Alzheimer’s Disease (AD) is often called the most common form of dementia.  All dementias are characterized by a progressive loss of mental functions.  Since 1906, AD has been considered to be a distinct form of dementia distinguishable from all other dementia by certain structures found in the brains of sufferers.  Although this has been the conventional wisdom among neurologists, psychologists, psychiatrists, gerontologists, and others medical professionals, a new breed of scientists are challenging that notion.  The conventional theories about AD may be trying to treat the wrong issue.

Until recently, AD was diagnosed through what’s called the clinical picture.  Because there were no blood tests, no x-ray or CT scans, no biopsy results that would definitively detect AD, a diagnosis depended on a doctor’s judgment.  This meant that the diagnosis could only be made after the disease process had progressed far enough to produce notable symptoms.  It also meant that diagnosing AD was a hit-or-miss problem heavily dependent on individual judgment calls.  In fact, traditionally the only way to definitively diagnose AD was by examining the brain after death. 

The changes in the brain in certain people with dementia have been investigated for a long time.  Around the time of the Civil War, scientists began noticing that the brains of people with dementia were atrophied (i.e., shrunken).  Alois Alzheimer was the first scientist to identify distinctive alterations of the brain of a person with what he called atypical dementia.  He found tangles of threadlike structures called neurofibrils in nerve cells.  These neurofibrils appeared in otherwise normal-seeming neurons. First a few disconnected threads appeared, then more appeared and tangled into dense bundles.  Finally, the interior of the cell was entirely taken up by knots of fibrils and the cell was destroyed.  Alzheimer also found widespread small deposits of a protein called amyloid beta in the brain.  These two features, neurofibrillary tangles and amyloid plaques, were considered to be the factors that defined AD as a distinct disease separate from other dementias.

Although AD was first described over a century ago, for most of that time there was little understanding of what caused the disease.  The protein structures Alzheimer discovered defined the disease so protein functioning has been the obvious target for research.  The theory that has dominated AD research for the last few decades is called the “amyloid beta hypothesis.”  According to this theory, proteins that help make the cell membranes of neurons are cut into shorter segments.  Some unknown process then causes these segments to fold incorrectly, and these wrongly-folded proteins are unable to be eliminated by the body.  These build up into the neurofibrillary tangles and plaques, causing the visible symptoms of AD.

Evidence is accumulating that protein-folding errors may have little, if anything, to do with the cause of AD.  The latest reflection of this is news of the cancellation of large-scale trials of what was supposed to be a promising new drug called semagacestat.  In test after test, semagacestat did exactly what it was supposed to do – stop the formation of the amyloid beta proteins.  According to the widely-accepted theory, less of the “bad” protein would reduce the progression of the disease.  When it was tested on people who had AD, though, the drug made their condition worse.  As the team leader for the company behind the drug said: “The fact that people got worse means there is biology we don’t understand.”

Another method of approaching AD has been through a class of drugs called acetylcholinesterase inhibitors, such as Aricept and Exelon.   These drugs do not try to affect the formation of amyloid plaques or fibrils, instead they instead try to increase the effectiveness of a certain neurotransmitter.  The theory is that, by supporting the transmission of signals from damaged or degraded neurons, the symptoms of AD will be reduced.  Two large-scale reviews of the evidence for this idea, however, found that there’s very little good-quality evidence that these drugs modify the course of AD.

The biological cause of AD, despite years of searching, remains elusive.  One thing we do know is that people with a particular genetic mutation to the apolipoprotein E (ApoE) gene are more likely to develop AD.  We know that although dietary and lifestyle factors have been proposed to reduce the risk of AD, the evidence for these claims is tepid.  Taking measures such as maintaining mental engagement, having an adequate folic acid intake, a diet low in trans-saturated fat and high in fruits and vegetables, while certainly healthy in general, either have small or unreliable effects on AD risk.  There is some evidence that physical activity programs can reduce memory problems in older adults, but it is still unknown if this applies to reducing the underlying mechanisms of AD.

Many of the factors proposed to increase AD risk have similarly-shaky connections, such as smoking, never being married, exposure to environmental contaminants, etc.  Stronger links have been found between chronic diseases like high blood pressure, chronic depression and metabolic syndrome and late-life decline in mental abilities.  The passing of a spouse is also strongly linked to mental decline.  Despite these links, there is still debate as to whether these links extend to AD or not.  The reason for distinguishing between mental decline and AD is that the one is a symptom while the other is a disease.  It is the same as distinguishing between reducing a fever and curing a case of the flu.

Although this may make it sound as if scientists know little more about AD today than they did in 1906, there are new developments.  If AD is not a disease of the metabolism or neurotransmitters, then there is some other factor or factors at work.  This factor may be inflammation.

Inflammation is the immune system’s response to injury or infection.  If this theory is correct it means that the conventional research has been targeting the wrong type of cell. 

The white blood cells that form the immune system in the rest of the body are not normally present in the brain.  The brain has its own cells responsible for the immune response called microglia.  Normally, microglia are dormant and waiting for a signal.  Even in this state, however, they are very sensitive to any changes in the brain’s internal environment.  When an injury or infection occurs, chemical changes in the brain activate the microglia.  When activated, these cells will engulf foreign bodies, digest them, and then attract T-cells from the circulation to assist in the destruction of the invader.  

Recently, it has been found that microglial cells are activated in the brains of people with AD, especially in areas that have atrophied.  Whatever is causing the inflammatory response in these areas is therefore leading to the deaths of neurons.

Another indicator of the inflammatory process has been the finding of many of the chemical signals that start and control the inflammatory process in the brains of people with AD.  By one estimate, at least 40 proteins associated with immune reactions are present in AD patients.  Researchers have also found that the inflammatory process may precede any visible symptoms of AD.

If this is the real disease process behind AD, fortunately there are many anti-inflammatory drugs that are already approved and in use.  It is already known that people that are on chronic anti-inflammatory drugs, e.g., for arthritis, have a about half the chance of developing AD as other people the same age.  Some of the newest anti-inflammatory drugs, like Enbrel and Celebrex, have shown promising early results.  Like any other drugs, anti-inflammatory drugs have tradeoffs but they also represent a new way to approach this dreaded disease. 

In addition to drugs, there are a variety of natural substances that have been shown to have significant antioxidant and anti-inflammatory properties.  The NrF2 genetic pathway regulates the production of important antioxidants and detoxification enzymes while controlling inflammatory factors in the human brain and nervous system.  Substances known to favorably activate the NrF2 pathway include resveratrol, curcumin, green tea and sulforaphane (derived from cruciferous vegetables).

The emergence of new uses for existing drugs and natural phytochemicals opens up exciting possibilities for preventing and treating AD.  For years, Alzheimer’s researchers have hoped to find some substance that would modify the actual disease process and not just treat the symptoms.  It is beginning to appear that the answer may have already been under our noses.

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Berchtold NC, Cotman CW. Evolution in the Conceptualization of Dementia and Alzheimer's Disease: Greco-Roman Period to the 1960s, Neurobiology of Aging, May 6, 1998, 19(3) 173-189

Cagnin A, Brooks DJ, Kennedy AM, et al. In-vivo measurement of activated microglia in dementia Lancet, 200111 Aug;358(9280) 461-467

Combs CK, Johnson DE, Karlo JC, et al. Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonists J Neurosci. 2000 Jan 15;20(2):558-67.

Eikelenboom P, van Exel E, Hoozemans JJ, Neuroinflammation – an early event in both the history and pathogenesis of Alzheimer's disease. Neurodegener Dis. 2010;7(1-3):38-41.

Kim J, et al. Naturally occurring phytochemicals for the prevention of Alzheimer’s deisease. J Neurochem. 2010 Mar;112(6): 1415-30

Imbimbo BP, Peretto I. Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease. Curr Opin Investig Drugs. 2009 Jul;10(7):721-30.

Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. 2005 Aug 6;331(7512):321-7.

Kolata, G. Doubt on Tactic in Alzheimer’s Battle. New York Times, August 19, 2010, p A14

Lautenschlager NT, Cox KL, Flicker L, et at. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37.

McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases, Brain Res Brain Res Rev. 1995 Sep;21(2):195-218.

McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. 1996 Aug;47(2):425-32.

Ping Z, et al. Sulphoraphane protects against hypoxic-ischemic injury through induction of NrF2-dependent phase 2 enzymes. Brain Res. 2010 Apr 24. [PMID: 20417626]