the cells that cause the damage, unreachable by the vaccines. Identification of "pre-symptomatic" Alzheimer's markers (imaging technique, blood and spinal fluid testing, genetic testing) is a very active area of research in the field of Alzheimer's.  Most of us believe to truly treat Alzheimer's we will need to find a way to identify pre-symptomatic individuals before they have symptoms of dementia. Presence of symptoms indicates widespread death of brain cells has already occurred.
 
The situation is analogous to the progress we have made with coronary artery disease. That is, there isn't much one can do for heart muscle damaged by multiple heart attacks from blocked coronary arteries. It is better to identify and treat mild coronary artery disease. Our current treatments of dementia are like treating someone for heart disease after multiple heart attacks... even that is better, as we can greatly minimize further heart attacks, but not worsening dementia.
 
A word on our current therapies; all are purely symptomatic, variably effective, variably tolerated. Neurotransmitters are biochemicals produced by our brain cells to act as a chemical signal between nerve cells, allowing them to communicate; the basis for all brain activity. We have 3 drugs that increase the "molecular longevity" of acetylcholine (a neurotransmitter involved in many brain pathways), by blocking the activity of acetyl cholinesterase, which breaks down acetylcholine, inactivating it. The 3 agents are: Aricept (donepezil) to become generic in 2010, Exelon (rivastigmine) available as a patch and galantamine ER now a generic daily extended release pill.
 
There are pros and cons to each, reasons to choose one over the other, switch from one to the other, beyond the scope of this article. We also have Namenda (memantine) which augments the function of another neurotransmitter, glutamate. These medications treat Alzheimer's in the way a brace might allow someone with polio to walk. The analogy is flawed insofar as the "polio" of Alzheimer's is progressive and eventually the chemical "braces" become less effective.
 
We do have other therapeutic avenues of investigation beyond a-beta. Alzheimer described "dystrophic neurites" and "neurofibrillary tangles" in his original description of the disease. Again, only since the late 1970's or so have we identified the molecular basis of these as due to abnormal tau-protein, normally involved in maintaining cell shape and intracellular molecular transport. The tau-protein changes, unlike the amyloid changes do correlate with actual cell death. On the other hand, high a-beta loads almost always lead to Alzheimer's.
 
The most common example is for people with Down Syndrome (they have 3 rather than the usual 2 copies of chromosome 21) who have an extra copy of the gene (found on chromosome 21) that codes for the APP protein   People with Down Syndrome almost universally develop Alzheimer's in their 40's and 50's. One of the great unanswered questions in this field is how to connect the amyloid and tau stories in a way that makes sense. One very recent and exciting area of research suggests a possible link. Briefly, when the APP protein is cleaved to form Aβ, one of the other fragments may have effects on cell-death pathways leading to the abnormal tau protein changes. That is, we may have been focusing on the wrong end of the APP protein, just because historically we focused on the amyloid plaques. When the only tool you have is a hammer, everything looks like a nail.
 
Somewhere between despair and blind optimism lies reality. Our symptomatic medications do improve the quality of life for most with Alzheimer's, sometimes a lot, sometimes a little, sometimes for a relatively short period of time, sometimes for years. Specialized living facilities (we now have a continuum - Assisted Living, Alzheimer's assisted living, Alzheimer's nursing home level care) provide appropriate care and support throughout the progression of this inevitably progressive disease. These facilities often permit family members to remain more as family members, less as caregivers.
 
Research travels many roads. It is always unclear in advance which will be blind alleys and which will get us to our destination. At least, as applies to Alzheimer's, we are actually on roads to more meaningful treatments.
.