UPDATE ON DEMENTIA AND ALZHEIMER'S DISEASE
From Dementia and Neuropsychiatry: An Update for Neurologists, Psychiatrists, Geriatricians, and Primary Care, presented
by the University of Vermont College of Medicine and Fletcher Allen Eldercare Services
| PRIMARY PREVENTION FOR ALZHEIMER’S DISEASE —Joseph Quinn, MD, Associate Professor of Neurology,
and Associate Director, Clinical Core, Oregon Health Sciences University, Portland
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| Introduction: little data available on prevention of Alzheimer’s disease (AD); difficult to plan clinical trials that need
populations in which some participants will progress to mild cognitive impairment or AD by end of trial; trials conducted
for long periods; interventions must be plausible and safe; outcome measures must be sensitive to change
within time frame of trial
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| Homocysteine lowering: as shown in epidemiologic studies, elevated homocysteine levels risk factor for dementia
and vascular disease, but mechanism unclear; multicenter trial showed that lowering homocysteine levels does not
slow progression of disease in patients who already have AD; 2 studies (New England Journal of Medicine and Lancet
) with similar patient populations and only slight difference in intervention reached opposite conclusions about
prevention of dementia with homocysteine-lowering strategies
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 | Study 1: ≈280 healthy patients randomized to receive 1) placebo or 2) folate plus vitamins B6 and B12 ; outcome measures
determined rate of cognitive decline; follow-up 2 yr; no significant decline in cognitive function seen in patients
given placebo, but significant decline seen in trail-making task (Part B of Reitan Trail Making Test) in treated
patients; authors concluded homocysteine-lowering strategies of no benefit
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| Study 2: inclusion and exclusion requirements similar to those in study 1; 400 participants in each group randomized
to receive placebo or folic acid; followed for 3 yr; data analysis more elaborate than in study 1; results showed benefits
in treated group in global cognitive function, memory function, and information-processing speed; authors concluded
folate supplementation slows cognitive decline associated with aging
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| Omega-3 fatty acids: epidemiologic studies show that populations that consume more fish oil or omega-3 fatty acids
have lower incidence of AD; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) thought to be active ingredients;
DHA most abundant polyunsaturated fat in human brain; more important for neurologic outcomes than
EPA; plays important role in structure and signaling; study shows that dietary levels of DHA determine levels in
brain; EPA scarce in human brain, but thought to promote vascular health; one negative study on use of omega-3
fatty acids in people with AD considered too small and too short to demonstrate treatment effects; large study under
way at National Institutes of Health (NIH); results expected in early 2009
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| Memory Improvement with Docosahexaenoic Acid Study (MIDAS): under way; participants ≥55 yr of age without
dementia but with subjective complaint of memory problems; randomized to placebo or DHA; interim analysis
showed rate of change not robust enough in original sample, and sample size therefore increased
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| Older People And omega-3 Long chain PUFA (polyunsaturated fatty acid) Study (OPAL): 4500 people 70 to 79 yr of
age without dementia; 2-yr treatment with combination of DHA and EPA; results expected in late 2008
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| Ginkgo biloba: Ginkgo Evaluation of Memory Study (GEMS) under way; 3000 individuals, ≥75 yr of age, without
dementia, randomized to placebo or standardized preparation of ginkgo; at 5-yr follow-up, too few persons converted
to dementia to be statistically significant, so follow-up to continue another 3.5 yr (“if you want to prevent
AD, enroll as a subject in one of these trials; even if you get placebo, you just don’t progress”)
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| Other ginkgo trials: results of European multicenter trial (GuidAge) expected in 2010; small Oregon pilot study found
people on ginkgo remained cognitively intact longer than those on placebo, but because of small number of participants,
statistical significance not reached; in analysis of people adhering to therapy appropriately, statistical significance
seen in number of ginkgo-treated participants who remained cognitively intact; however, more strokes and
transient ischemic attacks (TIAs) than in placebo group
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| Estrogen replacement: Women’s Health Initiative Memory Study (WHIMS) randomized women (65 to 79 yr of age)
to placebo, estrogen alone, or estrogen plus progestin; follow-up, 4 to 5 yr; in estrogen-only arm, 1.9% on estrogen
progressed to dementia, vs 1.3% on placebo (statistically significant); in estrogen plus progestin arm, 2% progressed to
dementia, vs 1% on placebo; basis for reports that women on hormone replacement therapy progressed to dementia
more rapidly than those on placebo; study conclusion that use of hormone therapy to prevent cognitive decline or dementia
in women ≥65 yr of age not recommended; role of estrogen in brain function of younger women unclear
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| Nonsteroidal anti-inflammatory drugs (NSAIDs): epidemiologic data suggest use of NSAIDs associated with
lower incidence of AD; Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) designed to study nondemented
people ≥70 yr of age who have first-degree relative with AD; patients randomized to receive naproxen, celecoxib,
or placebo; follow-up to be 5 yr, but midway through trial, study suspended (due to information from another
study showing increased cardiovascular risk with celecoxib); interim analysis (at 560 days) showed 0.5% of patients in
placebo group developed dementia vs 1.5% to 2% in treatment groups; speaker notes that conversion rates trivial (not
statistically significant) and counterintuitive (placebo performed better than treatment medications); authors concluded
no evidence of protective effects of naproxen or celecoxib; caveat—subsequent to ADAPT, other studies show
that some NSAIDs have specific effect of lowering β-amyloid levels, which may help account for protective effect of
NSAIDs seen in epidemiologic studies; not all NSAIDs, including naproxen and celecoxib, have this effect
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| Conclusions: large numbers of participants and long periods of time necessary to detect presence or absence of treatment
effect (limits enthusiasm for funding studies); placebo groups often do not progress to dementia or AD, making interpretation
of results tricky; interventions need to be safe, yet 3 of 5 interventions discussed above had level of morbidity not anticipated
when studies initiated; negative results in older populations do not mean that interventions started in midlife will not
be effective
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| ARE OBESITY AND DIABETES RISK FACTORS FOR ALZHEIMER’S DISEASE ?—Richard Pratley, MD, Professor
of Endocrinology, and Director, Diabetes and Metabolism Translational Medicine Unit, University of Vermont College
of Medicine, Burlington
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| Introduction: of several methods of identifying obesity, body mass index (BMI) used in epidemiologic studies; normal
BMI <25; overweight ≥25; obesity ≥30; severe obesity >40; other important marker waist circumference (indicates
amount of abdominal obesity and visceral fat; more visceral fat means greater risk for metabolic complications of obesity)
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| Medical complications of obesity: pulmonary complications include sleep apnea and asthma; nonalcoholic fatty
liver disease; gynecologic abnormalities; central nervous system abnormalities; cataracts; cardiovascular disease; cancers
of colon, breast, uterus, and prostate; diabetes
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| Diabetes: according to large studies, relative risk of developing diabetes 7 times greater in people with obesity than in
those without; in women with BMI >30, risk 27 times higher, and if BMI ≥40, risk 100 times higher; in United States,
57% increase in diabetes projected over next 20 yr; ≈7% of Americans have diabetes (overwhelming majority type 2),
but only two-thirds aware, since clinical symptoms often silent in early stages; type 2 diabetes continuum from normal
fasting glucose levels to impaired fasting glucose or impaired glucose tolerance (prediabetes) to full diabetes; type 2
diabetes disease of aging; speaker concerned that ≈20% of older population has diagnosed or undiagnosed diabetes
and another 20% has prediabetes
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| Metabolic syndrome: National Cholesterol Education Program (NCEP) defines as syndrome with abdominal obesity
and certain metabolic risk factors, including lipid abnormalities, high fasting plasma glucose levels, low high-density lipoprotein
cholesterol (HDL-C), and oftentimes hypertension; other criteria include having 3 of 5 symptoms (increased
waist circumference; high triglycerides; low HDL-C; high blood pressure; high fasting glucose); metabolic syndrome
strong risk factor for developing diabetes and part of cluster of risk factors for cardiovascular disease; current hypothesis
that people with metabolic syndrome have insulin resistance, which may result from abdominal or overall obesity; insulin
resistance associated with dyslipidemia, hypertension, prediabetes, and diabetes; insulin resistance also associated with
independent risk factors (eg, clotting abnormalities, systemic inflammation) for cardiovascular disease
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| Epidemiology: obesity, diabetes, and metabolic syndrome especially prevalent in ethnic minority population, which is
increasing in numbers, and in economically disadvantaged; in United States, 61% increase in obesity since 1991
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| Inflammation: literature search reveals strong correlation between degree of obesity and markers associated with inflammation
(eg, white blood cell count, C-reactive protein, interleukin-6); hypothesis that obesity and diabetes inflammatory
states; “this got us interested in what’s going on in the fat cells”
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| Fat cells: obese people have more and bigger fat cells than nonobese people; fat cells previously thought to be inert storage
vehicles for lipids and excess fat; now known to be metabolically very active (“they’re probably the largest endocrine
organ in the body”); leptin produced by fat cells exclusively, and plays role in regulation of body weight and
appetite; people who lack leptin (“there are about 5 or 6 in the world”) massively obese; fat cells also produce adiponectin
(insulin-sensitizing hormone), several cytokines, monocyte chemotactic factors, and activating factors, all of
which are inflammatory factors; fat cells also produce elements of alternative complement pathway, factors related to
hemostasis, all proteins necessary for renin-angiotensin system, and factors involved in lipid metabolism; now thought
that metabolic syndrome develops, in part, because of dysregulation of products produced by fat cells; as people get
fatter, fat cells get bigger, and as fat cells get bigger, they pour out more inflammatory cytokines; inflammatory cytokines
attract monocytes into adipose tissue where they differentiate into macrophages; macrophages, in turn, contribute
to inflammatory cytokines produced by fat cells; net effect metabolic complications of obesity, diabetes, and atherosclerosis;
bottom line—obesity, diabetes, and metabolic syndrome all proinflammatory states
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| Dementia: association found between obesity, diabetes, and metabolic syndrome and risk of developing dementia; typical
person who presents with dementia not obese, but people with preclinical dementia undergo period of weight loss that
may last up to 10 yr; shown that midlife obesity increases risk for AD; another study suggests association between vascular
dementia and obesity; Sacramento Area Latino Study on Aging (SALSA) found people with higher degree of
obesity less likely to develop AD, but people with more abdominal fat more likely to develop AD; SALSA also found
that people with type 2 diabetes had 2-fold higher risk of developing dementia over relatively short period; no association
found between metabolic syndrome and dementia; other studies show increased risk for mild cognitive impairment
and dementia among people with prediabetes
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| Cerebrovascular risk factors: also risk factors for AD; having had stroke or TIA increases risk for any dementia, not
just vascular type; midlife hypertension increases risk of developing AD; Health, Aging, and Body Composition
(Health ABC) study found patients with metabolic syndrome and evidence of inflammation (high C-reactive protein)
had 2-fold higher risk of developing AD; in other studies, individuals with high indexes of inflammation
tended to have more cognitive decline
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| Alzheimer’s disease: increasing evidence of vascular component to AD; mixed pathology often seen in brains of people
with AD, and improving prevention and treatment of cardiovascular disease may lower incidence of dementia and
AD
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| Mechanisms: dementia may be related to increases in inflammatory factors associated with having more fat cells, or to
insulin resistance, or to both; data for insulin resistance connection “spotty”; speaker suggests that measures of insulin
resistance may actually be measuring metabolic syndrome or aggregation of risk factors; study showed that people
with higher C-reactive protein levels more insulin resistant, and upper quartiles had poor performance on verbal memory
and global cognitive tests, suggesting association between inflammation, insulin resistance, and cognitive impairment;
another study suggested relationship between metabolism of insulin and β-amyloid; in summary, number of
studies suggest risk for dementia associated with peripheral hyperinsulinemia (likely reflects insulin resistance)
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| Physical activity as preventive mechanism: several studies show physical exercise results in up to 60% reduction
in new cases of diabetes over several years; however, intervention intensive and difficult to implement on public health
basis; increased physical activity also resulted in less metabolic syndrome
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| Conclusions: midlife obesity, metabolic syndrome, and diabetes associated with increased risk for dementia; additionally,
some studies show poor glucose control increases risk for dementia; mechanisms largely unknown, more research
(especially long-term) needed
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Suggested Reading
Bartzokis G et al: Apolipoprotein E affects both myelin breakdown and cognition: implications for age-related trajectories
of decline into dementia. Biol Psychiatry 62:1380, 2007; Beydoun MA et al: Plasma n-3 fatty acids and the
risk of cognitive decline in older adults: the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 85:1103, 2007;
Craft S: Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment.
Curr Alzheimer Res 4:147, 2007; Cummings JL et al: Disease-modifying therapies for Alzheimer disease: challenges
to early intervention. Neurology 69:1622, 2007; Feldman HH, Jacova C: Primary prevention and delay of onset of
AD/dementia. Can J Neurol Sci 34(Suppl 1):S84, 2007; Fishel MA et al: Hyperinsulinemia provokes synchronous increases
in central inflammation and beta-amyloid in normal adults. Arch Neurol 62:1539, 2005; Fratiglioni L et al:
Prevention of Alzheimer’s disease and dementia. Major findings from the Kungsholmen Project. Physiol Behav 92:98,
2007; Kivipelto M et al: Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.
Arch Neurol 62:1556, 2005; Lee YH, Pratley RE: The evolving role of inflammation in obesity and the metabolic
syndrome. Curr Diab Rep 5:70, 2005; Luchsinger JA, Mayeux R: Adiposity and Alzheimer’s disease. Curr Alzheimer
Res 4:127, 2007; McMahon JA et al: A controlled trial of homocysteine lowering and cognitive performance. N
Engl J Med 354:2764, 2006; Montine TJ et al: Quantitative in vivo biomarkers of oxidative damage and their application
to the diagnosis and management of Alzheimer’s disease. J Alzheimers Dis 8:359, 2005; Okura Y, Matsumoto
Y: Development of anti-Abeta vaccination as a promising therapy for Alzheimer’s disease. Drug News Perspect 20:379,
2007; Peila R et al: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology
2004, 63:228; Qiu WQ, Folstein MF: Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s
disease: review and hypothesis. Neurobiol Aging 27:190, 2006; Razay G et al: Obesity, abdominal obesity and
Alzheimer disease. Dement Geriatr Cogn Disord 22:173, 2006; Rosengren A et al: Body mass index, other cardiovascular
risk factors, and hospitalization for dementia. Arch Intern Med 165:321, 2005; Shumaker SA et al: Conjugated
equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women:
Women’s Health Initiative Memory Study. JAMA 291:2947, 2004; Stackman RW et al: Prevention of age-related
spatial memory deficits in a transgenic mouse model of Alzheimer’s disease by chronic Ginkgo biloba treatment. Exp
Neurol 184:510, 2003; Whitmer RA et al: Obesity in middle age and future risk of dementia: a 27-year longitudinal
population-based study. BMJ 330:1360, 2005.
Educational Objectives
| The goal of this program is to improve management of dementia and Alzheimer’s disease (AD) by providing new information
on prevention and risk factors associated with these illnesses. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Explain why there is little information available on the primary prevention of AD.
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| 2. Discuss 5 strategies that have been tried for primary prevention of AD and the outcomes of trials using those strategies.
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| 3. Describe the relationships between obesity, type 2 diabetes, and metabolic syndrome and dementia.
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| 4. Explore the relationship between obesity, type 2 diabetes, and metabolic syndrome and inflammation.
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| 5. Assess the mechanisms of inflammation that may influence the development of dementia.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported
nothing to disclose.
Acknowledgments
Drs. Quinn and Pratley were recorded at Dementia and Neuropsychiatry: An Update for Neurologists, Psychiatrists, Geriatricians,
and Primary Care, held September 14-16, 2007, in Stowe, VT, and sponsored by the University of Vermont College
of Medicine and Fletcher Allen Eldercare Services. The Audio-Digest Foundation thanks the speakers and the sponsors for
their cooperation in the production of this program.
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