book reviews

Miscellaneous books on Alzheimer's and other neurodegenerative diseases
Reviewed by: T.J. Nelson

Alzheimer's Solved (condensed edition)

Henry Lorin

A lzheimer's is solved? Henry Lorin thinks so. He believes that Alzheimer's disease is caused by a cholesterol deficiency in the brain, and that a diet with normal cholesterol may be protective against Alzheimer's. This idea came from watching his father-in-law develop Alzheimer's after years of a strict low-fat diet supplemented with statins, which are cholesterol-lowering drugs. Beta-amyloid, says Lorin, is not a cause of Alzheimer's, but is the body's temporary substitute for cholesterol. Its purpose is to serve as "a short-term 'bandage' for cell membranes until more cholesterol is provided." [p.94]

Lorin is a dentist, with no training in neuropathology, medicine, or biochemistry, and his presentation would have benefited from a review by someone more knowledgeable about the subject matter. His background as a non-scientist may explain why there is such a great number of factual errors in this book. There are also no data or statistics in this book, and no citations in the text that would allow anyone to check his sometimes bizarre assertions, such as the statement [p.91] that the brain serves as a reserve source of cholesterol for the skin. However, there are numerous uncited references in the Appendix, presumably left over from the earlier "uncondensed" edition.

Of course, the fact that his book has technical mistakes does not detract from the validity of his hypothesis. Beta-amyloid is a cholesterol-binding peptide. A mutant form of ApoE, a cholesterol-transporting protein, is a risk factor for Alzheimer's disease. The evidence for a connection between cholesterol and Alzheimer's disease is overwhelming.

However, there are several hurdles that Lorin's theory needs to overcome before it will gain traction among scientists:

  1. Cholesterol in the blood plasma is almost totally separate from cholesterol in the brain. Contrary to what Lorin says, it is far from certain that cholesterol crosses the blood-brain barrier in any significant quantity. Cholesterol is synthesized independently in the brain, and its synthesis is regulated independently of plasma cholesterol levels. In the brain, cholesterol is synthesized primarily in astrocytes and transported to neurons by ApoE and other carriers.
  2. Most statins, such as atorvastatin, also do not cross the blood-brain barrier very well, which means that a properly designed statin will have little or no effect on brain cholesterol levels.
  3. Vegetarians, who get no cholesterol in their diet, do not develop Alzheimer's disease at higher rates than people on normal diets. This fact alone doesn't mean too much, though, because humans can synthesize their own cholesterol. However, many causes of hypolipidemia are known, including hyperthyroidism, chronic infections, malnutrition, and alcoholism. None of these are associated with increased incidence of Alzheimer's disease. Diseases where cholesterol is severely decreased (such as Bassen-Kornzweig syndrome) are associated with mental retardation but not Alzheimer's.
  4. If statins caused Alzheimer's, we would expect APP transgenic mice treated with statins to get worse, which they don't.

Lorin also doesn't appreciate the complexity of the research findings. It is easy to comb the medical literature and find a paper that supports virtually any hypothesis. The hard part is deciding whether the conclusions in that paper are sound. Spurious correlations can result from misdiagnoses, sampling biases, and dozens of other causes. For example, if simvastatin caused memory loss, as has been reported in a few cases, it might be confused with Alzheimer's, creating a spurious correlation.

This doesn't mean that Alzheimer's could not be caused, somehow, by a lack of cholesterol reaching the neurons. Maybe there is some problem in the cholesterol/LDL receptor that prevents it from reaching its target. Or maybe the astrocytes stop exporting cholesterol for some reason. Or maybe there is some other explanation. Lorin is to be applauded for his determination in promoting his theory, and even more for publicizing the importance of cholesterol in health. But Lorin's arguments are too one-sided, and his theory as presented in this book is not on solid enough ground, to be of much help to Alzheimer researchers.

Dec 24, 2010

Neurotoxic Factors in Parkinson's Disease and Related Disorders
A. Storch and M. A. Collins, ed

P arkinson's disease is a progressive degenerative disease characterized by loss of dopamine-synthesizing cells in the substantia nigra, a region in the brain that uses the neurotransmitter dopamine to send signals to the caudate nucleus. The symptoms of Parkinson's disease are tremor, rigidity, slow movement, and gait freezing which slowly progresses to eventual paralysis.

Many scientists suspect that an environmental factor may be responsible for Parkinson's disease because its geographical distribution is not uniform. Parkinson's disease is slightly more common in rural areas than cities. There is also a very high prevalence of amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) among Japanese residents of the Kii peninsula in Japan and in Guam. This appears to be caused by ingestion of cycad, a natural plant that contains methylazoxymethanol, a naturally-occurring molecule that attacks the DNA of its victims to produce a syndrome closely resembling Parkinson's disease.

Another important clue about Parkinson's disease is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a synthetic molecule produced as an accidental byproduct by people attempting to manufacture pethidine (meperidine), a mu-receptor opioid agonist, in their bathtub. MPTP produces an irreversible, incapacitating paralysis in its victims that closely resembles advanced Parkinson's disease. MPTP is oxidized to MPDP+ in astrocytes by the enzyme monoamine oxidase type B, and then spontaneously oxidizes to MPP+ (1-methyl-4-phenylpyridine) which then kills dopaminergic neurons in the substantia nigra pars compacta. The mechanism of MPP+ toxicity has not been definitively established, but may be production of superoxide which reacts with nitric oxide in the cell. After a single exposure to MPTP, the victims are permanently paralyzed. Even with L-dopa treatment, many are unable to move normally for the rest of their lives. The main difference between MPTP poisoning and true Parkinson's disease is the absence of Lewy bodies, which are eosinophilic inclusions in the neurons of Parkinson's disease patients.

A third interesting molecule is 6-hydroxydopamine (6-OHDA). Although 6-hydroxydopamine cannot cross the blood-brain barrier, it can be formed spontaneously in the brain by reaction of dopamine with iron and hydrogen peroxide. This is consistent with the association of Parkinson's disease with physical brain trauma, which exposes neurons to iron from blood that is released during injury. However, the molecular sites affected during 6-OHDA poisoning are not exactly the same as those affected in Parkinson's disease.

Many other substances, including haloperidol, can induce parkinson-like syndromes, while smoking appears to protect against it. Much research has focused on searching for molecules in Parkinson's disease brains that are absent in normal brains. The holy grail is to find something in food or in the environment that not only selectively kills dopaminergic cells, but also produces Lewy bodies.

This book is a collection of scientific articles on these and other toxins including beta-carbolines, 1,2,3,4-tetrahydroisoquinoline and salsolinol, as possible causes of Parkinson's disease. Isoquinolines can be produced from phenylethylamine or dopamine itself by condensation with acetaldehyde produced from ethyl alcohol. This is interesting in view of the recent findings of mutations in the enzyme alcohol dehydrogenase in some Parkinsons patients. Beta-carbolines are nitrogen-containing molecules, sometimes found in food, that are structurally similar to MPTP. Some of the articles are review papers, and others are short BBRC-style research papers. The intended audience is researchers and graduate students familiar with neuroanatomy, biochemistry, and the pathology of Parkinson's disease. The writing style is typical scientific writing--precise and functional technical prose full of abbreviations.

January 15, 2005

The Myth of Alzheimer's:
What You Aren't Being Told About Today's Most Dreaded Diagnosis
Peter J. Whitehouse

P . J. Whitehouse is a former clinician and Alzheimer researcher who was involved in early research on cholinesterase inhibitors, which were regarded in the 1980s as possible treatments for Alzheimer's disease, but have failed to live up to expectations. In this book, written for the general public, he presents his opinion that Alzheimer's is not a disease, but part of normal aging.

There are many theories about the causes of Alzheimer's disease. It's frustrating for researchers because it cannot be accurately diagnosed, and because it occurs only in humans. There are no good animal or cellular models for it. There is, as yet, no effective treatment. Clearly, Alzheimer's is a different kind of disease than we are used to dealing with.

Whitehouse doesn't offer any convincing arguments why Alzheimer's is a myth. It is true we have no idea what causes it. But that is not to say we should give up, and accept Alzheimer's as a normal part of aging. Patients lose their memories and die from Alzheimer's disease. Telling them it's a normal part of aging may make them feel better, but is it really the truth? I am convinced it is not.

Oct 9, 2009

Neurological Disorders in Famous Artists
J. Bogousslavsky, F. Boller, eds

T his short book takes the concept of "always leave the reader wanting more" to an extreme. The authors, a collection of clinical neurologists, describe various cultural figures, including Nietzsche (who died of a stroke after a long and painful struggle with syphilis), Edgar Allen Poe (who had possible epileptic seizures), Van Gogh (who had bipolar disorder and absinthe/terpene abuse), Kant (who may have suffered from Lewy body dementia), Dostoevsky, Flaubert, Apollinaire, Guy de Maupassant, Ravel, Handel, Schumann, and Mussorgsky, among others. This is a fascinating and important subject, and the authors refrain from either politicizing or deconstructing the artists' works by attributing them to neuropsychiatric causes. Other less-famous disease-plagued artists, such as the famous cat painter whose paintings became more "electrical" in appearance as the painter's schizophrenia progressed, are omitted.

Some of the articles have color figures showing examples of relevant artwork. Particularly poignant are the paintings by Carolus Horn showing gradual deterioration in visualspatial ability as Alzheimer's disease relentlessly destroyed his parietal and inferior temporal cortex. This was manifested as a reduction in sophistication, a decrease in the use of perspective, and reduction in detail. His paintings ultimately became little more than a childlike scribbling.

It's no secret that most doctors and scientists aren't very good writers. Many of the book's authors are not native English speakers. However, the dazzling prose and brilliant creativity of the subjects of this book makes the authors' writing seem even more plodding, humorless, and mundane by comparison. One exception is on page 71, in the article on Dostoevsky, where one author actually cracks a joke.

A bigger fault with the book is that the while authors are understandably not equipped to discuss the artists' work in depth, they also seem unusually reluctant to give the reader much information about the pathology of the diseases beyond the basic diagnosis. This would be disappointing to members of the larger audience that will be attracted to this book hoping to learn some basic neuropathology. I would hate to be a student in these guys' classes. A typical lecture might be: "Today's lesson is Alphonse Daudet. He probably had tabes dorsalis. It's a disease. Okay, lesson's over, exam tomorrow, bye!"

August 21, 2005

Neurobiology of Alzheimer's Disease, 3rd ed.
(Molecular and Cellular Neurobiology Series)
David Dawbarn and Shelley J. Allen, eds.
Oxford University Press, 2007, 468 pages


O utstanding collection of up-to-date scientific articles on the biochemistry of Alzheimer's disease. The contributing scientists have done innovative research on Alzheimer's disease. Includes an appendix listing the protein sequences of the major proteins known to be involved in AD pathology, along with the known mutations. There are chapters on tau, beta-amyloid, inflammation, apolipoprotein E, neurotrophins, neurotransmitters, and presenilins. Other chapters discuss diagnostic techniques and possible treatment strategies. The articles provide a comprehensive background of the most promising directions of research in this field as of mid-2007. The only problem with it is that the style of English in many of the articles is abominable.

Sept 16, 2007

Molecular Mechanisms of Degenerative Diseases
Marie-Françoise Chesselet, ed

A zheimers disease is a rapidly-changing field. This book is a collection of monographs on various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and less well-known diseases like CAG trinucleotide repeat disorders that produce spinocerebellar ataxias, Huntington's disease, and spinobulbar muscular atrophy (SBMA). The chapters are about evenly divided among these three categories and give a good overview of their respective fields. Written at a level suitable for a graduate student, clinician or researcher. Chapters on Alzheimer's disease cover beta-amyloid toxicity, animal models, inflammation, proteolysis, tau and synuclein, and treatment approaches. The chapter on proteases was written shortly after beta-secretase (BACE1) was cloned back in 1999, so it contains no discussion of the recently-discovered proteolytic activation of alpha- and beta-secretases. Each of the 16 chapters has about 100-300 references, which will get the reader oriented to the literature up to the year 1999. Has 3 color figures, a few graphs, and a very mediocre index. Because of the close similarities among these diseases, people working in this field need to understand all of them. This book does an excellent job at getting the reader oriented.

October 8, 2002