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Apparent regression of symptoms of Alzheimer’s – a case report

First entered 09/02/2018
This item withdrawn for update. The patient is now living a normal life with apparent full cognition, memory both long-  and short-term and functions of normal living.

Publication of the full paper is still pending and it would be imperilled by prior publication on this site. A brief summary follows:


Patient is male aged 80, PhD, active and physically fit. Memory problems and family history caused self-referral to memory clinic.

Early 2017

Diagnosis of vascular dementia – no treatment offered.

07/2017  Cognition and memory lost to extent of non-recognition of close family and family house/address. Commenced taking PIPmixN 10ml daily – proven to be useful in Parkinson’s cases. Aggression caused by frustration somewhat reduced over next few months.

10/2017  Diagnosis changed to vascular dementia and Alzheimer’s. Donepezil 10mg daily prescribed. Memory improved.

11/2017  Started taking PIPmixND 15ml daily. Rapid improvement in cognition and both short and long-term memory. By end Dec 2017 he could hold a conversation with grandchildren.

02/2018   Massive improvement to extent of tackling crosswords and puzzles. Could go local shopping by himself. Resumed hobbies including photography. Downloading to PC.

04/2018   Shopping in city centre specialist photographic shops, reading technical books, fully conversant

Another case is progressing similarly.


Donepezil in Alzheimer’s disease: From conventional trials to pharmacogenetics
Ramón Cacabelos
Neuropsychiatr Dis Treat. 2007 Jun; 3(3): 303–333.

Palop JJ, Mucke L (2016) Network abnormalities and interneuron

dysfunction in Alzheimer disease. Nat Rev Neurosci 17:777–792.

4 Responses to "Apparent regression of symptoms of Alzheimer’s – a case report"

Andrew Carmichael

11th April 2021 at 12:39 pm

From John Toohey –
A stroke of genius or amazing serendipity.
Ascorbyl palmitate is an ester. Under normal conditions in the digestive tract, it would certainly be broken into the constituent parts by pancreatic enzymes which hydrolyze fatty acid esters (the enzymes are called esterases or lipases). Therefore, taken by mouth, AP would have no effect different from that of taking ascorbic acid alone. However, your patient was getting no less than three proven or probable esterase inhibitors!!! (trehalose, baicalein, and donezepil – structures shown in the attachment). The inhibitors would prevent the cleavage of ascorbyl palmitate permitting it to get absorbed intact and reach the brain. Experiments would be needed to prove this mechanism but, at present, it is the best explanation for the effect that you observed.

Andrew Carmichael

11th April 2021 at 1:34 pm

From John Toohey –
Andrew: In my previous communication, I did not stress the relationship of hyperhomocysteinemia (HHE) to cognitive impairment. There are numerous papers on this relationship (some are listed below) but the picture is complicated by two factors:
a) the role of HHE in causing vascular pathology and
b) the possible role of vascular pathology in causing dementia.
This gives sulfur metabolism a secondary role in causing dementia. However, this indirect mechanism (HHE > vascular defects > dementia) was rendered untenable when large clinical studis showed that correcting HHE with diet and vitamins had no effect in preventing vascular pathology.
This gives more importance to the mechanism of a direct damaging effect of sulfur metabolites in the brain. There are two theories:
a) the theory of Jakubowski that homocysteine thiolactone causes homocysteinylation of critical sulfhydryl sites (5,6, below) and
b) newly emerging evidence that HHE causes overproduction of damaging sulfur species.
A direct damaging effect of sulfur metabolites on the brain and the ability to trap these agents provides a remarkable and promising method for preventing (or reversing) dementia. Your findings suggest that ascorbic acid delivered inside the BBB can achieve this. Another possible agent is the lipid-soluble NEM derivative that I mentioned.
If you want a second opinion on these ideas, I suggest that you contact David Smith at Oxford who has written about the vascular aspect.
1. Price BR, Wilcock DM, Weekman EM, Hyperhomocysteinemia as a risk factor for vascular contribution to cognitive impairment and dementia. Front. Aging Neurosci., (2018) doi 10.3389/fnagi.2018.00350
2. Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine. Food Nutr. Bull., 29(5), S143-S172 (2008).
3. Sharma M, Twain M, Twain RK, Hyperhomocysteinemia: Impact of neurodegenerative disease . Basic Clin. Pharm. Toxicol. 117(5), 287-296 (2015) doi 10.1111/bcpt.12424
4. Seshadri S… al. Plasma homocysteine as a risk factor for dementia in Alzheimer’s Disease. New Eng. J. Med. (7), 463-483 (2002).
5. Sharma GS, et al. Protein N-homocysteinylation: from cellular toxicity to neurodegeneration. Biochim. Biophys. Acta, 1850 (11), 2239-45 (2015).
6. Peria-Kajan J, Jakubowski H. Paraoxonase 1 and homocysteine metabolism. Amino Acids, 43 (4) 1405017 (2012).

Andrew Carmichael

11th April 2021 at 2:22 pm

From John Toohey (to whom many thanks for guidance and advice)

Andrew: You may be surprised to learn that your findings may have propelled you to the frontier of chemistry known as “green chemistry” – in an vivo form. I will try to explain as briefly as possible. The literature is very large and in citing a few examples below, I am leaving out numerous other papers repeating and confirming the observations.

You included baicalein in your PIPmixND and you cite a paper relating it to AD; there are other papers on baicalein e.g. (1). But baicalein is only one of many flavones of plant origin that have similar structures and similar effects when tested with models of AD. The list includes quercetin (2), fisetin (3), cromolyn (4), ellagic acid (5) and its parent punicalagin (6) as well as ascorbic acid (7). This is not a complete list. All of these have shown effects in preventing dementia in mouse models and some studies have remarkable brain histology showing blockage of amyloid formation (e.g. fisetin and cromolyn).

All of these compounds are α,β-unsaturated carbonyls – a structure which allows them to undergo special reaction known as the “Michael addition” in which an alcohol (or, as found later, a thiol) undergoes a facile 1,4-addition. When the adduct is a thiol the reaction is called the “thiol Michael addition” (8). This is sophisticated chemistry and is now at the forefront of drug synthesis. It is called “green chemistry” because it uses few harmful solvents and chemicals and little expenditure of energy. To explain it, is necessary to go back to some elementary organic chemistry.

The simplest addition reaction involving carbonyl groups is the “aldol condensation” in which an alcohol adds to the carbonyl: R1 -C-OH + R2-C(O)H → R1-C(OH)-OR
R-SH compounds can replace the alcohol: R1-SH +R-C(O)H > R1-C(OH)R.
Long ago, Michael found that α,β-unsaturated cabonyl compounds undergo a similar reaction but it is a 1,4 addition. R1-CH=CH-C(O)H + R-SH > R1-CH(SR)-CH(OH)-R

The revolutionary chemistry began only 20 years ago when it was found that this reaction could be applied to numerous acceptor moleculs (maleimides, vinyl sulfone, acrylates, acryalamines, acrylonitriles, and more) – yielding routes to an incredible number of products many with drug function (9,10). The reactions are extremely facile and require no heating but some need to occur over several days (attractive features for occurring in vivo).

Relevance to Dementia. It is probably no coincidence that all of thecompounds that show effects in AD are prime candidates for undergoing the thiol Michael reaction. That provides circumstantial evidence for my previous prediction that these compounds are trapping and removing toxic sulfur compounds from the brain. Specific chemical testing for each compound is needed; the predicted reaction involving ascorbic acid has already been reported (11) and I have other unpublished data for H2S.

But what are the toxic sulfur compounds that need to be removed? Homocysteine itself is known to have many harmful effects but the main culprit is probably sulfane sulfur/hydrogen sulfide derived from the excessive homocystine. In HHE, the homocysteine occurs in the form of mixed disulfides one of which is the mixed disulfide with cysteine, cy-S-S-hcy. Research now in progress in New York is showing that this mixed disulfide is a highly active substrate for the enzyme cystathionase. The enzyme catalyzes C-S lysis resulting in the formation of cysteine persulfide cy-S-S-hcy > NH3 + ketobutyrate + cy-S-SH. Although this form of sulfur is required in many regulatory functions, it is highly toxic at supraoptimal concentrations and is a likely cause of the homocysteine-related dementia. Homocysteine is now a recognized cause of dementia (12) and the whole scenario seems to come together in a paper in which methionine feeding was used to induce hyperhomocysteinemia and the resulting brain pathology was corrected by ascorbic acid (13).

I know that most of this will be unintelligible to a lay person but I am sending it to you so that you can refer it to experts in the field (AD Smith, Refusm). to get their opinion. Some of the preliminary labwork is missing but the results from animal models, your observations, and the theoretical background suggest that it is apropos to embark on a full scale clinical trial.

An note on a different subject to correct your terminology “palmitoyl ascorbate” .
The International Union of Pure and Applied Chemsitry (IUPAC) has clearly defined rules for naming chemicals. Esters are named with the alcohol first ending with “yl” and the acid last ending with “ate”. See, for example, ethyl acetate.
Therefore, the compound in question is “ascorbyl palmitate”. You say that your term is used in UK but IUPAC does not make exceptions.

1. Li Y, et al., Therpeutic potential of baicalein in AD and PD. CNS Drugs, 31 (8), 639-52(2017) doi 10.2007/s40263-017-0451-y

2. Quercetin: Sabagol-Guaqueta AM et al. Neuropharmacol. 93, 134-145 (2015)
doi 10.1016/j.neuropharm.2015.01.027

3. Fisetin :a) Kumar H et al, Can J. Physiol.Pharmacol., 95(1), 32-42 (2017).
b) Nabavi SF et al., Curr.Topics Med. Chem., 16(17) 1910-5 (2016).
c)Currais A. et al., Afing Cell, 13(2), 379-90 (2014).

4. Cromolyn:a) Zhang C et al., Sci. Reports, 8, 1144 (2018) 10.1038/s541598-018-19641-2
b) same group, J. Biol. Chem., 290(4) 1966 (2015) doi 10.1074/jbc.M114.586602

5. ellagic acid: Bansal N, Yadar P, Kumar M, Drug Res., 67(7) 425-431 (2017).

6. punicalagin: Rojanathammanu L. et al J Nutr. 143 (5) 597-605 (2-13) 10.3945/jn.112.169616

7. Ascorbic acid: a) Basambomba LL, Carmichael PH et al., Ann. Pharmacother., 51(2), 118-124 (2017)

b) Charleton KE, et al., J. Nutr. Health Aging,8(2), 99-107 (2004)

8. Nair P et al. The thiol Michael addition Click reaction: a powerful and widely-used tool in materials chemistry. Chem. Materials. 26(1), 724-44 (2014). 1.1021/cm402180t

9. Sharma A. et al., This-Michael addition; and emerging stratefy in organic synthesis. Asian J. Org.Chem., 10.1002/ajoc.201700609

10. Li CJ, Trost BM, Green chemistry for chemical synthesis. PNAS, 105 (36), 13197-13202 (2008). doi 10.1073/pnas.0804348105

11. Drake BB et al. Complexes of dehydroascorbic acid with three sulfhydryl compounds. J.Biol. Chem., 143, 89-98 (1942).

12. Smith et al.: Homocysteine and dementia: an international consensus statement. J. Alz. Dis., 62(2), 561-570 (2018) doi 10.3233/JAD-171042

13. Boyacioglu M, et al…Exp. Toxicol. Pathol. 66(9-10), 407-13 (2014) 10.1016/j.etp.2014.06.004

Andrew Carmichael

11th April 2021 at 2:26 pm

A useful reference:
Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment.
Cheng B, Zhang Y, Wang A, Dong Y, Xie Z. Mol Neurobiol. 2015 Dec;52(3):1580-1589. doi: 10.1007/s12035-014-8959-3. Epub 2014 Nov 4. PMID: 25367886 Free PMC article

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