If current population trends continue and treatments that
arrest or reverse Alzheimer disease (AD) are not found,
the number of patients with AD in the United States is
projected to increase to more than 13 million by the year
2050.1 Numbers of persons afflicted with severe cognitive
impairment caused by traumatic brain injury and stroke also
continue to increase. Developing effective and cost-effective
treatment approaches for AD and the other dementias is clearly
an urgent priority.
In addition to conventional pharmacologic
treatments of dementia and
milder forms of cognitive impairment,
promising research findings are being
reported for many nonconventional
treatments. “Nonconventional” treatments
are those biologic, somatic,
mind-body, and energy-information
approaches not currently accepted in
Western biomedical psychiatry. This
column provides a brief overview of
the evidence for selected nonconventional
approaches used to treat dementia
and mild cognitive impairment in
the United States and other Western
countries. A review of more substantiated
approaches in this issue will be
followed in the next installment by highlights
of approaches for which there is
limited evidence at present.
Epidemiologic studies, case control
studies, and prospective trials suggest
that persons who consume a high-fat,
high-calorie diet are at significantly
greater risk for AD than are persons who
have moderate fat intake and restrict
total calories. A meta-analysis of findings
from 18 community-wide studies
concluded that the risk of AD increased
linearly at a rate of 0.3% with every
100-calorie increase in daily intake.2
However, a systematic review of 6 case
control studies and 3 cohort studies that
examined dietary preferences in dementia
concluded that there is no compelling
evidence for causal relationships
between specific dietary factors and the
risk of becoming demented.3 Consistent
relationships between dietary protein,
vitamins, and minerals and the risk of
dementia were not identified.
Evidence from epidemiologic studies
suggests that regular intake of foods
rich in omega-3 fatty acids may be
inversely related to cognitive impairment
or the rate of overall cognitive decline
in nondemented elderly persons. However,
findings to date are inconclusive.
A large epidemiologic study concluded
that consuming fish 2 to 3 times weekly significantly reduces the risk of cognitive
decline in elderly populations.4
Cognitive impairment scores were
analyzed for 2 groups of elderly men
(aged 69 to 89) with different dietary
preferences. High fish consumption was
inversely correlated with cognitive impairment.
Findings from a prospective
cohort study suggest that
persons who consume fish
at least weekly have a 60%
lower risk of AD than do
persons who seldom eat fish.5 However,
another study failed to show a correlation
between fish consumption and
the risk of AD.6
Moderate but not heavy consumption
of wine (2 to 4 glasses per day) is
also associated with a reduced risk of
AD.7 In a large 2-year follow-up study,
moderate alcohol consumption was
found to be associated with a significant
reduction in risk for both AD and
MEDICINAL HERBS AND
Standardized preparations of Ginkgo
biloba are widely used in Europe to
treat dementia and other neurodegenerative
diseases. More recently, use of
G biloba has become widespread in
North America. Systematic reviews
and early meta-analyses of double-blind
controlled studies show that standardized
preparations of G biloba in dosages
between 120 and 600 mg/d taken for
several weeks to 1 year result in consistent
modest improvements. These improvements
involve memory, general
cognitive functioning, and activities of
daily living in mild to moderate cases
of both AD and multi-infarct dementia
and are equivalent to improvements
seen with donepezil (Aricept), a conventional
However, a more recent meta-analysis
revealed inconsistent findings of 3
trials based on more rigorous research
protocols and commented on research
design problems in both recent and early impairtrials,
including the absence of standardized
ginkgo preparations and the
use of different dementia rating scales
across studies.14 Although most controlled
studies fail to support the claim
that ginkgo significantly improves
memory in severely demented patients,
the findings of one double-blind study
suggest that the rate of overall cognitive
decline is moderately slowed in
this population.15 A systematic review of
40 controlled and observational studies
suggests that ginkgo improves cognitive
symptoms associated with cerebral
vascular insufficiency, including impaired
concentration and memory loss.16
To date, there is uneven evidence
for beneficial effects of G biloba in dementia.
However, a review of research
findings suggests that G biloba extract
should be regarded as a
provisional approach for
the prevention or treatment
of mild cognitive impairment.
A meta-analysis of 11 clinical
trials of G biloba extract in elderly persons
who reported cognitive difficulties
but did not meet full diagnostic criteria
for dementia confirmed consistent
cognitive-enhancing effects.17 However,
more recent large studies on ginkgo in
mild cognitive impairment have yielded
negative findings.18 Long-term use of
G biloba extract in nonimpaired elderly
persons may improve the efficiency and
speed of information processing and
delay onset of mild cognitive impairment.
19,20 However, a recent, large
controlled trial failed to confirm a
consistent preventive effect.21
Because of its strong anti–platelet
aggregation factor profile, G biloba
extract increases the risk of bleeding
and should not be used by patients taking
aspirin, warfarin, heparin, or other medications
that interfere with platelet activity
and increase bleeding time. G biloba
preparations should be discontinued at
least 2 weeks before surgery.
This alkaloid derivative of the herb
Huperzia serrata is an important ingredient
of many compound herbal formulas
used in Chinese medicine to treat
mild cognitive impairment that occurs
with normal aging. Huperzine-A
reversibly inhibits acetylcholinesterase
and may also slow production of nitric
oxide in the brain, possibly reducing agerelated
neurotoxicity.22 Controlled trials
show consistent beneficial effects in both
age-related memory loss and AD at
dosages between 200 and 400 g/d.23,24 Infrequent adverse
effects include transient
This compound is
one of the most important
phospholipids in the brain and
is an essential component of nerve cell
membranes. The mechanism of action
is believed to be enhanced fluidity of
nerve cell membranes, indirectly resulting
in increased brain levels of many
important neurotransmitters.25 Brainderived
phosphatidylserine is probably
more effective than the soy-derived
product,26 possibly because of its higher
content of docosahexaenoic acid, an
omega-3 fatty acid, but recent concerns
have been raised over the risk of slow
viruses in infected bovine tissue. The
findings of large, double-blind, placebocontrolled
studies confirm improved
global functioning and memory in AD
and age-related cognitive decline at
typical dosages of 300 mg/d.27-31
increases mitochondrial energy
production and is used in many parts of
the world to treat cognitive impairments
that result from neurodegenerative diseases.
CDP-choline, 500 to 1000 mg/d,
improves overall energy metabolism in
the brain, increases brain levels of dopamine
and norepinephrine,32 and enhances
short-term memory in patients
with AD.33 Two Cochrane systematic
reviews concluded that CDP-choline
has consistent positive effects on the rate
of recovery in post-stroke patients and
in elderly persons who are cognitively
impaired because of cerebrovascular
disease.34,35 There is preliminary but
promising evidence of a beneficial effect
following traumatic brain injury.36
The findings of one small study suggest
a possible effect of CDP-choline, 1000
mg/d, in the early stages of AD.37
This is a substance that is related to
ubiquinone (coenzyme Q10), and like
that compound, it also increases intracellular
energy production in mitochondria.
Animal and human studies
have shown that idebenone, 360 mg/d,
may be more effective than tacrine
(Cognex)38 and possibly other conventional
treatments of cognitive impairtment in mild to moderate cases of AD.39
However, in a large multicenter, doubleblind,
trial, patients with probable early AD who
received varying dosages of idebenone
up to 300 mg tid did not experience slowing
in the rate of cognitive decline compared
with a control group.40
SOMATIC AND MIND-BODY
Exercise increases levels of brainderived
neurotrophic factors, probably
enhancing neural plasticity and new
synapse formation.41 Regular exercise
is associated with increases in the relative
size of the frontotemporal and parietal
lobes, which are important centers
for learning, memory, and executive
functioning.42 Long-term regular physical
activity is associated with a reduced
risk of all categories of dementia in
elderly men and women.
More than 2000 physically nonimpaired
men aged 71 to 93 years were
monitored with routine neurologic assessments
at 2-year intervals starting in
1991.43 At the end of the study period,
men who walked less than a quarter of
a mile daily had an almost 2-fold greater
probability of having any category of
dementia compared with men who
walked at least 2 miles each day. Factors
other than the level of physical activity
were accounted for, including the possibility
that limited activity could be a result
of early but undiagnosed dementia.
Findings of the Nurses' Health Study,
based on biannual mailed surveys over
10 years, showed that elderly women
aged 70 to 81 years who engaged in
regular vigorous physical activity were
significantly less likely to have dementia
than were women with more sedentary
lifestyles.8 Although regular exercise
is an important preventive strategy, it
is probably not an effective intervention
once dementia has begun. A
randomized controlled trial showed that
regular daily exercise in moderately
demented individuals receiving in-home
care reduces depressed mood but does
not improve cognitive functioning.44
1. Hebert LE, Scherr PA, Bienias JL, et al.
Alzheimer disease in the US population: prevalence
estimates using the 2000 census. Arch Neurol.
2. Grant W. Dietary links to Alzheimer's disease.
Alzheimer's Dis Rev. 1997;2:42-55.
3. Ernst E. Diet and dementia, is there a link? A systematic
review. Nutr Neurosci. 1999;2:1-6.
4. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D.
Polyunsaturated fatty acids, antioxidants, and cognitive
function in very old men. Am J Epidemiol.
5. Morris MC, Evans DA, Bienias JL, et al.
Consumption of fish and n-3 fatty acids and risk of
incident Alzheimer disease. Arch Neurol.
6. Engelhart M, Geerlings M, Ruitenberg A, et al.
Dietary intake of antioxidants and risk of Alzheimer's
disease. JAMA. 2002;287:3223-3229.
7. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine
consumption and dementia in the elderly: a prospective
community study in the Bordeaux area. Rev
Neurol (Paris). 1997;153:185-192.
8. Deng J, Zhou DH, Li J, et al. A 2-year follow-up
study of alcohol consumption and risk of dementia.
Clin Neurol Neurosurg. 2006;108:378-383.
9. Wong AH, Smith M, Boon HS. Herbal remedies
in psychiatric practice. Arch Gen Psychiatry.
10. Kanowski S, Herrmann WM, Stephan K, et al.
Proof of efficacy of the Ginkgo biloba special extract
EGb 761 in outpatients suffering from mild to moderate
primary degenerative dementia of the Alzheimer
type or multi-infarct dementia. Pharmacopsychiatry.
11. Oken BS, Storzbach DM, Kaye JA. The efficacy
of Ginkgo biloba on cognitive function in Alzheimer
disease. Arch Neurol. 1998;55:1409-1415.
12. Le Bars PL, Katz MM, Berman N, et al. A placebocontrolled,
double-blind, randomized trial of on
extract of Ginkgo biloba for dementia. North American
EGb Study Group. JAMA. 1997;278:1327-1332.
13. Itil TM, Eralp E, Ahmed I, et al. The pharmacological
effects of Ginkgo biloba, a plant extract, on
the brain of dementia patients in comparison with
tacrine. Psychopharmacol Bull. 1998;34:391-397.
14. Birks J, Grimley E. Ginkgo biloba for cognitive
impairment and dementia (Cochrane Review). In: The
Cochrane Library. Issue 2. Chichester, UK: John Wiley
& Sons; 2004.
15. Le Bars PL, Velasco FM, Ferguson JM, et al.
Influence of the severity of cognitive impairment on
the effect of the Ginkgo biloba extract EGb 761 in
Alzheimer's disease. Neuropsychobiology.
16. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet.
17. Hopfenmuller W. Evidence for a therapeutic
effect of Ginkgo biloba special extract. Meta-analysis
of 11 clinical studies in patients with cerebrovascular
insufficiency in old age [in German].
18. van Dongen M, van Rossum E, Kessels A, et al.
Ginkgo for elderly people with dementia and ageassociated
memory impairment: a randomized clinical
trial. J Clin Epidemiol. 2003;56:367-376.
19. Allain H, Raoul P, Lieury A, et al. Effect of two doses
of ginkgo biloba extract (EGb 761) on the dual-coding
test in elderly subjects. Clin Ther. 1993;15:549-558.
20. Semlitsch HV, Anderer P, Saletu B, et al. Cognitive
psychophysiology in nootropic drug research: effects
of Ginkgo biloba on event-related potentials (P300)
in age-associated memory impairment.
21. Cheuvront SN, Carter R III. Ginkgo and memory.
22. Zhao HW, Li XY. Ginkgolide A, B, and huperzine
A inhibit nitric oxide-induced neurotoxicity. Int
23. Wang Z, Ren Q, Shen Y. A double-blind controlled
study of huperzine A and piracetam in patients with
age-associated memory impairment and dementia.
In: Kanba S, Richelson E, eds. Herbal Medicines
for Nonpsychiatric Diseases. Tokyo: Seiwa Sholen
24. Zucker M. Huperzine-A: the newest brain nutrient.
Let's Live. 1999:47-48.
25. Pepeu G, Pepeu IM, Amaducci L. A review of
phosphatidylserine pharmacological and clinical
effects. Is phosphatidylserine a drug for the ageing
brain? Pharmacol Res. 1996;33:73-80.
26. Hibbeln JR, Salem N Jr. Dietary polyunsaturated
fatty acids and depression: when cholesterol does
not satisfy. Am J Clin Nutr. 1995;62:1-9.
27. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive
decline in the elderly: a double-blind placebocontrolled
multicenter study on efficacy of phosphatidylserine
administration. Aging (Milano).
28. Crook TH, Tinklenberg J, Yesavage J, et al. Effects
of phosphatidylserine in age-associated memory
impairment. Neurology. 1991;41:644-649.
29. Villardita C, Grioli S, Salmeri G, et al. Multicentre
clinical trial of brain phosphatidylserine in elderly
patients with intellectual deterioration. Clin Trials J.
30. Palmieri G, Palmieri R, Inzoli M, et al. Doubleblind
controlled trial of phosphatidylserine in patients
with senile mental deterioration. Clin Trials J.
31. Amaducci L. Phosphatidylserine in the treatment
of Alzheimer's disease: results of a multicenter study.
Psychopharmacol Bull. 1988:24;130-134.
32. Secades JJ, Frontera G. CDP-choline: pharmacological
and clinical review. Methods Find Exp Clin
Pharmacol. 1995;17(suppl B):1-54.
33. Alvarez XA, Laredo M, Corzo D, et al. Citicoline
improves memory performance in elderly subjects.
Methods Find Exp Clin Pharmacol. 1997;19:201-210.
34. Mitka M. News about neuroprotectants for the
treatment of stroke. JAMA. 2002;287:1253-1254.
35. Fioravanti M, Yanagi M. Cytidinediphosphocholine
(CDP Choline) for cognitive and behavioral
disturbances associated with chronic cerebral disorders
in the elderly (Cochrane Review). In: The
Cochrane Library. Issue 2. Chichester, UK: John Wiley
& Sons; 2004.
36. Spiers PA, Hochanadel G. Citicoline for traumatic
brain injury: report of two cases, including my own.
J Int Neuropsychol Soc. 1999;5:260-264.
37. Alvarez XA, Mouzo R, Pichel V, et al. Doubleblind
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.
38. Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Safety
and efficacy of idebenone versus tacrine in patients
with Alzheimer's disease: results of a randomized,
double-blind, parallel-group multicenter study.
39. Gutzmann H, Hadler D. Sustained efficacy and
safety of idebenone in the treatment of Alzheimer's
disease: update on a 2-year double-blind multicentre
study. J Neural Transm Suppl. 1998;54:301-310.
40. Thal LJ, Grundman M, Berg J, et al. Idebenone
treatment fails to slow cognitive decline in Alzheimer's
disease. Neurology. 2003;61:1498-1502.
41. Cotman CW, Berchtold NC. Exercise: a behavioral
intervention to enhance brain health and plasticity.
Trends Neurosci. 2002;25:295-301.
42. Haier RJ. Cerebral glucose metabolism and intelligence.
In: Vernon PA, ed. Biological Approaches to
the Study of Human Intelligence. Norwood, NJ:
Ablex Publishing; 1993:318-332.
43. Abbott RD, White LR, Ross GW, et al. Walking
and dementia in physically capable elderly men. JAMA.
44. Teri L, Gibbons LE, McCurry SM, et al. Exercise
plus behavioral management in patients with
Alzheimer's disease: a randomized controlled trial.