Download Minireview: Mechanisms by Which the Metabolic Syndrome and

Journal of Gerontology: BIOLOGICAL SCIENCES
2000, Vol. 55A, No. 5, B228–B232
Copyright 2000 by The Gerontological Society of America
Minireview: Mechanisms by Which the Metabolic
Syndrome and Diabetes Impair Memory
Meena Kumari, Eric Brunner, and Rebecca Fuhrer
International Centre for Health and Society, Department of Epidemiology and Public Health,
Royal Free and University College Medical School, London.
Type 2 diabetes is associated with an increased risk of cognitive dysfunction. These effects seem particularly true
for memory functions. This article examines how diabetes and the biological changes that occur with diabetes
such as hyperglycemia, changes in insulin concentration, hypertension, and changes in lipid levels might lead to
these alterations in cognitive functioning, with an emphasis on the mechanisms leading to changes in memory.
B
OTH type 1 (insulin-dependent diabetes mellitus, or
IDDM) and type 2 (non-insulin-dependent diabetes
mellitus, or NIDDM) diabetes have detrimental effects on
cognitive functioning (measures of verbal and numerical
reasoning, attention, concentration, verbal and visual memory, and verbal fluency) and may increase the risk of dementia. In type 1 diabetes, chronic hyperglycemia and the
recurrence of hypoglycemia appear to be associated with
loss of cognitive ability (1–3). A recent review of cognition
in type 2 diabetes concluded that despite the poor design
and lack of statistical power in many studies, type 2 diabetes
appears to be associated with an increased risk of cognitive
dysfunction in a wide array of cognitive tests (4). These
findings are borne out in larger epidemiological studies (5,6).
In particular, in those studies that examined it, loss of verbal
memory was most consistently associated with diabetes.
This article examines how diabetes and its risk factors
might lead to these changes in cognitive functioning, with a
particular focus on memory.
MEMORY
A number of biological structures are involved in learning and memory; the hippocampus and associated areas are
thought to be important in this regard (7), although no single
brain structure is “critical” in and of itself (8). Similarly, a
number of neurotransmitter systems have been implicated,
including gamma-aminobutyric acid ergic systems and the
cholinergic system. Particular emphasis has been placed on
the loss of cholinergic function associated with memory
loss in dementia. How might diabetes and its risk factors
modulate brain cholinergic mechanisms (9)?
The prevalence of type 2 diabetes increases with increasing age, which itself may be associated with decreased cognitive functioning and may independently account for some
cognitive decline. Memory for remote past events appears
to be intact with aging. In contrast, encoding and later retrieval of new information is compromised with increasing
age. Thus, the negative effects of aging are reflected in a
poorer performance in recall and recognition of lists of
words or word pairs, memory for short paragraphs, and
other verbal stimuli. Examinations of memory in elderly
B228
participants with type 2 diabetes have demonstrated a
poorer performance in recent memory but not immediate recall (4). Recently, studies concerning the early stages of the
disease and in the relatively young have attempted to distinguish the effects of diabetes on cognitive function from
those caused by aging. An impaired performance on a battery of cognitive tests measuring immediate and delayed
memory, attention, and verbal fluency was observed in nondiabetics with high 2-hour glucose and insulin following an
oral glucose challenge (impaired glucose tolerance), which
was similar in magnitude to the decrease seen in subjects
with diabetes (10). Individuals younger than 55 years old
with type 2 diabetes displayed a poorer performance on
memory and attention tests than age- and education-matched
controls (11). Thus, cognitive impairment may occur in the
early subclinical stages of the progression to diabetes and
in the relatively young. It would seem that diabetes and
impaired glucose tolerance may lead to a decline in memory independently of aging, or alternatively that diabetes or
the progression to diabetes represents a state of accelerated
aging.
DIABETES, THE METABOLIC SYNDROME,
AND ITS COMPONENTS
Diabetes is a complex metabolic disorder of heterogeneous aetiology. Type 1 diabetes occurs in the young and is
characterized by a diminished secretion of insulin. The disease is thought to be autoimmune in nature. Type 2 diabetes
is considerably more common and is characterized by insulin resistance. Age and obesity are major factors that contribute to the development of insulin resistance, and it has
been estimated that 35% of the variability in insulin action
can be explained by these two factors alone (12). The development of diabetes occurs in a number of overlapping rather
arbitrary stages; initially or preceding the onset of overt diabetes, there is a period of insulin resistance that is characterized by a compensatory hyperinsulinemia to maintain normal glucose concentrations and the progression from normal
to impaired glucose.
Insulin resistance is associated with a constellation of
factors termed the metabolic syndrome (also called syn-
METABOLIC SYNDROME AND COGNITION
drome X or insulin resistance syndrome), which in addition
to hyperglycemia, and hyperinsulinemia is characterized by
hypertension, dyslipidemia and increased central adiposity.
This period may be followed by a decompensation of the
system, with a relative decrease in insulin secretion that
leads to the onset of overt diabetes. Symptoms associated
with advanced diabetes (e.g., peripheral neuropathy) occur
in the final stage. Evidence that the early stages described
may be associated with changes in cognitive functioning
suggest that the metabolic syndrome and its components
(see above) may lead to changes in cognition. Although in
vivo it is likely that the mechanisms discussed below act in
concert with each other, for ease of discussion, the contributions of metabolic disturbances and hypertension are discussed separately here.
The metabolic disturbances that occur in the metabolic
syndrome are (a) hyperglycemia, (b) hyperinsulinemia, and
(c) dyslipidemia. Additionally, hypertension is a component
of the metabolic syndrome. Each will be discussed in turn.
Hyperglycemia
Both increases and decreases in glucose concentrations
can potentially alter cognitive function. The detrimental effects of hypoglycemia on cognitive function are well documented. Both acute and chronic hypoglycemia in type 1 diabetes are associated with declines in measures that test
intellectual functions and reaction time (1,13,14). In contrast, acute hyperglycemia might be expected to improve
memory, as glucose, in addition to its metabolic function,
acts as a substrate for acetylcholine and other neurotransmitters involved in memory and other cognitive processes
(15,16). However, a number of lines of evidence suggest
that chronically raised glucose concentrations lead to decreased cognitive functioning; poor glycemic control is associated with poor learning and memory, and the pharmacological improvement of glycemic control improves cognitive
function test performance in alder adults, although it is unclear whether this is due to glucose control or to the pharmacological intervention (17). Animal studies suggest mechanisms by which raised glucose might induce these changes.
Chronic, but not acute, hyperglycemia induced by streptozotocin leads to a decrease in acetylcholine synthesis and
release in the brain of rats (18). Chronic hyperglycemia in
rats also produces a significant loss of cortical neurons and,
paradoxically, relative neuroglycopenia induced by decreased glucose transfer across the blood–brain barrier.
Loss of cortical neurons would result in cognitive impairment, as memory is thought to be “stored” in the cortex (8)
and neuroglycopenia would result in decreased glucose
availability as a substrate for acetylcholine. As noted previously, decreased cholinergic transmission would result in
impaired memory.
Hyperinsulinemia
Insulin concentrations rise initially in the natural history
of type 2 diabetes to compensate for defective insulin action, whereas in type 1 diabetes insulin secretion is diminished, leading to treatment with exogenous insulin administration. In some cases, insulin is also administered in the
later stages of type 2 diabetes. Both animal and human stud-
B229
ies provide evidence of a role for insulin in the impairment
of a wide range of cognitive functions. High peak insulin response to glucose load has been found to be negatively correlated with learning ability in rats (19). In a study of over
5,500 subjects, direct effects of insulin on cognitive function were proposed. Serum insulin concentrations 2 hours
following glucose challenge were associated with a poorer
performance on the mini mental state examination (MMSE)
(20) in nondiabetic women without dementia independently
of cardiovascular risk factors and glucose levels (21). In
elderly subjects with persistent impaired glucose tolerance,
fasting insulin was associated with a poorer performance on
the MMSE and in a test of long-term memory (10). Insulin
treatment has also been associated with poorer performances in tests of verbal and visual memory (6). However,
these data should be treated with caution, as insulin treatment occurs in severe diabetes that is resistant to other
forms of treatment and thus may simply be a proxy for severity of diabetes. The effects of insulin in this regard require further investigation.
A number of mechanisms can be postulated by which insulin might alter cognitive functioning. Serum insulin concentration is significantly associated with cerebrospinal
fluid insulin, as insulin is transported across the blood–brain
barrier (22). Insulin receptors are present in the hypothalamus and hippocampus and mediate a decrease in cholinergic transmission (23,24). Hyperinsulinemia is also a risk
factor for atherosclerosis, which is associated with cerebrovascular disease. However, although a direct effect of insulin on cognitive function is plausible, the role of a chronically increased insulin secretion in the context of diabetes is
unclear, because hyperinsulinemia is not always apparent in
type 2 diabetes. This is especially true in the later stages of
the disease, when glucose toxicity may actually mediate diminished insulin secretion. The possible role of insulin in
cognitive decline associated with diabetes therefore remains
unclear and requires further investigation.
Dyslipidemia
Dyslipidemia is associated with the insulin resistance
syndrome. A limited number of studies have suggested a
role for raised triglyceride levels in cognitive impairment.
Triglycerides are inversely associated with verbal fluency
both cross-sectionally and prospectively (25) in diabetic patients. Hypertriglyceridemia in elderly patients with type 2
diabetes is associated with a decline in reaction times and
backward digit span independently of any changes in glucose
concentrations (25). High serum triglyceride levels are also
associated with slower reaction times in a series of tests and
with decreased verbal fluency in a small group of elderly subjects with normal glucose tolerance (26). Cognitive performance
is also improved in patients treated with a triglyceride-lowering compound, gemfibrozil. Raised triglyceride concentrations are associated with atherosclerosis, and so the mechanism to alter cognition may be similar to that discussed for
hypertension. Elevated triglyceride levels may also affect
cognitive performance by increasing blood viscosity and
impairing its rheological properties (27), which in turn
might alter cerebral perfusion and accelerate atherosclerosis. In support of this hypothesis, a recent report has de-
B230
KUMARI ET AL.
scribed a small negative association between delayed word
recall and plasma fibrinogen in a cohort of 14,000 middleaged adults (28). Furthermore, there is tentative evidence
from the findings that antithrombotic treatment (with aspirin or warfarin) is associated with better verbal fluency and
mental flexibility (29).
Hypertension and Cognitive Function
Raised blood pressure is a risk factor commonly associated with insulin resistance syndrome and type 2 diabetes
and has been the focus of much research on changes in cognitive function. There is a reduction in learning in spontaneously hypertensive rats, the most widely used animal model
of essential hypertension, which is additive with that seen
with age (30). This suggests that hypertension alters aspects
of cognition. However, until recently the role of hypertension in cognitive impairment was equivocal in humans; as
some studies found an association (31) whereas others did
not (32). More recent studies examining the effects of raised
blood pressure on changes in cognition over time have
shown that hypertension does indeed lead to cognitive impairment. A recent report has demonstrated that type 2 diabetes and high blood pressure are independently associated
with poorer performances on tests measuring immediate
and delayed memory for prose and that higher diastolic
blood pressure is associated with poorer performances on a
measure of verbal fluency (6). In another study of nondiabetics, hyperinsulinemia in hypertension was associated
with poor performances in cognitive tests reflecting calculation and verbal fluency (33). High diastolic blood pressure
in men aged 50 years was also found to be associated with
poorer performances on the MMSE 20 years later (34). How
might hypertension cause changes in cognitive function?
Again the cholinergic system can be implicated as, in the
spontaneously hypertensive rat, decreased nicotinic receptor
sensitivity to acetylcholine has been observed (35,36). A
further mechanism that can be postulated is that hypertension is known to be associated with cerebrovascular disease,
lacunar brain infarct, and brain white matter lesions. These
alterations can be incurred directly or indirectly, for example, through accelerated atherosclerosis (37). Impaired cognitive performance in hypertension is associated with white
matter lesions when an assessment is made by magnetic resonance imaging (38).
DEMENTIA AND INSULIN RESISTANCE AND DIABETES
Most cognitive abilities decline with advancing age,
though the progression of mild cognitive impairment to dementia is not the most common evolution. The evidence is
inconclusive as to whether cognitive impairment and dementia exist on a continuum or represent distinct processes
(39). It is unclear whether the factors or processes that affect
cognitive decline are the same as those that predict dementia. Dementia can be broadly split into two types; Alzheimer’s type and vascular dementia. Alzheimer’s disease (AD)
is a degenerative brain disorder characterized by neuronal
and synaptic degeneration and an increased number of senile plaques and neurofibrillary tangles compared with nondemented individuals of the same age. AD involves substantial loss of elements of a number of transmitter systems,
the best described of which is the cholinergic system (40).
AD is characterized by decreased brain glucose turnover,
which results in decreased cholinergic transmission and memory impairment. The causes and pathogenesis of its most
common form are multifactorial and are largely unknown.
Vascular dementia is less common and is caused by cerebrovascular and ischemic brain damage, that is, a combination of multiple cerebral infarcts, lacunas, and ischemic white
matter lesions, a demyelination of the periventricular white
matter.
One of the best known risk factors for developing Alzheimer’s disease is carrying the ⑀4 allele of the apolipoprotein E (Apo ⑀4) gene, but it is not necessary to carry the Apo
⑀4 allele to develop Alzheimer’s disease (41). Recent studies
have reported an association between features of the insulin
resistance syndrome (hyperglycemia and hyperinsulinemia)
and newly detected Alzheimer’s disease (5,42). Incidence
of AD reported in this study was as high in the insulin resistance group as in the carriers of the Apo ⑀4 allele (42). In
addition to the mechanisms by which hyperglycemia might
lead to cognitive impairment discussed above, it can be hypothesized that hyperglycemia might mediate accelerated
progression of AD by means of advanced glycation endproducts (AGEs). These are products of glycation of proteins, and they accumulate in tissues as a function of time
and blood glucose concentrations. They are found in amyloid plaques of AD (43) and are thought to accelerate the
plaque deposition that occurs in AD. Thus, hyperglycemia
and hence an increased production of AGEs may contribute
to the formation of amyloid plaques in AD. This hypothesis
requires further investigation.
Vascular dementia is caused by cerebrovascular and ischemic brain damage. Several lines of evidence suggest that
multiple infarcts and ischemic white matter lesions associated with hypertension are vascular causes of dementia. Performances on the MMSE were worse in a hypertensive
group with white matter lesions than in the normotensive
group and hypertensive group without such lesions. White
matter lesions also occur in Alzheimer’s disease, indicating
a role for hypertension in the etiology of both types of dementia. Hypertension and white matter lesions are strongly
implicated in the etiology of a particular dementia syndrome, Binswanger’s syndrome (44). A recent longitudinal
study reported that raised blood pressure predicted the incidence of both vascular dementia and Alzheimer’s disease
after 15 years (45,46), suggesting that hypertension is indeed a risk factor for dementia.
CONCLUSIONS
There is now substantial evidence to support the conclusion that type 2 diabetes is associated with memory impairment and dementia. These alterations in cognitive function
may represent accelerated aging in diabetes, although evidence in this regard is poor. There is literature suggesting that
both the metabolic control and the hypertension that occurs as
a consequence of diabetes are involved in the etiology of the
cognitive impairment that may occur. The literature on the
mechanisms with regard to cognitive impairment is unclear.
Evidence suggests a role for glycemic control in both memory decline and dementia. The role of insulin, hypertension,
METABOLIC SYNDROME AND COGNITION
and dyslipidemia in loss of memory functions is less convincing, although these factors are associated with decline in
other functions such as verbal fluency. Their role in dementia
is also apparent. It is unclear if these factors are using the
same or different mechanisms to cause these changes in cognition. It is possible that different pathways may converge in
the case of dementia. The literature describing cholinergic
transmission and factors associated with diabetes has been
highlighted in this article. A number of transmitter pathways
that are associated with memory and cognitive functioning
have not been discussed. More research is needed to further
characterize these mechanisms. The association between factors associated with diabetes and cognitive function as well as
dementia provides the individual with means to control the
onset of these consequences of aging and pathology by modification of lifestyle and behavior.
Acknowledgments
M. Kumari, E. Brunner, and R. Fuhrer are members of the Whitehall II
study team. The Whitehall II study has been supported by grants from the
Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (R01
HL36310), US, NIH: National Institute on Aging (R01 AG13196), US, NIH;
Agency for Health Care Policy Research (R01 HS06516); and the John D. and
Catherine T. MacArthur Foundation Research Networks on Successful Midlife
Development and Socio-economic Status and Health. R. Fuhrer is a Research
Scientist with INSERM (Institut National de la Santé et de la Recherche Médicale, Paris, France) presently on leave to University College, London.
Address correspondence to Dr. Meena Kumari, International Centre
for Health and Society, Department of Epidemiology and Public Health,
Royal Free and University College Medical School, London, WC1 6BT,
UK. E-mail: [email protected]
References
1. Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative cognitive
impairment following recurrent severe hypoglycaemia in adult patients
with insulin-treated diabetes mellitus. Diabetologia. 1991;34:337–344.
2. Amiel SA, Gale E. Physiological responses to hypoglycemia. Diabetes
Care. 1993;16:48–55.
3. Lincoln NB, Faleiro RM, Kelly C, Kirk BA, Jeffcoate WJ. Effect of
long-term glycemic control on cognitive function. Diabetes Care.
1996;19:656–658.
4. Strachan MWJ, Deary IJ, Ewing FME, Frier BM. Is type II diabetes
associated with an increased risk of cognitive dysfunction? Diabetes
Care. 1997;20:438–445.
5. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler
MMB. Association of diabetes mellitus and dementia: The Rotterdam
Study. Diabetologia. 1996;39:1392–1397.
6. Elias PK, Elias MF, D’Agostino RB, et al. NIDDM and blood pressure
as risk factors for poor cognitive functioning. The Framingham Study.
Diabetes Care. 1997;20:1388–1395.
7. Hasselmo ME, Wyble BP, Wallenstein GV. Encoding and retrieval of
episodic memories: role of cholinergic and GABAergic modulation in
the hippocampus. Hippocampus. 1996;6:693–708.
8. Redish AD, Touretzky DS. Cognitive maps beyond the hippocampus.
Hippocampus. 1997;7:15–35.
9. Everitt BJ, Robbins TW. Central cholinergic systems and cognition.
Ann Rev Psychol. 1997;48:649–684.
10. Vanhanen M, Koivisto K, Karjalainen L, et al. Risk for non-insulindependent diabetes in the normoglycaemic elderly is associated with
impaired cognitive function. Neuroreport. 1997;8:1527–1530.
11. Dey J, Misra A, Desai NG, Mahapatra AK, Padma MV. Cognitive
function in younger type II diabetes. Diabetes Care. 1997;20:32–35.
12. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of
NIDDM. In: Alberti KGMM, Zimmet P, DeFronzo RA, Keen H, eds.
International Textbook of Diabetes Mellitus. 2nd ed. New York:
Wiley; 1997:635–711.
B231
13. Deary IJ, Crawford JR, Hepburn DA, Langan SJ, Blackmore LM,
Frier BM. Severe hypoglycemia and intelligence in adult patients with
insulin-treated diabetes. Diabetes. 1993;42:341–344.
14. Draelos MT, Jacobson AM, Weinger K, et al. Cognitive function in
patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia. Am J Med. 1995;98:135–144.
15. Sherman KA, Gibson GE, Perrino P, Garrett K. Acetylcholine formation from glucose following acute choline supplementation. Neurochem
Res. 1991;16:1009–1015.
16. Ragozzini ME, Unick KE, Gold PE. Hippocampal acetylcholine release during memory testing in rats: Augmentation by glucose. Proc
Natl Acad Sci USA. 1996;93:4693–4698.
17. Gradman TJ, Laws A, Thomson LW, Reaven GM. Verbal learning
and/or memory improves with glycemic control in older subjects with
non-insulin-dependent diabetes mellitus. J Am Geriatr Soc. 1993;41:
1305–1312.
18. Welsh B, Wecker L. Effects of Streptozotocin-induced diabetes on
acetylcholine metabolism in rat brain. Neurochem Res. 1991;16:453–
460.
19. Long JM, Davis BJ, Garofalo P, Spangler EL, Ingram DK. Complex
maze performance in young and aged rats: response to glucose treatment and relationship to blood insulin and glucose. Physiol Behav.
1992;51:411–418.
20. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12:189–198.
21. Stolk RP, Breteler MMB, Ott A, et al. Insulin and cognitive function in
an elderly population. Diabetes Care. 1997;20:792–795.
22. Baura GD, Foster DM, Porte D, et al. Saturable transport of insulin
from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest. 1993;92:
1824–1830.
23. Shibata S, Liou SY, Ueki S, Oomura Y. Inhibitory action of insulin on
suprachiasmatic nucleus neurons in rat hypothalamic slice preparations. Physiol Behav. 1986;36:79–81.
24. Palovcik RA, Phillips MI, Kappy MS, Raizada MK. Insulin inhibits
pyramidal neurons in hippocampal slices. Brain Res. 1984;309:187–
191.
25. Perlmuter LC, Goldfinger SH, Shore AR, et al. Cognitive function in
non-insulin-dependent diabetes. In: Holmes CS, ed. Neuropsychological and Behavioural Aspects of Diabetes. New York: Springer-Verlag;
1990:222–238.
26. Helkala E, Niskanen L, Viinamaki H, Partanen J, Uusitupa M. Shortterm and long-term memory in elderly patients with NIDDM. Diabetes
Care. 1995;18:681–685.
27. Koenig W, Sund M, Ernst E, Mraz W, Hombach V, Keil U. Association between rheology and components of lipoproteins in human
blood. Circulation. 1992;85:2197–2204.
28. Cerhan JR, Folsom AR, Mortimer JA, et al. Correlates of cognitive
function in middle-aged adults. Atherosclerosis Risk in Communities
(ARIC) Study Investigators. Gerontology. 1998;44:95–105.
29. Richards M, Meade TW, Peart SS, Brennan PJ, Mann AH. Is there any
evidence for a protective effect of antithrombotic medication on cognitive function in men at risk of cardiovascular disease? Some preliminary
findings. J Neurol Neurosurg Psychiatry. 1997;62:269–272.
30. Meneses A, Castillo C, Ibarra M, Hong E. Effects of aging and hypertension on learning, memory and activity in rats. Physiol Behav. 1996;
60:341–345.
31. Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR. Untreated
blood pressure level is inversely related to cognitive functioning: the
Framingham study. Am J Epidemiol. 1993;6:353–364.
32. Scherr PA, Hebert LE, Smith LA, Evans DA. Relation of blood pressure
to cognitive function in elderly. Am J Epidemiol. 1991;134:1303–1315.
33. Kuusisto J, Koivisto K, Mykkanen L, et al. Essential hypertension and
cognitive function. The role of hyperinsulinemia. Hypertension. 1993;
22:771–779.
34. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension
is related to cognitive impairment: a 20-year follow up of 999 men.
Hypertension. 1998;31:780–786.
35. Gattu M, Pauly JR, Boss KL, Summers JB, Buccafusco JJ. Cognitive
impairment in spontaneously hypertensive rats: role of central nicotinic receptors. I. Brain Res. 1997;771:89–103.
36. Gattu M, Terry AV, Pauly JR, Buccafusco JJ. Cognitive impairment in
B232
37.
38.
39.
40.
41.
42.
KUMARI ET AL.
spontaneously hypertensive rats: role of central nicotinic receptors.
Part II. Brain Res. 1997;771:104–114.
Bots ML, van Swieten JC, Breteler MMB, et al. Cerebral white matter
lesions and atherosclerosis in the Rotterdam Study. Lancet. 1993;341:
1232–1236.
Breteler MMB, van Swieten JC, Bots ML, et al. Cerebral white matter
lesions, vascular risk factors, and cognitive function in a populationbased study: the Rotterdam Study. Neurology. 1994;44:1246–1252.
Huppert FA, Whittington JE, eds. Dementia and normal ageing. Cambridge: Cambridge University Press; 1994.
Kasa P, Rakonczay Z, Gulya K. The cholinergic system in Alzheimer’s disease. Prog Neurobiol. 1997;52:511–535.
Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400.
Kuusisto J, Koivisto K, Mykkanen L, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease
independently of apolipoprotein E4 phenotype: cross sectional population based study. Br Med J. 1997;315:1045–1049.
43. Li YM, Dickson DW. Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque
deposition in Alzheimer’s disease. Neurosci Lett. 1997;226:155–158.
44. Olsen CG, Clasen ME. Senile dementia of the Binswanger’s type. Am
Fam Physician. 1998;58:2068–2074.
45. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of
blood pressure and dementia. Lancet. 1996;347:1141–1145.
46. Ross GW, Launer LJ, Petrovitch H, et al. The association between
midlife blood pressure and dementia: The Honolulu-Asia Aging
Study. Neurology. 1998;50:A229.
Received April 2, 1999
Accepted September 21, 1999
Decision Editor: Jay Roberts, PhD