Alzheimer Disease-Amyloid-beta Hypothesis Controversy- Part XXVI of a XXVIII Part Series on AD

(12/22/13)- "The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the amyloid radiotracer florbetaben 18F (NeuraCeq, Piramal Imaging GmbH) for Alzheimer's diagnosis.

"NeuraCeq is a radiopharmaceutical indicated for positron emission tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment," the CHMP said."

(6/7/07)- Recent Developments in Alzheimer's Disease- On May 15, 2007, this author attended the Psychiatry Grand Rounds given by Mount Sinai School of Medicine in NYC. The presenter was Guilio Maria Pasinetti, MD, Ph.D of the Mount Sinai staff. His topic was "Anti-hypertensive drugs as a beta-amyloid lowering treatment in Alzheimer's disease".

He described how memory deterioration is associated with the conversion of soluble monomeric amyloid protein into high weight soluble oligomeric amyloid beta which leads to memory deterioration. These soluble oligomeric amyloid beta peptides either lead directly to cognitive decline or lead to the development of amyloid plaques that result in cognitive decline.

He then went on to point out that there are now 56-57 antihypertensive drugs on the market that attempt to deal with hypertension. He divided them into seven different classes depending on their route of action.

While antihypertensive drugs have not proved effective as a class of drugs in dealing with cognitive impairments in meta studies, his study group tested each drug and has found that certain of these drugs do have a positive effect on memory in rats bred for Alzheimer's disease expression.

The next step would be to research in human trials the 6 drugs he found effective. These drugs included the K-sparing diurectic Amiloride, the calcium-channel receptor blocker Nicardepine, Propraolol HCL, Carvedilal, Valsartan, and Lorsartan with all others showing no statistically reliable memory enhancement qualities.

If this result holds up, we will have another series of medication to deal with the progressive deterioration of memory in Alzheimer's disease. Confirmation of this fact will take many years, with no guarantee that the same results will be shown in adults.

(6/4/06)- Is there a scientific controversy brewing between researchers in the search for drugs to combat Alzheimer’s disease? A letter in the peer reviewed professional journal Drugs & Aging 2006;23(2):179 from researchers at the John Douglas French Alzheimer’s Foundation at Case Western University suggests that the implication of amyloid-beta cascade hypothesis as a source of responsibility for Alzheimer disease cognitive decline, the hallmark symptom of the disease, may be a fallacy. The drugs have no effect on the progression of the disease.

We cite the following abstract of an article, "Treating Alzheimer’s Disease by Inactivating Bioactive Amyloid-Beta Peptide" by Liu & Schubert to give our readers an idea of the amyloid-beta hypothesis:

"Treating Alzheimer's disease (AD) is one of today's biggest unmet medical needs. The drugs currently available transiently relieve some symptoms but have no significant effects on the progression of the disease. Progress in the past decade suggests that the amyloidogenesis of the inactive monomeric amyloid ß peptide () into a subset of toxic polymers is responsible for neurodegeneration in AD.

Not all forms of aggregates are damaging, for there are patients whose brains accumulated large amounts of in the form of plaques, but they had no obvious neurodegeneration and symptoms of dementia. Since can polymerize into many types of polymers or aggregates, the form of that induces neurodegeneration in AD, defined here as bioactive , is not clear.

Preventing the formation of bioactive or inactivating previously formed bioactive is a promising approach for treating AD. This review describes our efforts to develop a cell-based assay for detecting bioactive , to verify the concept of bioactive in an animal model of AD and in post mortem brain tissue from AD patients, and to use this assay to screen for drugs that can inactivate bioactive .

These studies show the proof in principle that inactivating bioactive is a promising approach to treat AD. Several promising compounds that can inactivate bioactive species are also described. (Liu, Yuanbin; Schubert, David. Current Alzheimer Research, Volume 3, Number 2, April 2006, pp. 129-135.)"

It is this hypothesis, the basis of the medications for AD that are now on the market and in the pipeline of a number of pharmaceutical companies that is put into question. The authors of this letter, Lee, Zhu, Perry & Smith state: "In fact, using transgenic approaches, a clear disconnect between amyloid-beta and cognitive decline has recently been uncovered." The authors refer to a study done by Saura et al that appeared in the J Neurosci 2005; 25(29):6755-64. The authors even suggest that "amyloid-beta is beneficial in certain circumstances" citing three studies: J Neuropathol Exp Neurol 2001 60(8):759-67; Peptides 2002 ;23(7):1333-41; Ann NY Acad Sci 2004 ;1019:14. They are suggesting that some of the drugs presently being used "may actually exacerbate the disease process."

Pharmaceutical companies have spent untold amounts of dollars to come up with the four drugs presently on the market. While they may be beneficial in treating some of the symptoms of the disease, they do not seem to be targeting the core symptom. Can they afford to scrap their present approach, pointing out the limited value of their money making medications?

We would also suggest our readers check the Mark A. Smith et al article in Lancet 2002; 359(9320):1864-5 titled "Predicting the failure of amyloid-beta vaccine".

For some additional articles on Alzheimer's disease please see the following:

See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients
See: Part IV-Alternative Treatments for AD
See: Part V-Possible New Drugs for Alzheimer's Disease
See: Part VI-Early Diagnosis
See: Part VII-Metrifonate
See: Part VIII-Implications of a Longer Life Expectancy
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease-Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test (PST)
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII -Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See: Alzheimer's Disease Part XV-Cerebrolysin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVII-Summary
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease-Part XXI- AD and the Brain
See: Alzhemer's Disease-Part XXII-Lewy Bodies Disease
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV- Plus Psychosis
See: Part XXVI- Hypothosis
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD


Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated 12/22/13

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