A New Paradigm for Alzheimer's Disease Research

From lost hope emerges a new perspective. After more than a century of research into Alzheimer’s disease we have reached a research cul-de-sac. By eradicating the plaques and tangles from the brain, a series of studies reported that the disease worsened ^1,2. What this tells us is that the disease is more complex then just a build up of mis-folded proteins.

In panic, the National Institute on Aging, coopting the Alzheimer’s Association, published new guidelines for Alzheimer’s disease in 2011.³  These guidelines effectively transformed a clinical disease--a disease defined by its behavioral manifestations—into a pre-clinical disease. What this means is that now Alzheimer’s disease exists before there are any clinical manifestations. This seems counterintuitive given the studies showing that drugs that cleared the plaques and tangles—the only pre-clinical indicators--did not cure Alzheimer’s disease and in fact made it worse. But the increasing power of the pharmacological industry in establishing the research agenda seems limitless. Now pharmaceutical companies can experiment with patients before they even start showing symptoms of the disease. In effect, curing a disease before the clinical disease emerges. But so far, they have had little success. 

Since the early 1990 pharmaceutical companies have been attempting to halt early onset dementia among an unfortunate community in Medellin, Colombia. Discovered by Francisco Lopera in 1984, this heritable variant of Alzheimer's disease share a common ancestor—a 16th-century Spanish colonist who to this day has infected 5,000 patients in 25 families. ⁴  The reason why this approach—trying to find a biological cause of the disease--has been so resilient despite mounting evidence contradicting this approach, is that there has not been a competing theory to challenge it. Until now.

A crescendo of mounting criticism has established that Alzheimer’s disease is more complex than a cascade of misfolded proteins. That even though people might have the plaques and tangles, some do not express the disease, while some who express Alzheimer’s disease have been shown to have no significant plaques and tangles. In addition, with older adults, multiple studies have shown that the correlation between plaques and tangles and Alzheimer’s disease declines with age. One way to explain these anomalies is to broaden the study of Alzheimer’s disease. One such approach is to see it as a public health disease. ⁵

A public health perspective argues that there are multiple traumas to the brain. Some of these can be a virus or bacteria, while some are physical (like a concussion). We are seeing more and more how physical trauma causes dementia among NFL football players. But sometimes this trauma is managed and contained. A good example of this process is looking at stroke victims where we see more than 30 percent improving. In such cases, the penumbra—the protective cells that surround the initial trauma—is contained and the death of cells remains localized. Two factors promote this healthy brain. One is blood supply—Perfusion, while the other is growing your brain--Plasticity.

Perfusion allows for the brain to receive adequate nutrients and energy to heal itself. Having a healthy brain improves the chances that a trauma is contained. Plasticity on the other hand ensures that there is enough flexibility in the brain that if the brain needs to contain an area that other parts can take over that lost function. Without these two factors the penumbra will continue to grow and affect larger areas of the brain—and such damage will go beyond plaques and tangles. This broader public health interpretation of Alzheimer’s disease assimilates both the traditional Amyloid Cascade hypothesis and explains the increasing number of studies showing how external factor influence the incidence of Alzheimer’s disease.

The beauty of this public health approach is that we do not have to wait another hundred years before we realize that we are in a research cul-de-sac. We can start implementing programs that reduce and lower the exposure to traumas. Reduction of concussions (in sport, military, recreational activities) should be made a priority. Programs that educate on the effects of smoking and heavy drinking on the brain need to be promoted, as well as programs that address environmental toxicity both in the air and in our water. For perfusion, city walkability programs, and social engagement programs all promote walking, swimming, light exercise, gardening among other activities. While improving plasticity involves social activities, dancing, music and other cognitive exercises.

Pharmaceutical influence can determine federal research policy, but with knowledge, individuals can protect themselves and their family from exposure to this deadly disease that we still do not fully understand.

A version of this article can be found in:

Garrett MD & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9. Page 2 of 9.

A complete story of this blog can be found in my recently published book: 

Garrett MD (2015).The Politics of Anguish: How Alzheimer’s disease became the malady of the 21st century.

References.

1. Gilman S., Koller M., Black R.S., Jenkins L., Griffith S.G., Fox N.C, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64:1553–62.

2. Boche D., Donald J., Love S., Harris S., Neal J.W., Holmes C., et al. (2010). Reduction of aggregated tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol, 120: 13–20.

3. Jack  C.R., Albert M.S., Knopman D.S., McKhann G.M. Sperling R.A., Carrillo M.C., ... & Phelps C. H. (2011). Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7(3):257-262.

4. Lopera F., Ardilla A., Martínez A., Madrigal L., Arango-Viana J.C., Lemere C.A., ... & Kosik K.S. (1997). Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Jama, 277(10): 793-799.

5. Garrett MD & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9. Page 2 of 9

© USA Copyrighted 2016 Mario D. Garrett

Bad Drugs and Older Adults

Bad Drugs

Drugs work in mysterious ways. Sometimes it benefits us, other times there are negative side effects. Half of all adverse drug occurs when five or more drugs are taken and it is nearly certain that there will be a reaction when eight or more drugs are taken. How dangerous can this be?

Sometimes prescribed medications cause death. The Danish physician and researcher Peter C. Gøtzsche from the Nordic Cochrane Centre, estimates there are 15 times more suicides among people taking antidepressants than are reported by the US Food and Drug Administration. By looking at Danish prescription statistics for antipsychotics, benzodiazepines, and antidepressants he estimated that the death rate for older adults was between 1 and 2 percent.  Based on these Danish death rates he estimates that for the U.S. and European Union combined an estimated 539,000 older adults die from these drugs every year. But it is not just antidepressants that can cause adverse reaction. Especially with older adults because our metabolism changes with age, the filtering of the drug in our bodies is compromised and becomes less efficient. Drugs remain in our blood longer. As a result, the effect of drugs changes as we age.

Every few years the American Geriatrics Society (AGS) releases an updated and expanded Beers Criteria (after the originator of the first list, Mark Beers)--a list of potentially inappropriate medications for older adults that is developed from reviewing over 6,700 clinical studies. The report is complex, technical and detailed and needs to be reviewed with your physician. However, as a summary, it is important to realize how common bad side effects are for most of the medications that we take.

For example, among patients aged 65 years and older, insulin or warfarin (Coumadin®) was the cause of one in every three drug reactions that resulted in an emergency hospital visit and was responsible for nearly half of all drug reaction hospitalizations. Analgesics for chronic pain cause slowed breathing and caused constipation. NSAIDs, such as ibuprofen (Advil®) and naproxen (Aleve®), are generally not recommended for the older adults because of stomach and intestine irritation and possibly raising blood pressure. While acetaminophen (Tylenol®) increased the risk of hypertension by a third. Some medication prescribed for schizophrenia and bipolar disorder Aripiprazole (Abilify®), clozapine (Clozaril®), and risperidone (Risperdal®) may increase blood sugar indirectly due to weight gain. Decongestants and other anticholinergics that we can get at the pharmacy without a prescription can cause confusion, urinary retention and other problems. For example Pseudoephedrine (Sudafed®) can raise blood pressure. Researchers found that half of all older adults taking anticholinergics showed mental decline.  Beta-blockers like Atenolol (Tenormin®), sotalol (Betapace®) prescribed for hypertension, arrhythmias, and thiazide diuretics, such as chlorothiazide (Diuril®) and indapamide (Lozol®) prescribed for hypertension and congestive heart failure can increase the risk of diabetes. Corticosteroids such as prednisone and methylprednisone (Medrol®) prescribed for arthritis or asthma increase blood sugar and can lead to type 2 diabetes. Erectile dysfunction medications like sildenafil (Viagra®), tadalafil (Cialis®) and other medications may cause visual and hearing disturbances. The biggest category of drugs taken by older adult  is statins for cholesterol, where atorvastatin (Lipitor®), simvastatin (Zocor®) and other statins may create very low levels of cholesterol that may lead to depression, memory loss and confusion. Some statins may cause liver damage. Congestive heart failure medications such as digoxin (Lanoxin®) and diuretics are at risk for electrolyte imbalances and therefore risk poisoning the body through increased toxicity. Hip fracture is increased among elderly patients who take proton pump inhibitors such as lansoprazole (Prevacid®), esomeprazole (Nexium®) and omeprazole (Prilosec®) and to a lesser extent by H2-blockers such as cimetidine (Tagamet®) and famotidine (Pepcid®).

Because so many medications are excreted via the kidney, it is important for elderly patients to have kidney function assessed regularly. Impaired kidney function may require adjustment of medication dosages. What we eat can also influence how these drugs react in our body. Certain drugs have dietary implications, including foods to avoid and nutrients that are essential. Some medications should be taken on an empty stomach, some with food.

Older adults also use drugs that they buy from the dispensary without getting a doctor’s prescription. These “over-the-counter” drugs are readily available, and people again feel that they are safe. Nearly half of prescription users also take at least one over-the-counter medication. In addition, there is an increased use of herbal or dietary supplements (eg, ginseng, ginkgo biloba extract, and glucosamine) by older adults. Almost three-quarters of older adults use at least one prescription drug and one dietary supplement. Sometimes we do not tell our doctor that we are taking these supplements because we think they are not important. But herbal medicines may interact with prescription drugs and lead to adverse events. Such adverse events as when ginkgo biloba extract is taken with warfarin, causing an increased risk of bleeding, or when St. John's wort is taken with serotonin-reuptake inhibitors, increasing the risk of too much serotonin causing symptoms ranging from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures). Severe serotonin syndrome can be fatal if not treated. A study of the use of 22 supplements found potential interactions between supplements and medications in half of these supplements.

We do not know all of the ill effects of medications on older adults, especially among older women, because these drugs are rarely, if ever, tested among older adults. The drug-drug interactions, side-effects, cost of medications, medications that should have been stopped ages ago, and medications that are inappropriate for older adults suggest that the fewer drugs you take the safer you are. Some people cannot reduce their medications, but by discussing your medications with your physician, you can start the discussion to try and reduce and possibly eliminate some of your drugs. In some cases replacing medication with other treatments, such as psychotherapy, exercise, social activities or some behavior modification training might be worth exploring especially for behavioral concerns. For some who have found a balance, their medication regime is sustaining life. But it seems that there are many others who are struggling to find this balance.

© USA Copyrighted 2016 Mario D. Garrett