Statin-Associated Memory Loss: One Mechanism Identified

One Mechanism Identified by Sharon Hope

The article later on this page by Sharon Hope was inspired by her husband, Michael's, unfortunate experience with the statin drug, Lipitor.

After four trouble-free years on 10 mg daily, Michael experienced an abrupt and near fatal bout of rhabdomyolysis. On recovery, a major loss of short-term memory was evident, which has slowly improved. However, this former CEO of his company is no longer employable because of his persistent memory dysfunction.

On reviewing his medical history for other evidence of cognitive loss, Sharon and other family members recalled multiple episodes in Michael of apparent amnesia of the transient global type both before and after his rhabdomyolysis hospitalization, giving evidence that other cognitive side effects had occurred in addition to short-term memory loss.

Multiple doctors from a wide variety of clinical specialties have been involved with Michael's care and elaborate testing has been done. The final diagnosis remains - short-term memory loss, etiology unknown.

Journal publications reviewing ADRs include "Statin-associated memory loss: analysis of 60 case reports and review of the literature" by Wagstaff, et al [5], examining ADR reports to the United State's Federal Drug Administration (FDA), and "Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid lowering agents," by Tatley and Savage [6], reviewing the increase in ADR reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM). Published case reports have detailed individual or multiple patients experiencing statin-associated impairment of short term memory or amnesia [7, 8, 9, 10,11,12].

Anecdotal and other information on statin-associated amnesia and memory loss, less constrained to clinical and statistical data and more oriented to impact on patient daily living and quality of life, has been published in books [13, 14, 15], magazines [16], and newspapers [17, 18]. The journal article, "Implications of statin adverse effects in the elderly," by Golomb, emphasizes that the elderly are more vulnerable to and less likely to recover from statin ADRs [19]. Muldoon, et al [20,21], repeatedly succeeded in identifying and measuring cognitive changes in statin patients in placebo-controlled trials, and identified the specific neuropsychological tests most sensitive to statin cognitive damage. Golomb reported that patients that experienced statin-associated memory loss were subsequently unable to recover more than 85% of their pre-statin cognitive abilities after halting the statin, and upon rechallenge, they were unable to recover more than 85% of the previously recovered cognitive ability [22].

Memory loss not only affects the patient but the family, regardless of cause. It is commonly acknowledged that upon the death of an elderly spouse, the risk that the surviving spouse will die within one year increases. However, Christakakis and Allison [23] found that hospitalization for a diagnosis of psychiatric disease or dementia resulted in an even greater increase in risk of mortality for the care giving spouse, and that risk was also higher than if the diagnosis had been cancer or stroke. Damjanovic, et al, [24] found that caregivers of Alzheimer's patients experienced a decline in immune cells due to chronic stress, as evidenced by accelerated telomere erosion.

The incidence of statin patients developing memory loss or amnesia is underreported. Golomb, et al, found that physicians were more likely to deny than endorse the association between statins and cognitive ADRs when the symptoms were reported by the patient [25].

METHODS: Retrospective review using Pub Med, a service of the National Library of Medicine and the National Institutes of Health, and other sources.

RESULTS: Memory is formed by Long Term Potentiation (LTP) in the Hippocampus, whereby a change in the shape of a synapse ensures that subsequent signaling will follow the same pathway between neurons [26]. Researchers at University of California at Irvine, in a recent publication of physical evidence of LTP [1,27], demonstrated the physical process for formation of memory and verified the necessary environment for this change in shape. The researchers demonstrated that phosphorylated cofilin (pCofilin) caused actin polymerization, affecting actin filaments (f-Actin) to achieve a larger synapse. They used NMDA receptor agonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a product of nitric oxide synthase (NOS), to disrupt memory formation. A retrospective review of the literature indicates that CPP prevents new memory formation and erases existing memory.

Thus, both pCofilin and f-Actin are essential to forming memory, but they are products of Rho, which is produced in the mevalonate pathway. Statins interfere with the mevalonate pathway, by inhibiting HMG CoA reductase, and thereby inhibit other downstream products, including production of Coenzyme Q 10, dolichols, and Rho, and thus inhibit f-Actin and pCofilin. Statins affect the actin cytoskeleton, inhibit RhoA activation, andCofilin phosphorylation [28,29,30,31,32].

Statins upregulate Nitric Oxide, which produces CPP [33,34,35], thereby increasing the substance that erases existing memory and prevents formation of new memory.
Researchers report that cholesterol and Coenzyme Q10 are needed for memory function [36,37,38,39,40]. Cholesterol and Coenzyme Q10 production are also inhibited by statins, and likely contribute to statin cognitive ADRs, as may other mechanisms, above and beyond the suppression of LTP.

Only in retrospect and with the evolving pattern of cognitive damage associated with the use of Lipitor in other people was Sharon's attention directed to the possible role of Lipitor on her husband's cognition.
Only after learning of the Pfrieger report (2003) announcing the vital role of cholesterol in memory and the formation and function of synaptic connections involved in the function of memory, did Sharon experience the "Eureka" moment of awareness that directed her to this present manuscript.

Gradually she has accumulated relevant research and put her findings together that probe ever more deeply into the molecular mechanics of memory, supporting her suspicions of statins' negative effect on cognitive function.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

by Sharon Hope

ABSTRACT: HMG CoA reductase inhibitors, the cholesterol-lowering class of statin drugs, are associated with memory loss. A recent publication provided evidence of long term potentiation (LTP) [1], demonstrating the physical process for formation of memory and verifying the necessary environment, which must include actin and cofilin. The researchers used (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a product of nitric oxide synthase (NOS), to prevent new memory formation and erase existing memory. A survey of the literature indicates that statins inhibit Rho, essential for actin and cofilin, and that statins upregulate NOS, and thereby CPP. This suggests that one mechanism responsible for statin memory loss is the modification of the hippocamal synaptic environment by these statin actions. Thus, statin memory loss is a pharmacologically predictable outcome of statin treatment. Prescribing physicians should monitor statin patients for cognitive decline and intervene prior to significant impact to quality of life.

PURPOSE: Identify the mechanism by which HMG CoA reductase inhibitors, the cholesterol-lowering class of statin drugs, induce memory loss.

BACKGROUND: Cognitive adverse drug reactions (ADRs), including, amnesia, transient global amnesia, aphasia and impairment of short term memory, have been documented in association with statins. The damage is measurable and persistent, affects both the patient and family caregiver, and is underreported.

The Australian Adverse Drug Reactions Bulletin listed Simvastatin under "Drugs that make you forget," referring to reports of memory impairment or amnesia, including transient global amnesia, associated with drug therapy in 1998 [2]. In 2004, Australia's National Prescribing Service Limited released a fact sheet entitled "Statins and Memory Loss," based on reports of statins and amnesia or memory loss in Australia, specific to Atorvastatin, Fluvastatin, Pravastatin, and Simvastatin [3]. In 2005, the Canadian Adverse Reaction Newsletter identified adverse reaction reports of amnesia, to include forgetfulness, memory disturbance, memory impairment and memory loss, submitted to Health Canada in association with Atorvastatin, Cerivastatin, Lovastatin, Pravastatin, Rosuvastatin, and Simvastatin [4].

CONCLUSIONS: Statins are the most prescribed class of drugs in the world, and in the history of the world, and there is a bias against reporting of adverse effects. Even so, memory impairment has been established as an adverse effect of statin drugs, and various mechanisms may be involved. However, the fact that statins inhibit Rho and upregulate NOS, and thereby interfere with LTP, is sufficient to indicate that statin memory loss is a pharmacologically predictable statin outcome.

Prescribing physicians should monitor for statin memory loss, and consider establishing a pre-statin cognitive baseline using the statin sensitive neuropsychiatric tests. When memory loss is identified, the physician should proactively intervene, treat the patient and family through recovery, and file an ADR report. Emergency and other physicians should consider statin-associated memory loss in evaluation of patients presenting with Transient Global Amnesia, amnesia, memory loss, or aphasia.

Researchers should build on the understanding of LTP, recognize statin interference with LTP is repeatable, which is consistent with Muldoon's and with Golomb's findings [20,21,22], and begin to identify treatment toward recovery for statin memory loss patients based on this new understanding.

ACKNOWLEDGEMENTS AND AFFILIATION: The author wishes to thank Michael Hope for his inspiring courage and strength in working for nearly a decade toward recovery from his own statin ADRs. The author's affiliation is to her spouse, and to other families impacted by statin adverse effects. Author served as a patient advocate on the Advisory Board for the Robert Wood Johnson University of California at San Diego
(RWJ/UCSD) Statin Effects Study.

1. Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G. Evidence that long-term potentiation
occurs within individual hippocampal synapses during learning. J Neurosci. 2007 Jul 25.
27(30):8031-9. PMID: 17652593
2. Drugs That Make You Forget. Australian Adverse Drug Reactions Bulletin. 1998 Aug. Volume 17,
Number 3, section 3, page 3.
3. Statins and memory loss. National Prescribing Service Limited. 2004 Nov. Fact Sheet 18.
4. Statins and memory loss. Canadian Adverse Reaction Newsletter. 2005 Oct. Volume 15, Issue 4.
Statin-associated Memory Loss - One Mechanism Identified
Sharon Hope, 10/9/2007, page 4 of 5
5. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: analysis of 60
case reports and review of the literature. Pharmacotherapy. 2003 Jul. 23(7):871-80. PMID:
6. Tatley M, Savage R. Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for
the use of lipid-lowering agents. Drug Saf. 2007. 30(3):195-201. PMID: 17343428
7. Orsi A, Sherman O, Woldeselassie Z. Simvastatin-associated memory loss. Pharmacotherapy. 2001
Jun. 21(6):767-9. PMID: 11401190
8. McCarthy MW, Hendrick AE. ADR of the Month. Newsletter, University of Virginia Health System
Department of Pharmacy Services Drug Information Center. 2001 Sept. Vol. 6 No. 9.
9. Do HMG-CoA reductase inhibitors impair memory? The Tablet, a general member benefit published
by the British Columbia Pharmacy Association. 2001 Sept. Volume 10 no 8.
10. King DS, Wilburn AJ, Wofford MR, Harrell TK, Lindley BJ, Jones DW. Cognitive impairment
associated with atorvastatin and simvastatin. Pharmacotherapy. 2003. 23(12):1663-7. PMID:
11. Galatti L, Polimeni G, Salvo F, Romani M, Sessa A, Spina E. Short-term memory loss associated with
rosuvastatin. Pharmacotherapy. 2006 Aug. 26(8):1190-2. PMID: 16863497
12. Padala KP, Padala PR, Potter JF. Simvastatin-induced decline in cognition. Ann Pharmacother. 2006
Oct;40(10):1880-3. Epub 2006 Aug 29. October, 2006 Oct; Epub August 29, 2006. 40(10):1880-3..
PMID: 16940411
13. Graveline, D, Cohen JS, McCully KS. Lipitor, Thief of Memory. Publisher: Duane Graveline
(November 1, 2006). ISBN-10: 1424301629, ISBN-13: 978-1424301621
14. Graveline D. Statin Drugs: Side Effects and the Misguided War on Cholesterol. Publisher: Duane
Graveline; 3rd edition (2006). ISBN-10: 0970081790
15. Cohen, JS. What You Must Know About Statin Drugs & Their Natural Alternatives. Square One
Publishers (December 2004). ISBN-10: 0757002579, ISBN-13: 978-0757002571
16. Laise E. The Lipitor Dilemma. Smart Money Magazine. November 2003. 90-96.
17. Graedon J, Graedon T. People's Pharmacy: Are Cholesterol Drugs Linked to Memory Loss?.
Newspaper Columns, Editorial. 2006 Feb 13.
18. Dickey, F. The OD MD. Los Angeles Times Magazine. February 15, 2004.
19. Golomb BA. Implications of statin adverse effects in the elderly. Expert Opin Drug Saf.. 2005 May.
4(3):389-97. PMID: 15934847
20. Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, Manuck SB. Effects of
lovastatin on cognitive function and psychological well-being. Am J Med.. 2000 May. 108(7):538-
46. PMID: 10806282
21. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of
simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004 Dec.
117(11):823-9. PMID: 15589485
22. Golomb, BA. Clinical follow-up after stopping statin treatment. Paper presented at the 4th Conference
of the International Coenzyme Q10 Association Beverly Hilton, Los Angeles, April 14-17 2005,
14:30 pm, PST. Saturday, April 16th. Unpublished.
23. Christakis NA, Allison PD. Mortality after the hospitalization of a spouse. N Engl J Med. 2006 Feb 16.
354(7):719-30. PMID: 16481639
24. Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen, H, Laskowski B, Zou Y, Beversdorf
DQ, Weng NP. Accelerated telomere erosion is associated with a declining immune function of
caregivers of Alzheimer's disease patients. J Immunol. 2007 Sep 15. 179(6):4249-54. PMID:
25. Golomb BA, McGraw JJ, Evans MA, Dimsdale JE. Physician response to patient reports of adverse
drug effects: implications for patient-targeted adverse effect surveillance. Drug Saf. 2007. 30(8):669-
75. PMID: 17696579
26. Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G. Evidence that long-term potentiation
occurs within individual hippocampal synapses during learning. J Neurosci. 2007 Jul 25.
27(30):8031-9. PMID: 17652593
27. McDermott, T. Chasing Memory, a four-part series from the Los Angeles Times. Los Angeles Times.
August 19, 20, 21, 22.
28. Koch G, Benz C, Schmidt G, Olenik C, Aktories K. Role of Rho protein in lovastatin-induced
breakdown of actin cytoskeleton.. J Pharmacol Exp Ther. 1997 Nov. 283(2):901-9. PMID: 9353412
Statin-associated Memory Loss - One Mechanism Identified
Sharon Hope, 10/9/2007, page 5 of 5
29. Fernandez-Hernando C, Suarez Y, Lasuncion MA. Lovastatin-induced PC-12 cell differentiation is
associated with RhoA/RhoA kinase pathway inactivation. Mol Cell Neurosci. PMID: 15951198
30. Brown JH, Del Re DP, Sussman MA. The Rac and Rho hall of fame: a decade of hypertrophic
signaling hits. Circ Res. 2006 Mar. 31;98(6):730-42. PMID: 16574914
31. Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res. 2005 Dec. 9;97(12):1232-5.
PMID: 16339495
32. Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T,
Heller J. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and
activation of endothelial nitric oxide synthase. Hepatology. 2007 Jul. 46(1):242-53. PMID:
33. Tousoulis D, Antoniades C, Stefanadis C. Statins ameliorate atherosclerosis induced by inhibition of
nitric oxide synthase: Another novel vascular protective mechanism?. Int J Cardiol. 2007 Jun 12;
[Epub ahead of print]. PMID: 17570544
34. Duplessis CA, Fothergill D. Investigating the potential of statin medications as a nitric oxide (NO)
release agent to decrease decompression sickness: A review article. Med Hypotheses. 2007 Sep 11;
[Epub ahead of print]. PMID: 17855002
35. Hasan SM, Joe M, Alshuaib WB. Oxidative stress alters physiological and morphological neuronal
properties. Neurochem Res. 2007 Jul, Epub 2007 Mar 28. 32(7):1169-78.
36. Langsjoen PH, Langsjoen JO, Langsjoen AM, Lucas LA. Treatment of statin adverse effects with
supplemental Coenzyme Q10 and statin drug discontinuation. Biofactors. 2005. 25(1-4):147-52.
PMID: 16873939
37. Golomb BA, Jaworski B. Statins and dementia. Arch Neuro. 2001 Jul. 58(7):1169-70. PMID:
38. Tsai HI, Tsai LH, Chen MY, Chou YC. Cholesterol deficiency perturbs actin signaling and glutamate
homeostasis in hippocampal astrocytes. Brain Res. 2006 Aug, Epub 2006 Jul 7. 9;1104(1):27-38.
PMID: 16828067
39. Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW. Brain cholesterol turnover required for
geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A. 2006 Mar,. Epub 2006
Feb 27. 7;103(10):3869-74.. PMID: 16505352
40. Thelen KM, Rentsch KM, Gutteck U, Heverin M, Olin M, Andersson U, von Eckardstein A, Bjorkhem
I, Lutjohann D. Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of
pravastatin. J Pharmacol Exp Ther. 2006 Mar Epub 2005 Nov. 316(3):1146-52. PMID: 16282522

Sharon Hope
October 9, 2007

Contact e-mail:

Books From Amazon

The Dark Side of Statins
The Statin Damage Crisis
Cholesterol is Not the Culprit
Statin Drugs Side Effects
Lipitor, Thief of Memory

Over 12,000 reader posts:

spacedoc Forum