Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7300.1447 (Published 16 June 2001) Cite this as: BMJ 2001;322:1447All rapid responses
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To the Editor:
Kivipelto and co-workers’ (1) longitudinal data add important
information on risk factors for dementia. These findings are of particular
interest, since we have observed that very old patients with autopsy-
documented Alzheimer’s Disease (AD) had had significantly greater serum
total and LDL cholesterol than had patients with non-AD dementias (2).
However, the conclusions are clouded, since neither the diagnosis of
AD nor its clinical distinction from other dementias is currently possible
without pathological confirmation. The authors cite an earlier clinico-
pathological study at their primary institution indicating high
pathological correlation with clinical AD diagnosis (3). However, in that
study, and in many other clinico-pathological studies of dementia,
including our own (2,4,5): (a) the large majority of those with clinical
dementia show some degree of AD changes at autopsy; and (b) an important
minority show coexistence of AD changes and wtih other abnormalities,
especially vascular changes or excessive Lewy bodies. One should then
anticipate their findings: that clinically diagnosed dementia cases of the
greatest frequency (AD) would also prove to have pathological AD changes;
and that some degree of AD pathologic change would also be found in most
(here 80%) of clinically diagnosed vascular dementia (VaD) cases.
In a related vein, several reviewers have further noted that the
relationships of AD and VaD are not well defined, and of the need to
reassess the role of vascular factors in AD, as well as inVaD (5). In view
of the above, I would hope that Kivipelto, et al., will not rely on
clinical distinction of dementias, and also analyze their longitudinal
data for the relationships of blood pressure and cholesterol with all
their dementia cases. Since autopsy rates in Finland are historically
high, one also looks forward with great interest to confirming the present
findings with future pathological studies.
References:
1. Kivipelto M, Helkala E-L, Laakso MP, Hanninen T, Hallikainen M,
Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s disease
in later life: longitudinal, population based study. BMJ 2001;322:1447-
1451.
2. Lesser G, Kandiah K, Libow LS, Likourezos A, Breuer B, Marin D, et al.
Elevated serum total and LDL cholesterol in very old patients with
Alzheimer’s disease. Dement Geriatr Cogn Disord 2001;12:138-145.
3. Kosunen O, Soininen H, Paljarvi L, Heinonen O, Talasniemi S, Riekkinen
Sr PJ. Diagnostic accuracy of Alzheimer’s disease: a neuropathological
study. Acta Neuropathol 1996;91:185-193.
4. Lim A, Tsuang D, Kukull W, Nochlin D, Levernz J, McCormick W, et al.
Clinico-neuropathological correlation of Alzheimer’s disease in a
community-based case series. J Am Geriatr Soc 1999;47:564-569.
5. Nyenhuis DL, Gorelick PB. Vascular dementia: a contemporary review of
epidemiology, diagnosis, prevention,and treatment. J Am Geriatr Soc
1998;46:1437-1448.
Sincerely,
Gerson T. Lesser, MD
Assistant Professor
Dept. of Geriatrics & Adult Development,
Mt. Sinai School of Medicine
and
The Jewish Home and Hospital,
120 West 106 Street,
NY NY 10025
DISCLAIMER: I am sole author and have no professional, financial or
other conflicts of interest concerning these matters.
Competing interests: No competing interests
Editor:
Kivipelto et al 1 report that raised systolic blood pressure
or high serum cholesterol concentrations in midlife increases the risk of
Alzheimers Disease in later life.
This is based on an odds ratio of 2.3(95% confidence interval 1.0-5.5) for
raised blood pressure and an odds ratio of 2.1 (95% confidence interval
1.0-4.4)for raised serum cholesterol as stated in the abstract.
This claim is based on data which is not statistically significant and
therefore may be due to chance alone.In addition, this abstract data does
not correlate with any of the data presented in the results.
Only patients with both risk factors have a significant association with
Alzheimers Disease with an odds ratio of 3.5 (95% confidence interval 1.6-
7.9). However the multiple analysis may have increased the chance of
finding significant results and has not been corrected for.
Their conclusion that raised systolic blood pressure or high serum
cholesterol concentrations in midlife increases the risk of Alzheimers
disease is therefore not a correct interpretation of their data.
1 Kivipelto, Helkala, Laakso, Hanninen, Hallikainen, Alhainen, Soininen,
Tuomilehto and Nissien. Midlife vascular risk factors and Alzheimer's
disease in later life:longitudinal, population based study.BMJ
2001;322:1447-1451,
Competing interests: No competing interests
The article by Kivipelto et al [1] not only demonstrates
how raised blood pressure and high serum cholesterol
are important risk factors in the pathogenesis of
Alzheimer's disease but to some extent confirms that
multi infarct dementia and Alzheimer's disease, the two
major players in dementia, share the same origin. In
consequence one has to argue that the response of the
brain to these factors is what determines ultimately the
clinical picture to be seen.
We have been told how to differentiate these two
entities clinically by tests like the Hachinski Ischaemic
Score [2] and perhaps we have always been wrong
considering Alzheimer's a neurodegenerative disease
and not a vascular disease. Perhaps we should
consider them in the same way that we consider the
effects of hypertension, hypercholesterolemia and other
factors on the heart, resulting in heart failure and
myocardial infarction, perhaps we should consider
them two sides of the same coin.
The study also implies that other risk factors for
ischaemic heart disease should be studied in this
context and that the medical profession needs to be
even more aggressive in the management of the
primary conditions to prevent secondary end organ
damage in brain and heart and its huge burden in our
society.
Bibliography:
1. Kivipelto M et al "Midlife vascular risk factors and
Alzheimer's disease in later life: longitudinal,
population based study" BMJ (2001) 322:1447-51.
2. Moroney JT et al "Meta-analysis of the Hachinski
Ischaemic Score in pathologically verified dementias".
Neurol (1997) 49:1096-1105.
Competing interests: No competing interests
I read this article with interest and hope but regret that I cannot
adequately assess the methodology and therefore the validity of this
paper, for which I take the editors and reviewers significantly to task.
There is a grossly inadequate description in the published paper, nor is
the extra figure on the website adequate.
Would the authors please specify
a) Inter and intra-rater reliability of the MMSE on this occasion,
and the general psychometric properties of the version they used and its
validity statistics when given in Finnish compared with the original
development in English.
b) The neuropsychological tests used in Phases 2 and 3, and provide
references to their validity when administered in Finnish.
c) The details of the general and neurological examinations to which
subjects were subjected.
d) Details of the process for determining the diagnosis, and the
process for settling disputes among authors.
Further, could the authors specify whether they tested regression
assumptions prior to performing multiple logistic regression analyses, and
could they publish the validity statistics of the analyses. Having started
out with this sample, could the authors please provide us with information
about power of the post-hoc analyses, and what corrections they used for
multiple comparisons.
Finally, it would have been helpful had the authors commented on the
perceived difference in rates of dementia among northern Europeans and
Japanese individuals developing dementia that, if memory serves me
correctly, has reportedly been more related to vascular events than
Alzheimer's disease when compared to a North American population.
While the information presented is interesting academically, I regret
that the flaws in the study as published prevent me from taking away any
information.
I look forward to the authors' reply.
Competing interests: No competing interests
Miia Kivipelto et al. (1) examined the relation of midlife raised
blood pressure and serum cholesterol concentration to Alzheimer’s disease
in later life, and concluded that raised blood pressure and high serum
cholesterol concentration, and particularly the combination of these
risks, increase the risk of the disease in later life. In a early
biophysical-semeiotic research (2, 3), briefly referred in the site:
http://utenti.tripod.it/la_piazzetta/professione/professione.htm.; title:
“Diagnosi Semeiotico-biofisica Precoce della Malattia di Alzheimer”, I
gathered interesting data, which agree with those referred in the
excellent paper, due to the fact that there is notoriously an association
between high serum cholesterol, raised blood pressure and, finally,
hyperinsulinism. Briefly, in healthy, from the microcirculatory point of
view, during stress test both vasomotility (chaotic-deterministic
oscillations of arterioles) and vasomotility (chaotic-deterministic
fluctuations of nutritional capillaries and post-capillary venules)
particularly in hippocampus, pre-frontal and parietal cerebral regions
are maximally activated. (2, 3, 4, 5). On the contrary, in individuals
with a family history positive for Alzheimer’s disease and, of course, in
patients in the first stages, under identical conditions appears a
particular form of microcirculatory activation, characterized by increased
vasomotility and decreased vasomotion (i.e. dissociated type). In a few
words, the flow- and flux-motion in the cerebral microcirculatory bed
appears to be clearly decreased, due to the dangerous phenomenon of the so
-called “microcirculatory blood-flow centralization”. Unfortunately, it is
generally admitted that diagnosing Alzheimer’s disease, particularly in
initial stages, is very difficult. In my 44-year-long clinical experience
the test of acute pick of insuline secretion (2, 3) proved to be reliable
in bed-side recognizing this (and other numerous) disorder, even in its
first stage. Although insulin isn’t necessary in the glucose utilizations
of cerebral neurons, surely in both cerebral cortex and hippocampus there
is a largely amounts of insulin receptors (6). In initial stages of the
disease has been demonstrated a scarse glucose metabolism in cerebral
tissue: venous glucose level appears to be slightly decreased (6). The
authors, in addition, demonstrated that O2 consumption is unchanged, due
to the fact that the neurons utilize other “endocellular” substances
rather than glucose, probably causing neurons death (7). Although insulin
isn’t necessary in glucose utilizations of cerebral neurons, however in
both cerebral cortex and hippocampus there is surely a largely amounts of
insulin receptors (6). In addition, in the initial sages of the disease
has been demonstrated a scarse glucose metabolism in cerebral tissue:
venous glucose level appears to be slightly decreased (6). These authors,
moreover, demonstrated that O2 consumption is unchanged, due to the fact
that the neurons utilize other “endocellular” substances rather than
glucose, probably causing neurons death. In summary, in the complex and
non completely understood pathophysiology of Alzheimer’s disease does
exist a fault response of cerebral insulin receptors, while the hormon
acts likily as a growth factor.
From these work hypothesis, in a previous clinical research I observed
that acute pick of insulin secretion (2, 3, 4) in healthy activates the
microcirculation in all biological systems, while in patients at “real”
risk of Alzheimer’s diesease and, naturally, in patients involved by the
disease, even in early stage, microcirculatory activation is totally
absent. Importantly, in no other cerebral disorders, including cerebral
arteriosclerosis, I did observe the absence of insulin-receptors responce,
i.e. the absense of microcirculatory activation, type I, associated.
Yours.
Stagnaro Sergio MD., Member NYAS and AAAS
1) Mia Kivipelto et al.Midlife vascular risk factors of Alzheimer's
disease in later life: longitudinal population based study. BMJ. 323: 1447
-1451, 2001.
2) Stagnaro S., Valutazione percusso-ascoltatoria della
microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz.
Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e
Acta Med.Medit. 145, 163 1986
3) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la
manovra di Ferrero- Marigo nella diagnosi clinica della
iperinsulinemia-insulinoresistenza. Acta Med. Medit. 13, 125 1997
4 Stagnaro S., Stagnaro-Neri M., Valutazione percusso-
ascoltatoria degli attacchi ischemici transitori e della insufficienza
cerebrovascolare cronica in pazienti trattati con mesoglicano. Atti, IX
Congr. Naz. It. Patologia Vascolare. Copanello, 6-9 Gennaio 1987. A cura
di R. Del Guercio, G. Leonardo e G. Zanini. Pg. 765, Monduzzi Ed. Bologna
1987
5) Stagnaro S., Stagnaro-Neri M., Il Test dell’Apnea nella
Valutazione della Microcircolazione cerebrale in Cefalalgici. Atti, Congr.
Naz. Soc. Ita. Microangiologia e Microcircolazione. A cura di C. Allegra.
Pg. 457, Roma 10-13 Settembre 1987. Monduzzi Ed. Bologna 1987
6) Hoyer S. Models of Alzheimer’s disease: cellular and molecular
aspects. Journal of Neurotrasmission.(Suppl.) 49, 11,
1997.
7) Baringai M. Is Apoptosis Key in Alzheimer’s Disease? Science.
281, 1301, 28 August
1998
Competing interests: No competing interests
Cholesterol, synaptic function and Alzheimer’s disease
To update readers
on the hot subject of cholesterol and Alzheimer's pathogenesis (
BMJ 2001;
322:
1447-51 and BMJ
2001; 323: 771 ) we would like to notice that today the role
of cholesterol in AD is mainly discussed in the context of the reduction
of amyloid burden by lowering cholesterol (for reviews see Ref.
1). This viewpoint is based on more then dozen reports implicating
cholesterol in amyloid precursor protein processing and amyloid b
protein (Ab) generation in cell cultures and
in laboratory animals.
The paper by Yamazaki et al. [ 2 ] and very
recent contribution by Puglielli et al. [ 3
] further reported that cellular generation of Ab
is modulated by cholesterol compartmentation and intracellular cholesteryl-ester
levels.
We would like to add important missing discussion venue.
The biochemical relation of cholesterol
and Ab is bidirectional. Furthermore, modulation
of neuronal cholesterol dynamics by soluble form of Ab,
a normal human protein, likely to have important consequences for neuronal
and synaptic function.
We and others reported previously that near physiological concentrations
of Ab inhibit cholesterol esterification [ 4,5 ]. Ab also increases lipid
synthesis (specifically that of cholesterol and phospholipids) in PC12
and rat primary neuronal cell cultures, fetal brain, and in ex vivo hippocampal
slices; cellular cholesterol uptake (see Ref. 6 for
detailed bibliography); and lipid efflux [ 7 ]; and
modulates membrane physical properties [ 8,9
].
Taken together, the data by Puglielli et al. and our data indicate feedback
functional relation between Acyl-coenzyme A:cholesterol acyltransferase-catalyzed
cholesterol esterification, cholesterol esterase-catalyzed cholesteryl-ester
hydrolysis [ 10 ], and Ab.
In this light additional facilitation of neuronal cholesterol synthesis,
cholesterol cellular uptake and cholesterol efflux by Ab
[ 6,7 ] may contribute to the
efficiency with which neurons coordinate the influx, efflux, synthesis,
and esterification of free cholesterol, and the release of cholesterol
from the ester storage pool [ 10 ].
However, the failure in the dynamic equilibrium of the complex processes
of tight regulation of intracellular cholesterol is important not only
for the excessive Ab generation [ 3
], but also for synaptic functional failure and excessive tau phosphorylation,
another Alzheimer’s hallmarks. Thus, neuronal cholesterol homeostasis decay
(experimentally achieved by cholesterol synthesis inhibition or increased
cholesterol efflux) causes paired helical filaments (PHF)-tau phosphorylation
and is sufficient to induce neurotransmission and synaptic plasticity impairment
in rat hippocampus [ 6,11 ].
As it was proposed [ 12 ] and discussed [ 6
], the change in both Ab
and tau protein neurochemistry may independently help to recover synaptic
function and plasticity, the neurodegeneration aim, that in AD may well
be caused by neuronal cholesterol turnover misregulation[ 6,13 ], a welcome question
indeed.
There are many more open questions in this ever interesting functional
relations. The answers should facilitate Alzheimer’s cure and basic knowledge
on how and what for neuronal cells handle cholesterol.
References
1. Simons, M., Keller, P., Dichgans, J. &
Schulz, J.B. Cholesterol and Alzheimer’s disease: Is there a link? Neurology57,
1089-1093 (2001) [ PubMed
Citation ] [ Full
Text at Neurology ]; Golde, T.E. & Eckman, C.B. Cholesterol modulation
as an emerging strategy for the treatment of Alzheimer's disease. Drug
Discovery Today
6, 1049-1055 (2001) [ PubMed
Citation ] [ Full
Text at BioMedNet ]; Wolozin, B. A fluid connection: Cholesterol and
Ab.Proc. Natl. Acad. Sci. USA98,
5371-3 (2001) [ Full
Text at PNAS ].
2. Yamazaki, T., Chang, T.Y., Haass, C. &
Ihara, Y. Accumulation and aggregation of amyloid beta-protein in late
endosomes of Niemann-pick type C cells. J. Biol. Chem. 276,
4454-4460 (2001) [ PubMed
citation ] [ Abstract
and Full Text at J Biol Chem ].
3. Puglielli L, Konopka G, Pack-Chung E, et
al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation
of the amyloid beta-peptide. Nature Cell. Biol.10, 905-912
[ PubMed
Citation ] [ Abstract
and Full text at Nat Cell Biol ].
4. Koudinov, A.R., Koudinova, N.V. & Berezov,
T.T. Alzheimer's peptides Ab1-40 and Ab1-28 inhibit the plasma cholesterol
esterification rate. Biochem. Mol. Biol. Inter.38, 747-752
(1996) [ PubMed
Citation ] [ Reprint Order
].
5. Liu, Y., Peterson, D.A. & Schubert,
D. Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol
homeostasis.
Proc. Natl. Acad. Sci. USA95, 13266-13271 (1998).
[ PubMed
Citation ] [ Abstract
and Full text at PNAS ]
6. Koudinov, A.R & Koudinova, N.V. Essential
role for cholesterol in synaptic plasticity and neuronal degeneration.
FASEB
J.15, 1858-1860 (2001), published online June 27, 2001, 10.1096/fj.00-0815fje.
[ PubMed
Citation ] [ Abstract
and Full text at FASEB J ] [ Reprint
Order ].
7. Michikawa, M., Gong, J.S., Fan, Q.W., Sawamura,
N. & Yanagisawa, K. A novel action of Alzheimer's amyloid beta-protein
(Abeta): oligomeric Abeta promotes lipid release. J. Neurosci.21,
7226-7235 (2001). [ PubMed
Citation ] [ Abstract
and Full Text at J Neurosci ]
8. Chochina, S.V., Avdulov, N.A., Igbavboa,
U., Cleary, J.P., O'Hare, E.O. and Wood, W.G. Amyloid beta-peptide(1-40)
increases neuronal membrane fluidity. Role of cholesterol and brain region.
J Lipid Res.42, 1292-1297 (2001) [ PubMed
Citation ] [ Full
text at J Lip Res ].
9. Muller, W.E., Kirsch, C. and Eckert, G.P.
Membrane-disordering effects of beta-amyloid peptides Biochem Soc Trans.29, 617-623 (2001) [ PubMed
Citation ].
10. Simons, K. & Ikonen, E. How cells
handle cholesterol. Science290, 1721-1726 [ PubMed
citation ] [ Full
Text at Science ].
11. Fan, Q.W., Yu, W., Senda, T., Yanagisawa,
K. & Michikawa, M. Cholesterol-dependent modulation of tau phosphorylation
in cultured neurons. J. Neurochem.76, 391-400 (2001). [
PubMed
citation ] [ Abstract
and Full Text at J Neurochem ].
12. Mesulam. M.M. (1999) Neuroplasticity
failure in Alzheimer's disease: bridging the gap between plaques and tangles.
Neuron. 24, 521-529 (1999). [ PubMed
citation ] [ Full
Text at Neuron ].
13. Matthies, H., Schulz, S., Hollt, V. &
Krug, M. Inhibition by compactin demonstrates a requirement of isoprenoid
metabolism for long-term potentiation in rat hippocampal slices. Neurosci.79,
341-346 (1997). [ PubMed
citation ] [ Abstract
and Full Text at Neuroscience ].
14. The earlier version of this letter was submitted to Nature
Cell Biology on October 8, 2001 to comment on the paper by Puglielli,
L. et al. [ 2 ].
15. Authors [ Internet
Office ]
Competing interests: No competing interests