I voted for this being a silly question or at least an ill-phrased one since I am fully aware that the consensus criteria for the diagnosis of AD require both Abeta plaques and tau tangles in the context of dementia for the diagnosis of definite AD, so one cannot have AD without plaques or tangles. There is no requirement of alpha-synuclein inclusions, so I think the more accurate assertion, by me, is that AD definitely is a double brain amyloidosis (i.e. Abeta and tau amyloid are essential for the diagnosis) while alpha-synuclein amyloid deposits are present in more than 50 percent of sporadic and familial AD cases. So in this subset, which does represent the majority of AD cases, one can assert, as I have, that AD is a triple brain amyloidosis with tau, Abeta and alpha-synuclein amyloid deposits.

View all comments by John Trojanowski

I agree.

View all comments by Gorazd Bernard Stokin

Re-defining AD as an Amyloidosis is a sign of academic pedantry and narrow horizons, beyond which lie, unseen and unimagined, the ultimate causes of brain protein aggregation. This is laboratory language--classification without explanation; the field investigator is impatient with names, and knows enough of the pathology to get out there, hunt down the cause, and get rid of the disease, as streetwise epidemiologist Joseph Goldberger did so brilliantly with pellagra 100 years ago. Amyloid accumulations, once seen in chronic infections, and still seen in certain rare genetic disorders, are bound to excite protein chemists, neuropathologists, and other laboratory hermits, whose narrow training in the fashionable paradigm of DNA and protein ideology makes them incapable of seeing outside the brain. That 17th Century champion of scientific induction, Francis Bacon, once warned that "Nothing is learned from the thing itself --the inquiry must be enlarged, so as to become more general." How many AD researchers try to integrate into their work the broad knowledge on epidemiology,...  Read more

Re-defining AD as an Amyloidosis is a sign of academic pedantry and narrow horizons, beyond which lie, unseen and unimagined, the ultimate causes of brain protein aggregation. This is laboratory language--classification without explanation; the field investigator is impatient with names, and knows enough of the pathology to get out there, hunt down the cause, and get rid of the disease, as streetwise epidemiologist Joseph Goldberger did so brilliantly with pellagra 100 years ago. Amyloid accumulations, once seen in chronic infections, and still seen in certain rare genetic disorders, are bound to excite protein chemists, neuropathologists, and other laboratory hermits, whose narrow training in the fashionable paradigm of DNA and protein ideology makes them incapable of seeing outside the brain. That 17th Century champion of scientific induction, Francis Bacon, once warned that "Nothing is learned from the thing itself --the inquiry must be enlarged, so as to become more general." How many AD researchers try to integrate into their work the broad knowledge on epidemiology, nutrition, discordant twin analysis etc., which is indensable for inductive reasoning? How many even know that the oxidising analgesic phenacetin once caused AD pathology in abusers of the drug? I never see this vital clue to AD mentioned, yet the Lancet published a superb paper on it in 1972, for all to read. Who's not doing their homework? The classical amyloidoses have known causes; so what's the hurry to re-badge AD as Amyloidosis, not even knowing what causes it (except in younger, genetic cases)? Staring down a microscope at protein aggregates is known to cause a rush of blood to the commercial nucleus (adjacent to the limbic area), depriving the rational centres of the glucose needed to fire up the Etiology Neurons and prevent the visualisation of drug targets in the occipital cortex . Sporadic diseases do not arise in the body until an external cause enters the picture. Sporadic AD and PD, for example, mean the patient was born with completely normal genes for APP, tau and alpha-synuclein, so any aggregation and other mischief involving this trio merely reflect the action of an underlying environmental cause, the discovery of which matters 1,000 times more than re-branding the disease half-way though the job in hand. New names are hypnotic, and may help the understanding, but with no cause found, all we have is Idiopathic Triple Brain Amyloidosis. Is that an explanation of the disease, or just a tag for a bunch of unexplained proteinaceous blobs harbouring profitable drug targets, blobs that would arouse no interest at all if composed of fatty material, eg. lipofuscin. Sporadic AD, correctly defined (by myself !), is a Nutritional Cerebroretinal Lipid Peroxidation Disorder (like its prenatal partner, ADHD), as described in my Hypothesis Factory submission. It's cause is the chronic ingestion of refined, vitamin E-depleted, polyunsaturated food-oils (Ref 1). APP and tau are victims of primary membrane peroxidation, aggravated by secondary beta-peptide induced peroxidation, and by aqueous oxidation processes. AD cases are in general in very good physical health (Ref 2), consistent with the known beneficial effects of the 0mega-6 Essential Fatty Acids (EFA) in polyunsaturated food-oils, which maintain healthy cell membrane function throughout the body. EFA-adequate mitochondrial membranes, for example, prevent respiratory uncoupling, impaired ATP output (Ref 3), and the widespread aqueous oxidation seen in cancer, diabetes and vascular disease. Lipid peroxidation due to refined oil-induced vitamin E deficiency seems to be confined to cortical synapses of association areas and retinal rod cells, which have very high membrane densities of long-chain EFA; arachidonic acid is the source of the 9-carbon neurotoxic peroxidation product 4-hydroxynonenal, that inactivates synaptic glucose and glutamate transporters, and probably APP alpha-secretase as well (with obvious consequences). But about half of all AD cases appear to present with depression, probably based on chronic anxiety (with its neurotoxic raised homocysteine and cortisol), and often have a history of heart disease, hypertension, prostate trouble etc., all controlled by now, by the EFA in vegetable oils. AD is rarely seen with type 2 diabetes, which develops only with sustained fatty diet ; pre-diabetes reverses with low-fat diet or with a switch to vegetable oils rich in EFA. Anxious people come from high-fat pregnancies, which raise foetal cortisol levels, and make up about 50% of all people in high fat-consuming populations. The worse half of this anxious group are clearly diagnosable nervous worriers, who often die before 60, especially if they smoke or eat much fat. More prudent cases will survive longer, to face the later risk of Parkinson's disease, that is associated with lifelong anxiety disorder and also with stress-related vascular disease and diabetes. So in that fraction of American people consuming refined oils, half will be congenitally calm and cheerful, free of cortisol and homocysteine problems, and may drift into AD very slowly; but the anxious half may go downhill faster, from Triple Neurotoxinosis (!)--beta-peptide, cortisol and homocysteine. Now just add Apo E4 to that! Pregnancy diets high in fat and also low in folic acid invite homocysteine to damage the foetal brain, lowering IQ somewhat. Hence the link between early -life academic failure, poor composition skills etc., and later AD risk. I suspect these people are simply anxious, with lifelong cognitive problems, like the lower-ranked nuns in the Nun Study; refined oils would then lead to AD with Lewy bodies. One of the teacher nuns lived past 100, with mild memory problems only, but lots of AD plaques at autopsy. Highly intelligent and active all her life, I propose that she was the calm product of a low-fat pregnancy, with undimmed IQ and excellent composition skills in early life, and demented very slowly due to some refined oil intake perhaps in her later decades. Nobody has looked at the nunnery diet! Being prime candidates for unipolar depression and eventual Parkinson's, but steered towards AD by their cooking and salad oils, people with anxious brains are likely to have both AD pathology (even a few tangles can disconnect a pre-shrunk anxious hippocampus), and some gunked-up synuclein scattered about, Lewy-fashion, in the cortex and mid-brain. Those were the autopsy findings I once saw in an anxious Australian male, product of a high-fat pregnancy, who consumed imported refined peanut oil for about 4 decades. These "Anxious-heimer's" cases, emerging from fatty pregnancies, but consuming healthier (but refined) oils in later life could be re-defined as suffering from Double Lipid Whammy! (They need Quadruple Therapy--see below) And that is how dietary fatty acids can cause sporadic AD and Parkinson's, simply by disturbing delicate cell membranes for many years. In AD we see unprotected EFA arriving in synaptic membranes, there to undergo peroxidative chain reactions, for want of vitamin E. In PD we most often start in the womb, with fatty maternal diet causing EFA-deficient membranes in mother, placenta and foetus, creating an anxious brain--perhaps from the effects of cortisol crossing the placenta, plus oxidative activation of foetal PLA2 and COX enzymes, with PGE2 and IL-1 beta then driving up CRF and cortisol levels. Prostaglandin E2 derives from the mobilisation of Arachidonic Acid ("AA"), and it is fascinating to see the contrasting roles of this long-chain EFA in PD (where free AA may help create the typical anxious Parkinson's personality), while in AD it sits in the synaptic membrane waiting to bust in half, to release a neurotoxic unsaturated aldehyde into the synapse and the synaptic cleft. And so an Essential Fatty Acid becomes a deadly enemy to the brain, leaving in its wake a cerebral battlefield littered with Amyloid, Tau and (half the time) Synuclein--casualties of great wars of oxidation and peroxidation. But who started the war? Finally, knowing causes, we can start both prevention, and much-improved treatment for existing cases. Low-fat diet in pregnancy means a calm child and a long life, with PD very unlikely. Vitamin E-adequate food-oils will prevent both ADHD and AD. To paraphrase May West--That's Prevention! Inositol powder ( together with healthy diet) treats existing anxiety comprehensively, reversing most stress effects throughout the brain and body, including folate loss and homocysteine generation in blood vessels oxidised by cortisol-activated NADPH oxidase. Early AD in calm folk may stop if vitamin E is given together with fishoil, an untried combination of two known treatments which may work better together. And Double Lipid Whammies (Anxious-heimer's) must have inositol and folic acid in addition, to do a proper job. I know a lady with this problem in Florida, who has perked up somewhat on this Quadruple Therapy, despite being late-stage dementia. We must start earlier in future. No other Anxious-heimers cases --half or more of all AD cases--have been given Quad Therapy yet; let's do it.

References:
Ref 1. Peers R (1993) Vegetable Oils and Alzheimer's Disease. New Zealand Medical Journal 108:461 Ref 2. Wolf-Klein G et al (1988) Are Alzheimer Patients Healthier? JAGS 36: 219-224 Ref 3. Klein P and Johnson R (1954) Phosphorus Metabolism In Unsaturated Fatty Acid Deficient Rats. JBC 103:211

View all comments by Robert Peers