ARTICLE
Auteur(s) : Tobias
Hartmann1,2, Klaus Fassbender2, Marcusow
Grimm1
1Institute for Neurobiology and Neurodegeneration,
Saarland University campus Homburg, Kirrberger Str.
Forschungsgebaude 61.4, D-66421 Homburg, Germany. Fax:
+49-6841-1647801
2Depart. for Neurology, Saarland University campus
Homburg, Kirrberger Str. Forschungsgebaude 61.4, D-66421 Homburg,
Germany
Introduction
When Alois Alzheimer a century ago identified amyloid plaques as
the hallmark and molecular manifestation of dementia in the
elderly, he set the stage for what has now become a major
scientific effort – treating and preventing Alzheimer’s disease
(AD).
Dementia and lipid physiology, especially concerning
cholesterol, have recently been discovered to be very closely
linked. This linkage has been observed on all levels of research.
Until recently little indication existed for a link between AD,
Amyloid Precursor Protein (APP) processing and cholesterol
homeostasis. However, this picture has changed dramatically over
the last years. First indications that lipids may play an important
role in APP processing and Aβ production are given by the finding
that all proteins involved in APP processing are integral membrane
proteins. Taking into consideration that the Aβ producing cleavage
by the γ-secretase takes place in the middle of the membrane it is
reasonable to assume that the lipid environment of the cleavage
enzymes influences Aβ production and hence AD pathogenesis [1].
Moreover, cellular and biochemical studies show that APP processing
and the proteases involved are sensitive to cholesterol and
cholesterol trafficking [2-6]. In vivo studies revealed that
cholesterol feeding increases Aβ42 production and amyloid burden
whereas lowering cholesterol by medication (e.g. statins) decreases
Aβ production and amyloid burden [3, 7, 8]. Accordingly statin
treatment is associated with a reduced AD risk in some
epidemiological studies [9-11]. First preliminary clinical trials
have led to mixed results. High statin dosage reduced cerebral Aβ
levels and disease progression in mild AD [8]. When treatment
duration was doubled beneficial effects were observed in mild and
moderate AD [12]. However, low statin dosage treatment for up to
twelve months did not show, aside from some potential secretase
inhibition, any clinical benefit [13, 14]. It is now clear that the
Aβ generating machinery is an integral part of the body’s lipid
homeostasis regulating system which causes it to respond very
sensitively to changes in lipid levels [15]. Moreover, it is
becoming ever more evident, that there are several more routes
through which lipids can have either a beneficial or a detrimental
impact on the brain. Especially the n3-fatty acids docosahexaenic
acid (DHA) and eicosapentaenoic acid (EPA) represent promising
candidate and a first clinical trial ended with positive
results.
Disease etiology
Alzheimer’s disease is a progressive neurodegeneration typically
affecting the elderly. There is currently no cure or prevention
available. Treatment is limited to symptomatic interventions which
offer some relief to patients and care givers for a limited time.
While there has been major progress in AD research, non-symptomatic
treatments are still in an experimental stage [16]. A conglomerate
of individual risk factors including genetic and environmental
factors causes the vast majority of AD cases. AD can be caused by
auto-somal dominant mutations too. While these familial AD cases
occur only very rarely the identification of the mutated genes has
let to the decipherment of important molecular mechanism leading to
AD. From this it has been concluded that enhanced production of
Amyloid beta (Aβ) peptides cause AD. Especially overproduction of
the long Aβ42 peptide causes early onset Alzheimer’s disease.
Whereas in disease extreme amounts of these peptides accumulate in
the brain, their levels remain low outside of the brain and in
absence of AD. Because of the accumulation of Aβ42 in all AD cases
it is assumed that such Aβ42 overproduction is likewise involved in
the pathogenesis of sporadic AD as well. Aβ is a physiological
cleavage product from the APP, a protein of uncertain function
which is ubiquitously expressed, but expression is especially high
in neurons. Aβ release is a two step procedure. Cleavage is
initiated by BACE 1, which is followed by γ-secretase cleavage.
Both proteases are membrane bound, but only the latter one cleaves
intramembranously. The proteolytic cascade resulting in Aβ release
is, that of a regulated intramembrane proteolysis (RIP). RIP
processing had first been recognized in cholesterol de novo
synthesis up-regulation. Very few cellular processes are determined
by a RIP mechanism and once this coincidence was noted it was
suggested that there this mechanistic similarity might also
indicate functional overlaps [17, 18].
Indeed, Aβ production is under physiological conditions tightly
regulated and its production rate is highly sensitive to
alterations of the cellular membrane composition.
Mechanistic lipid link
Vascular factors and factors related to diet, including blood lipid
levels and adiposity, have been linked with an increased risk of
dementia and AD. In addition, the Apolipoprotein Eε4 allele (APOE),
a protein involved in lipid metabolism, is the most frequent
genetic susceptibility factor for dementia. These studies have
provided the basis for first reports and replication studies on
relationships between overweight and obesity and AD [19, 20], high
adiposity and cerebro-vascular diseases [21, 22], an obesity- and
sex hormone-related marker and blood brain barrier integrity, high
blood cholesterol in midlife and subsequent AD [20, 23], and low
blood cholesterol and AD in late life [24] and high blood pressure
both at midlife and late-life and AD [25, 26]. It was also shown
that a combination of midlife hypertension, obesity, and
hypercholesterolemia increases the risk of dementia 6-fold [27].
Insights into the molecular mechanisms governing the molecular link
between lipid homeostasis and AD were gained when APP γ-secretase
knock-out animals and cells were investigated. The γ-secretase is a
multi-metric protease complex, which does the final Aβ releasing
intramembrane scission in APP. Moreover, it is this very
proteolytic event which determines whether the potentially
neurodegeneration causing Aβ42 or the two amino acids shorter Aβ40
is produced. Aβ40 overproduction might increase the risk for
vascular dementia, but is not known to represent a risk for AD.
Typically γ-secretase produces 10-times more Aβ40 than Aβ42.
Mutations in the active center of γ-secretase, which is formed by
one of the two presenilin genes (PS1 and PS2) shift the balance
towards Aβ42. Indeed there is a direct correlation between the age
of disease onset and the overproduction rate of Aβ42 [28]. The
relevance of Aβ42 overproduction for AD is further confirmed by
familial AD mutations in the APP gene. These mutations
predominantly increase Aβ42 production too. Absence of both PS
genes abolishes the cellular γ-secretase activity entirely. The PS
knock-out causes early embryonic lethality, which presumably is not
due to altered APP processing but to defective processing of other
γ-secretase substrates. However, cells and conditional knock-out
animals are viable and can be studied. PS knock-out cells show a
peculiar lipid phenotype which resembles a defective sterol
regulatory binding protein defect, because cholesterol de novo
synthesis is strongly increased in PS1/ PS2 double knock-out cells
and tissue of conditional knock-out animals. However, not only
cholesterol levels are affected, but sphingolipids are equally
increased, extending the impact of these mutations. Curiously, PS
mutations which cause early onset familial AD differ somewhat in
their effect. There cholesterol levels are still notably elevated,
as compared to the wild type situation, but sphingolipids are not
increased but rather than that decreased [15]. The answer to this
phenomenon became clear when wild type cells were treated with
γ-secretase inhibitors. Even in the presence of γ-secretase the
inhibition of the proteolytic activity was sufficient to mimic the
PS knock-out phenotype with increased cholesterol and sphingomyelin
levels. Therefore γ-secretase has to influence lipid homeostasis
via one of its proteolytic substrates. The analysis of APP
knock-out cells and animals then revealed that this substrate is
APP, the Aβ peptide precursor. Moreover, lipid homeostasis of PS or
APP knock-out cells is rescued once they are incubated with Aβ
peptides. Eventually the inverse cholesterol and sphingolipid
regulation observed with the PS familial AD mutations could be
resolved when the knock-out cells where studied in presence of Aβ42
or Aβ40. It was found that Aβ40 reduces the cellular
3-hydroxy-3-methyglutaryl coenzyme A reductase (HMGR) activity, the
key regulated enzyme of cholesterol de novo synthesis. Strikingly,
this enzyme is the target of the SREBP RIP mechanism extending the
analogy between the original cholesterol regulation and that of the
“AD” regulatory lipid cycle even further. Moreover the HMGR is also
the direct target of statins, thus providing a molecular reasoning
for the experimental statin therapy for AD.
Interestingly, Aβ42 has no effect on cholesterol de novo
synthesis. But Aβ42 activates sphingomyelinases (SMases). SMases
degrade sphingomyelin and therefore the increased Aβ42 production
in PS familial AD mutations elevates, rather than lowers
sphingomyelin levels. This also explains why cholesterol levels are
still increased, although at a lower level, because the Aβ42
production apparently causes reduced Aβ40 levels and hence results
in reduced HMGR inhibition [15]. Importantly, already the rather
small physiological Aβ concentrations are sufficient to trigger
this regulatory cascade and thus represent physiological events
which occur in absence of AD too. This regulatory mechanism also
extends beyond cholesterol and sphingolipids, because it contains
feed-back mechanisms which are apparently involved in AD as well.
The molecular layout of this feedback is known in far less detail,
but the combined knowledge of gathered from molecular, clinical and
epidemiological studies clearly highlights their importance for AD.
E.g. cholesterol [2], cholesterol esters [29] and sphingomyelin
[15] regulate Aβ production providing feed-back and similar
evidence exists for some other lipids including gangliosides [30]
and some n3-fatty acids, especially DHA and EPA [31, 32].
DHA
Fish oil or pure DHA decreased Aβ production in neuroblastoma and
CHO cells in a dose dependent manner suggesting that DHA is
involved in down regulation of the amyloidogenic pathway [32].
Furthermore dietary DHA reduces the production and accumulation of
Aβ and decreases Aβ42 levels in aged Alzheimer mouse models [33].
In rats, administration of DHA had positive effects on the learning
ability and suppressed the increase in lipid peroxide and reactive
oxygen species levels in the cerebral cortex and hippocampus,
suggesting an elevated anti-oxidative defence [34]. The intake of
DHA or fish oil (contains DHA and EPA) rich diets by APP/PS1
transgenic mice resulted in decreased hippocampal Aβ levels [32].
The molecular mechanisms responsible for these effects remain
largely unknown. Partly, this process might involve sub-cellular
organization likely including lipid raft domains, which are
affected by their relative content in cholesterol, saturated and
non-saturated fatty acid containing lipids, governing structural
integrity, membrane fluidity and functional properties in general.
Unsaturated fatty acids increase fluidity, whereas cholesterol
results in a stiffening of the respective membranes. Considering an
average healthy EPA and DHA containing diet, high levels of DHA are
incorporated into the human brain. DHA is the most abundant n-3
PUFA in the brain making up to 6% of the brain’s dry weight [35]
and is implicated in various functions. First of all, as an
important membrane component, DHA is responsible for optimal
membrane-protein interaction in signal transduction [36, 37].
Moreover, DHA enhances the gene expression in the brain including
genes such as synuclein and serine palmitoyl transferase [38].
Long-term deficiency of DHA in the diet leads to cognitive
impairment [39, 40]; however, the level of DHA in the brain and
partially the cognitive performance can be restored by DHA
administration. Additionally, DHA plays an important role in
neurodegeneration. Lower level of DHA in the brain makes dendrites
more vulnerable to h-amyloid [41] and impairs learning in
h-amyloid-infused rats [42]. DHA is also the main antioxidant in
the human brain. DHA is an essential fatty acid that can be
acquired by several means. Either DHA is taken up from the diet or
it is synthesized from a-linolenic acid and eicosapentaenoic acid
(EPA), fatty acids that can only be acquired from diet [43, 44].
Direct uptake of dietary DHA and synthesis from EPA are by orders
of magnitude more effective than synthesis from linolenic acid
through EPA [45]. Marine fish represent the most effective dietary
source for DHA. Others DHA/EPA sources are meats like brain, liver
and vessels. With the changes in dietary life-style it is clear
from this list of sources that DHA uptake has drastically declined
in the European population, especially fast within the last one or
two decades. The n-6 to n-3 ratio was around 1-2 in the diet of our
ancestors, and it is estimated to be now 10 or worse [46]. The
brain has two major escape routes from this situation. DHA turnover
is very slow, thus short term limited supply may not be
problematic. If supply remains low or absent other fatty acids are
used instead, including fatty acids like arachidonic acid (AA).
This has several implications, including altered membrane
properties and increased propensity to inflammation. Accordingly,
once DHA supply increases, these substitute fatty acids are swiftly
replaced by DHA.
Clinical perspective
DHA dependent Aβ production, neuronal function, cognitive
performance and inflammation are all important factors for AD. It
thus seems reasonable to assume that targeting lipids, diet or
specifically DHA might provide protective or therapeutic potential
for AD. Indeed this interpretation is supported by epidemiological
and clinical data. A recent study indicated that Mediterranean diet
might protect against AD [47] and other studies showed a negative
correlation between fish consumption and AD [48-50].
Very recently one study was complete in which AD patients were
given DHA. In this pilot trial patients at the initial clinical
stage of AD (very mild AD) showed a stabilization of their
cognitive performance while those given a placebo continued to
decline over the study period of 12 month. Interestingly, those
patients already at later stages of the disease showed no cognitive
benefit [51]. Although statin treatment has not yet been tested
with very mild AD patients these findings suggest that statins may
provide a more effective treatment whereas DHA the more universally
applicable alternative for prevention. However, the use of DHA for
AD is a very recent development and further research may help to
increase its effectiveness. In either case it is obvious from the
limited number of patients thus far studied with either treatment
that more large scale studies are needed. It is furthermore obvious
from the preliminary data available that the future of AD therapy
might reside with disease prevention or very early treatment to
maximize effectiveness. This approach had been hampered severely by
the inability to identify from the healthy elderly population those
who are at highest risk to develop AD. Recent advances in molecular
diagnostics have largely removed this issue [52].
The future challenges therefore will be to decipher the
molecular pathways which link the neurodegeneration in Alzheimer’s
disease with lipids and based on that to optimize the therapeutic
approach.
References
1 Grziwa B, Grimm MO, Masters CL, Beyreuther K,
Hartmann T, Lichtenthaler SF. The Transmembrane Domain of
the Amyloid Precursor Protein in Microsomal Membranes Is on Both
Sides Shorter than Predicted. J Biol Chem 2003; 278: 6803-8.
2 Simons M, Keller P, de Strooper B,
Beyreuther K, Dotti CG, Simons K. Cholesterol
depletion inhibits the generation of beta-amyloid in hippocampal
neurons. Proc Natl Acad Sci USA 1998; 95: 6460-4.
3 Fassbender K, Simons M, Bergmann C, et al.
Simvastatin strongly reduces levels of Alzheimer’s disease
beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo.
Proc Natl Acad Sci USA 2001; 98: 5856-61.
4 Runz H, Rietdorf J, Tomic I, et al.
Inhibition of intracellular cholesterol transport alters presenilin
localization and amyloid precursor protein processing in neuronal
cells. J Neurosci 2002; 22: 1679-89.
5 Burns M, Gaynor K, Olm V, et al.
Presenilin redistribution associated with aberrant cholesterol
transport enhances beta-amyloid production in vivo. J Neurosci
2003; 23: 5645-9.
6 Ehehalt R, Keller P, Haass C, Thiele C,
Simons K. Amyloidogenic processing of the Alzheimer
beta-amyloid precursor protein depends on lipid rafts. J Cell Biol
2003; 160: 113-23.
7 Refolo LM, Pappolla MA, Lafrancois J,
et al. A cholesterol-lowering drug reduces beta-amyloid
pathology in a transgenic mouse model of Alzheimer’s disease.
Neurobiol Dis 2001; 8: 890-9.
8 Simons M, Schwarzler F, Lutjohann D,
et al. Treatment with simvastatin in normocholesterolemic
patients with Alzheimer’s disease: A 26-week randomized,
placebo-controlled, double-blind trial. Ann Neurol 2002; 52:
346-50.
9 Wolozin B, Kellman W, Ruosseau P,
Celesia GG, Siegel G. Decreased prevalence of alzheimer
disease associated with 3-hydroxy-3- methyglutaryl coenzyme A
reductase inhibitors. Arch Neurol 2000; 57: 1439-43.
10 Jick H, Zornberg GL, Jick SS, Seshadri S,
Drachman DA. Statins and the risk of dementia. Lancet 2000;
356: 1627-31.
11 Rockwood K, Darvesh S. The risk of dementia in
relation to statins and other lipid lowering agents. Neurol Res
2003; 25: 601-4.
12 Sparks DL, Sabbagh MN, Connor DJ, et al.
Atorvastatin for the treatment of mild to moderate Alzheimer
disease: preliminary results. Arch Neurol 2005; 62: 753-7.
13 Hoglund K, Wiklund O,
Vanderstichele HEikenberg O, Vanmechelen E,
Blennow K. Plasma levels of beta-amyloid(1-40),
beta-amyloid(1-42), and total beta-amyloid remain unaffected in
adult patients with hypercholesterolemia after treatment with
statins. Arch Neurol 2004; 61: 333-7.
14 Sjogren M, Gustafsson K, Syversen S,
et al. Treatment with simvastatin in patients with Alzheimer’s
disease lowers both alpha- and beta-cleaved amyloid precursor
protein. Dement Geriatr Cogn Disord 2003; 16: 25-30.
15 Grimm MO, Grimm HS, Patzold AJ, et al.
Regulation of cholesterol and sphingomyelin metabolism by
amyloid-beta and presenilin. Nat Cell Biol 2005; 7: 1118-23.
16 Tschäpe J, Hartmann T. Therapeutic Perspectives in
Alzheimer’s Disease. Rec Pat CNS Drug Discov 2006; 1: 119-27.
17 Brown MS, Goldstein JL. A proteolytic pathway that
controls the cholesterol content of membranes, cells, and blood.
Proc Natl Acad Sci USA 1999; 96: 11041-8.
18 Brown MS, Ye J, Rawson RB, Goldstein JL.
Regulated intramembrane proteolysis: a control mechanism conserved
from bacteria to humans. Cell 2000; 100: 391-8.
19 Gustafson DR, Rothenberg E, Blennow K,
Steen B, Skoog I. An 18-year follow up of overweight and
risk for Alzheimer’s disease. Arch Intern Med 2003; 163:
1524-8.
20 Kivipelto M, Ngandu T, Fratiglioni L,
et al.Obesity and vascular risk factors at midlife and the
risk of dementia and Alzheimer disease. Arch Neurol 2005; 62:
1556-60.
21 Gustafson D, Lissner L, Bengtsson C,
Björkelund C, Skoog I. A 24-year follow-up of body mass
index and cerebral atrophy. Neurology 2004; 63: 1876-81.
22 Gustafson D, Steen B, Skoog I. Body mass index
and white matter lesions in elderly women. An 18-year longitudinal
study. Intl J Psychogeriatrics 2004; 16: 327-36.
23 Solomon A, Kareholt I, Ngandu T, et al.
Serum cholesterol changes after midlife and late-life cognition:
twenty-one-year follow-up study. Neurology 2007; 68: 751-6.
24 Mielke MM, Zandi PP, Sjögren M, et al.
Elevated total cholesterol levels in late-life associated with a
reduced risk of dementia. Neurology 2005; 64: 1689-95.
25 Skoog I, Lernfelt B, Landahl S, et al.
15-year longitudinal study of blood pressure and dementia. Lancet
1996; 347: 1141-5.
26 Kivipelto M, Laakso MP, Tuomilehto J,
Nissinen A, Soininen H. Hypertension and
hypercholesterolaemia as risk factors for Alzheimer’s disease:
potential for pharmacological intervention. CNS Drugs 2002; 16:
435-44.
27 Kivipelto M, Ngandu T, Laatikainen T,
Winblad B, Soininen H, Tuomilehto J. Risk score for
the prediction of dementia risk in 20 years among middle aged
people: a longitudinal, population-based study. Lancet Neurol 2006;
5: 735-41.
28 Duering M, Grimm MO, Grimm HS,
Schroder J, Hartmann T. Mean age of onset in familial
Alzheimer’s disease is determined by amyloid beta 42. Neurobiol
Aging 2005; 26: 785-8.
29 Puglielli L, Konopka G, Pack-Chung E,
et al. Acyl-coenzyme A: cholesterol acyltransferase modulates
the generation of the amyloid beta-peptide. Nat Cell Biol 2001; 3:
905-12.
30 Zha Q, Ruan Y, Hartmann T, Beyreuther K,
Zhang D. GM1 ganglioside regulates the proteolysis of amyloid
precursor protein. Mol Psychiatry 2004; 9: 946-52.
31 Florent S, Malaplate-Armand C, Youssef I,
et al. Docosahexaenoic acid prevents neuronal apoptosis
induced by soluble amyloid-beta oligomers. J Neurochem 2006; 96:
385-95.
32 Oksman M, Livonen H, Hogyes E, et al.
Impact of different saturated fatty acid, polyunsaturated fatty
acid and cholesterol containing diets on beta-amyloid accumulation
in APP/PS1 transgenic mice. Neurobiol Dis 2006; 23: 563-72.
33 Lim GP, Calon F, Morihara T, et al. A
diet enriched with the omega-3 fatty acid docosahexaenoic acid
reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci
2005; 25: 3032-40.
34 Hashimoto M, Hossain S, Shimada T, et al.
Docosahexaenoic acid provides protection from impairment of
learning ability in Alzheimer’s disease model rats. J Neurochem
2002; 81: 1084-91.
35 Yehuda S, Rabinovitz S, Mostofsky DI.
Essential fatty acids are mediators of brain biochemistry and
cognitive functions. J Neurosci Res 1999; 56: 565-70.
36 Litman BJ, Mitchell DC. A role for phospholipid
polyunsaturation in modulating membrane protein function. Lipids
1996; 31(Suppl): S193-S197.
37 Schley PD, Jijon HB, Robinson LE,
Field CJ. Mechanisms of omega-3 fatty acid-induced growth
inhibition in MDA-MB-231 human breast cancer cells. Breast Cancer
Res Treat 2005; 92: 187-95.
38 Kitajka K, Puskas LG, Zvara A, et al. The
role of n-3 polyunsaturated fatty acids in brain: modulation of rat
brain gene expression by dietary n-3 fatty acids. Proc Natl Acad
Sci USA 2002; 99: 2619-24.
39 Moriguchi T, Greiner RS, Salem Jr. N.
Behavioral deficits associated with dietary induction of decreased
brain docosahexaenoic acid concentration. J Neurochem 2000; 75:
2563-73.
40 Salem Jr. N, Moriguchi T, Greiner RS,
et al. Alterations in brain function after loss of
docosahexaenoate due to dietary restriction of n-3 fatty acids. J
Mol Neurosci 2001; 16: 299-307; (discussion 317-21).
41 Calon F, Lim GP, Yang F, et al.
Docosahexaenoic acid protects from dendritic pathology in an
Alzheimer’s disease mouse model. Neuron 2004; 43: 633-45.
42 Hashimoto M, Hossain S, Agdul H, Shido O.
Docosahexaenoic acid-induced amelioration on impairment of memory
learning in amyloid beta-infused rats relates to the decreases of
amyloid beta and cholesterol levels in detergent-insoluble membrane
fractions. Biochim Biophys Acta 2005; 1738: 91-8.
43 Sprecher H. Metabolism of highly unsaturated n-3 and n-6
fatty acids. Biochim Biophys Acta 2000; 1486: 219-31.
44 Williard DE, Harmon SD, Kaduce TL, et al.
Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids
in differentiated rat brain astrocytes. J Lipid Res 2001; 42:
1368-76.
45 Horrocks LA, Yeo YK. Docosahexaenoic acid-enriched
foods: production and effects on blood lipids. Lipids 1999;
34(Suppl): S313.
46 Simopoulos AP. Evolutionary aspects of diet and
essential fatty acids. World Rev Nutr Diet 2001; 88: 18-27.
47 Scarmeas N, Stern Y, Tang MX, Mayeux R,
Luchsinger JA. Mediterranean diet and risk for Alzheimer’s
disease. Ann Neurol 2006; 59: 912-21.
48 Kalmijn S, Launer LJ, Ott A, Witteman JC,
Hofman A, Breteler MM. Dietary fat intake and the risk of
incident dementia in the Rotterdam Study. Ann Neurol 1997; 42:
776-82.
49 Barberger-Gateau P, Letenneur L, Deschamps V,
Peres K, Dartigues JF, Renaud S. Fish, meat, and
risk of dementia: cohort study. BMJ 2002; 325: 932-3.
50 Morris MC, Evans DA, Bienias JL, et al.
Consumption of fish and n-3 fatty acids and risk of incident
Alzheimer disease. Arch Neurol 2003; 60: 940-6.
51 Freund-Levi Y, Eriksdotter-Jonhagen M,
Cederholm T, et al. Omega-3 fatty acid treatment in 174
patients with mild to moderate Alzheimer disease: OmegAD study: a
randomized double-blind trial. Arch Neurol 2006; 63: 1402-8.
52 Hansson O, Zetterberg H, Buchhave P,
Londos E, Blennow K, Minthon L. Association between
CSF biomarkers and incipient Alzheimer’s disease in patients with
mild cognitive impairment: a follow-up study. Lancet Neurol 2006;
5: 228-34.
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