It improves cognitive functions as well as cerebral blood flow and bioelectrical activity 
Dr. Edward R. Rosick


You have to begin to lose your memory, if only in bits and pieces, to realize that memory is what makes our lives. Life without memory is no life at all, just as intelligence without the possibility of expression is not really intelligence. Our memory is our coherence, our reason, our feeling, even our action. Without it, we are nothing.
— Luis Buñuel

Imagine a disease that robs you of your memory: in essence, it robs you of you, as the great filmmaker Buñuel saw so clearly. Unfortunately, there is such a disease. It’s all too real, and it’s becoming an epidemic of the twenty-first century—not because it’s contagious, but because we’re getting older as a society, and our imprudent lifestyle (poor diet and lack of exercise) encourages its development.

In 1906, a German neuropathologist, Dr. Alois Alzheimer, gave the first clinical description of the disease that eventually bore his name. The most common type of dementia in those aged 65 or older, Alzheimer’s is characterized by a progressive decline in memory and cognition, as well as functional and behavioral disturbances. It currently afflicts over 4 million people in the United States. With our rapidly aging population (about 30% of Americans will be 65 or older by the year 2050), it is estimated that at least 14 million people will be stricken with Alzheimer’s during the coming few decades.1,2

Alzheimer’s Causes Multiple Brain Damage

Although the causes of Alzheimer’s are still largely unknown, scientists do know how the disease causes its terrible effects. There are several pathological changes that occur in the brains of Alzheimer’s victims, the most obvious of which (through brain imaging or at autopsy) is the loss of substantial amounts of brain tissue. Less obvious—but visible under the microscope at autopsy, and highly characteristic—are harmful deposits called senile plaques and neurofibrillary tangles. Major culprits in these destructive phenomena are the invisible processes of oxidative damage caused by free radicals, and inflammation of neuronal tissue.

Also invisible, but pernicious in its consequences, is a marked reduction, in certain regions of the brain, in cholinergic function—brain activity that depends on the neurotransmitter acetylcholine, which is vitally important for memory formation and retention. This is another hallmark of Alzheimer’s disease, and it represents the most attractive target for medicinal therapy.

CDP-Choline—An Alternative to Drugs

The most important and widely used anti-Alzheimer’s drugs are acetylcholinesterase inhibitors, so called because they inhibit the action of acetylcholinesterase, an enzyme that breaks down acetylcholine molecules (this is a necessary function that can, however, get out of balance). By interfering with the action of this enzyme, the drugs effectively increase the amount of acetylcholine available to the brain’s neurons. Although they can sometimes halt the progress of the disease for a matter of months and slow down its further progress, they cannot stop it altogether or prevent the inevitable outcome.* Nor can they affect any of the neuropathological changes that make Alzheimer’s so devastating. In addition, most such drugs are expensive and can have unpleasant side effects.

*The notable standout in this gloomy picture is galantamine, a “drug” that is really a nutritional supplement. Unlike the other acetylcholinesterase inhibitors, galantamine can often bring about significant improvements in the patient’s cognitive condition for about a year, before the decline resumes. (See the article on page 19 of this issue.)

Fortunately, there are some safe, natural supplements that can also be used to protect mind and memory. One of these is CDP-choline (short for cytidine-5’-diphosphocholine), a compound that functions as an intermediate in the biosynthesis of cell-membrane phospholipids. CDP-choline (also known as citicoline) is a precursor to acetylcholine and has shown considerable promise in studies of people with Alzheimer’s, cognitive deficits, and poor memory; in addition, some preliminary studies have shown that CDP-choline can aid victims of stroke.3

CDP-Choline Tested on Various Brain Functions

Researchers in Spain conducted a randomized, double blind, placebo-controlled study in 1999 on the effects of CDP-choline in patients with mild to moderate Alzheimer’s disease.4 Thirty male and female patients, average age 74, were assigned to two groups, receiving either 1000 mg/day of CDP-choline or placebo for 12 weeks, after a 2-week drug washout period. During both the washout phase and a 1-week post-treatment discontinuation phase, all patients received placebo. Testing was done at the beginning and end of the 12-week period.

The primary outcome measures were: (1) the Alzheimer’s Disease Assessment Scale (ADAS); (2) a cognitive subscale of the ADAS (ADAS-cog), which includes assessment of several aspects of memory, learning, and language; and (3) the Clinical Interview-Based Impression of Change (CIBIC), a global assessment that measures either improvement or deterioration on a 7-point scale.

In addition, the researchers evaluated various aspects of brain hemodynamics (mainly blood-flow velocities), using Doppler ultrasonography, and brain bioelectrical activity, using EEG (electroencephalography).

Results Agree with Those of Previous Studies

The researchers found that, compared with placebo, CDP-choline did not produce statistically significant improvements in the ADAS, ADAS-cog, or CIBIC scores for the treatment group taken as a whole, although the trends shown in the measured changes favored CDP-choline, i.e., there was a tendency toward improvement with CDP-choline, and a stronger tendency toward deterioration with placebo. Thus, CDP-choline tended to be beneficial over the 12-week duration of this study, although not to the degree one might have wished. The authors stated, “These data are in agreement with previous studies demonstrating that citicoline improves mental functioning in elderly nondemented subjects and in patients with senile dementia of the vascular or the Alzheimer type.”

They also found, however, that two subgroups of patients did show statistically significant improvements in their ADAS scores (but not in their ADAS-cog or CIBIC scores) with CDP-choline. These groups were: (1) patients who had a gene called APOE e4, which increases one’s risk for Alzheimer’s disease, and (2) patients who were only mildly demented, i.e., in the initial stages of the disease.

The Right Trends, but Little Statistical Significance

In evaluating the patients’ brain hemodynamics, the researchers measured blood flow in the left and right middle cerebral arteries. Here they found a similar pattern to that observed in the cognitive tests: the results for the patients on placebo showed a significant worsening over 12 weeks, while those for the patients on CDP-choline showed improvement or no change—but not, for the most part, to a statistically significant degree of difference. An exception was found when the data for flow velocities in the two arteries were combined, and a statistically significant improvement with CDP-choline did emerge.

The pattern was repeated yet again when the researchers studied the patients’ brain bioelectrical activity. Although there were no statistically significant differences, the patients taking CDP-choline showed a tendency toward increased activity, while the opposite occurred in the patients on placebo.

A Candid Admission

In a candid admission, the researchers stated that the results observed might have been attenuated by the fact that all the patients selected for the study had been taking CDP-choline during several months before the selection. Because CDP-choline’s procognitive activity, in their own words, “seems to last for at least 1 month after withdrawal,” and because the washout period before the trial began was only 2 weeks long (i.e., at least 2 weeks too short), the cognitive worsening in the placebo group and the cognitive improvement in the CDP-choline group might both have been greater had the trial been designed more sensibly—in which case the results might have been statistically significant.

In short, CDP-choline is probably more effective than this study would suggest, and a recently published meta-analysis supports this view.5 (For more on CDP-choline, see “Citicoline Helps Protect Brain Function” in the June 2003 issue.)

CDP-Choline—A Safe, Effective Supplement

Having watched a family member suffer the debilitating effects of Alzheimer’s disease, I know first-hand the emotional and psychological toll this terrible affliction takes on patients and the family members who care for them. For people with Alzheimer’s, as well as those healthy elderly persons who want to keep their brains sharp and their memories intact, CDP-choline can be a valuable, safe, and effective supplement.


  1. Grundman M, Thal L. Treatment of Alzheimer’s disease. Neurol Clinics 2000; 18(4):807-28.
  2. Mayeux R, Sang M. Treatment of Alzheimer’s disease. New Engl J Med 1999; 341:1670-9.
  3. Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Alt Med Rev2004;9(1):17-31.
  4. Alvarez XA, Mouzo R, Pichel V, et al. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer’s disease patients. Effects on cognitive performance, brain bioelectrical activity, and cerebral perfusion. Methods Find Exp Clin Pharmacol 1999;21(9):633-44.
  5. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. John Wiley & Sons, Chichester, UK.


Ginkgo biloba—An Ancient Herb for a Healthy Brain

The ginkgo tree, Ginkgo biloba, is believed to be the oldest tree species on earth. Ancient Chinese medical manuscripts indicate that humans have been using extracts of ginkgo leaves for the last 5000 years to treat a myriad of conditions, including age-related memory loss.1 The basis for ginkgo’s remarkable efficacy is primarily its ability to promote improved blood circulation in the brain, along with potent antioxidant and anti-inflammatory properties.

Modern research has shown that ginkgo extracts can provide protection against the most common pathological changes seen in the brains of Alzheimer’s patients. One study reported that ginkgo protected the brain against the age-related loss of cholinergic neurons and increased the uptake of acetylcholine in the hippocampus, a brain structure vitally important to memory and learning.2

Helping to combat Alzheimer’s disease is invaluable, but ginkgo can be beneficial to healthy adults as well. British researchers recently examined the effects of 120 mg/day of a Ginkgo biloba extract called LI 1370* on the activities of daily living (ADLs) and various aspects of mood and sleep in 1570 healthy, free-living men and women (average age 65).3 They were recruited from a 4-month ginkgo study and were invited to continue uninterrupted for another 6 months, but in a manner of their choosing—meaning that they could volunteer to take ginkgo extract or not take it (placebo was not being used), regardless of their prior status.

*This is a standardized ginkgo extract that is similar in composition to the more commonly used extract EGb 761.

Thus, the volunteers spontaneously divided themselves into four groups, based on whether they had previously been on ginkgo (G) or not (X), and whether, for the 6-month continuation, they elected to go on ginkgo or not. These four groups can be called G-G, G-X, X-G, and X-X. One would expect that the G-G group would have the best results, and the X-X group the poorest. We’ll see in a moment.

All the volunteers completed two sets of evaluations via mail-in questionnaires at the end of the 10-month trial (baseline evaluations with these tests had not been made at the beginning of the trial, however, so there was no solid frame of reference). One was the Line Analogue Rating Scale (LARS), a commonly used measure of various aspects of mood and alertness. The other was the Self-Rated Activities of Daily Living (SR-ADL) scale, which is used to assess the ability of people to perform common, everyday tasks (a notoriously problematic area for Alzheimer’s patients), along with memorization and concentration skills.

Overall, the results were what one might expect with ginkgo: the longer and the more recently an individual had been on ginkgo, the better the results. On the LARS rating, for example, the G-G group experienced the greatest improvement in mood by the end of the 10-month period, followed by the X-G group; then came the G-X and X-X groups, neither of which had experienced significant improvement. On the SR-ADL rating, the pattern was the same, albeit on a different level: the G-G group showed no appreciable change in their ability to cope with ADLs, and the other three groups showed slightly declining abilities, in the descending order X-G, G-X, and X-X.

Despite the self-admitted methodological flaws in their study, the authors concluded,

… this study demonstrates measurable improvements in the activities of daily living, mood, and alertness in a large group of healthy elderly volunteers. It suggests that … 120 mg/day is effective in producing higher subjective ratings of competence in managing the activities of daily living, particularly when compared with groups of volunteers not receiving any treatment.


  1. Jonas W, Levin J. Essentials of Complementary and Alternative Medicine.Lippincott Williams and Wilkins, Philadelphia, 1999.
  2. DeFeudis FV, Drieu K. Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 2001;1(1):25-58.
  3. Trick L, Boyle J, Hindmarch I. The effects of Ginkgo biloba extract (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers. Phyto Res 2004; 18:531-37.



Dr. Rosick is an attending physician and clinical assistant professor of medicine at Pennsylvania State University, where he specializes in preventive and alternative medicine. He also holds a master’s degree in healthcare administration.