Context The prevalence of mixed dementia, defined as the coexistence of Alzheimer
disease (AD) and vascular dementia (VaD), is likely to increase as the population
ages.
Objectives To provide an overview of the diagnosis, pathophysiology, and interaction
of AD and VaD in mixed dementia, and to provide a systematic literature review
of the current evidence for the pharmacologic therapy of mixed dementia.
Data Sources, Study Selection, and Data Extraction The Cochrane Database of Systematic Reviews was searched using the keyword dementia. MEDLINE was searched for English-language articles
published within the last 10 years using the keywords mixed
dementia, the combination of keywords Alzheimer disease, cerebrovascular disorders, and drug therapy, and the combination of keywords vascular
dementia and drug therapy.
Evidence Synthesis Dementia is more likely to be present when vascular and AD lesions coexist,
a situation that is especially common with increasing age. The measured benefits
in clinical trials for the treatment of mixed dementia are best described
as statistically significant differences in cognitive test scores and clinician
and caregiver impressions of change. In these studies, the control groups’
scores typically decline while the treatment groups improve slightly or decline
to a lesser degree over the study period. Nevertheless, even the patients
who experience treatment benefits eventually decline. Cholinesterase inhibitor
(ChI) therapy for mixed dementia shows modest clinical benefits that are similar
to those found for ChI treatment of AD. The N-methyl-D-aspartate (NMDA) antagonist memantine also shows modest clinical
benefits for the treatment of moderate to severe AD and mild to moderate VaD,
but it has not been studied specifically in mixed dementia. The treatment
of cardiovascular risk factors, especially hypertension, may be a more effective
way to protect brain function as primary, secondary, and tertiary prevention
for mixed dementia.
Conclusions Currently available medications provide only modest clinical benefits
once a patient has developed mixed dementia. Cardiovascular risk factor control,
especially for hypertension and hyperlipidemia, as well as other interventions
to prevent recurrent stroke, likely represent important strategies for preventing
or slowing the progression of mixed dementia. Additional research is needed
to define better what individuals and families hope to achieve from dementia
treatment and to determine the most appropriate use of medication to achieve
these goals.
Alzheimer disease (AD) and vascular dementia (VaD) are common causes
of dementia in the United States and will likely affect an increasing number
of patients in the coming decades.1 Most reports
focus on AD and VaD as separate uncomplicated clinical entities, yet there
is increasing evidence that, particularly in older patients, the brain lesions
associated with each pathological process often occur together2 and
that AD and VaD brain lesions interact in important ways to increase the likelihood
of clinically significant cognitive decline.3,4 This
coexistence of AD and VaD pathology is often termed mixed dementia.2
We sought to systematically assemble information on the emerging diagnostic,
clinical, and pathological issues related to AD, VaD, and their coexistence,
and on the implications for treatment. We then present the results of a systematic
literature review of the pharmacologic treatments for mixed dementia.
Pathology and Clinical Criteria
The brain lesions of AD—namely, extracellular amyloid plaques
and intracellular neurofibrillary tangles—and VaD—namely, cerebral
infarctions, multiple lacunar infarctions, and ischemic periventricular leukoencephalopathy5—often occur together.6-8 Autopsy
series from dementia clinics report that coexisting vascular pathology occurs
in 24% to 28% of AD cases.7,9 Community-based
autopsy studies consistently find higher proportions of both VaD and mixed
dementia, probably because individuals who are older and have more medical
comorbidities are less likely to be referred to academic centers. One such
autopsy study of patients diagnosed clinically with AD found that 42 (45%)
of the 94 cases that met the accepted neuropathological criteria for AD also
had significant cerebrovascular pathology.6 A
community-based autopsy study in the United Kingdom found that the primary
pathological diagnosis in those with dementia was AD in 59% of cases and VaD
in 16%. However, when findings were reconsidered without a primary diagnosis,
AD pathology was present in 61% of cases and cerebrovascular pathology was
present in 54%, with clinical dementia most often associated with the coexistence
of both AD and cerebrovascular pathology.8 As
with other aspects of geriatric practice,10 the
search for a single unifying diagnosis to explain symptoms and signs, also
known as the Occam’s razor rule, likely does not apply to older patients
who are at-risk for neurodegeneration from both AD and cerebrovascular disease.
The diagnosis and treatment of patients with both AD and VaD brain pathology
is made more complex by the current lack of consensus on appropriate clinical
criteria and terminology.2 The National Institute
of Neurological Disorders and Stroke–Association Internationale pour
la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) diagnostic
criteria for VaD do not include a category for mixed dementia, recommending
instead the term AD with cerebrovascular disease.5 Alternatively, the Hachinski Ischemic Score,11 the International Classification
of Diseases, 10th Revision (ICD-10),12 and
the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV)13 all include
a mixed dementia category although the specific diagnostic criteria differ.2
Other coexisting pathologies are also common in dementia. Pathological
Parkinson disease is present in about 20% of patients with AD, and about 50%
of cases of dementia with Lewy bodies are associated with AD pathology.9,14 Nevertheless, the term mixed dementia is widely recognized and is the most commonly used term
for the AD and VaD combination.
Interaction of AD and VaD
Alzheimer disease pathology occurs frequently in asymptomatic elderly
individuals and clinical dementia is more likely to be present when AD is
accompanied by strokes and cerebrovascular-related brain changes.3,15 The cognitive consequences of vascular
lesions are cumulative,16 so VaD and perhaps
also mixed dementia are potentially preventable if vascular risk factors are
controlled and strokes do not recur.17
There is also emerging evidence that the cascade of events leading to
the development of AD brain plaques and tangles may be due to ischemia resulting
from cerebrovascular disease.4,18,19 The
association of the apolipoprotein E (APOE) ε4
genotype with an increased risk for both AD and cardiovascular disease further
suggests a potential link between atherosclerosis, cerebrovascular disease,
and AD.19,20 Conversely, amyloid
deposition in cerebral blood vessels due to AD increases the risk for hemorrhagic
strokes and subsequent VaD.21 These common
pathways leading from cerebrovascular disease to both AD and VaD support the
notion that when there is evidence of both cerebrovascular disease and a gradual
progressive dementia, the illness should be conceptualized as the coexistence
of interacting pathological processes resulting in mixed dementia.
We define mixed dementia as cognitive decline sufficient to impair independent
functioning in daily life resulting from the coexistence of AD and cerebrovascular
pathology, documented either by clinical criteria or by neuroimaging findings.
We first searched the Cochrane Database of Systematic Reviews using
the keyword dementia. The title and abstracts of
the 134 systematic reviews identified by this search were assessed for relevance
to this review. Any review of medication therapy for Alzheimer disease, vascular
dementia, mixed dementia, cognitive impairment, or cognition (N = 34
reviews) was retained. We searched MEDLINE for English-language articles published
within the last 10 years. We reviewed the title and abstracts of all 107 articles
identified using the keywords mixed dementia; 31
articles identified using the combined keywords Alzheimer
disease, cerebrovascular disorders, and drug therapy; and 28 articles identified using the combined
keywords vascular dementia and drug therapy. We then performed a manual search of the reference lists
of the relevant retrieved articles. We did not include publications that were
judged to be irrelevant to this review based on the title and abstract. Randomized,
double-blind, placebo-controlled trials (RCTs) with results reported as intention-to-treat
analyses were considered to be the highest quality data and are the focus
of this review. Large prospective cohort studies, meta-analyses, and systematic
literature reviews were also included, as deemed appropriate, to supplement
the RCT results.
Cholinesterase Inhibitors
Galantamine. An RCT of galantamine for patients
with either probable VaD or AD with coexisting cerebrovascular disease showed
treatment benefits for cognitive and functional outcomes (Table).22 Patients with baseline
scores of 10 to 25 on the 30-point Mini-Mental State Examination (MMSE) treated
with 24 mg/d of galantamine showed a small improvement (–1.7; 95% CI,
–0.9 to –2.5) over 6 months on the 11-item (70-point) Alzheimer
Disease Assessment Scale-cognitive subscale (ADAS-cog) while those in the
placebo group showed a small decline (1.0; 95% CI, 0.5-1.5; P<.001). A subgroup analysis of only those patients with mixed dementia
(AD with coexisting cerebrovascular disease) showed similar outcomes to those
of the subsample of patients with probable VaD.
Rivastigmine. An RCT of rivastigmine showed
treatment benefits similar to the galantamine trial.23 A
clinical scale—the Modified Hachinski Ischemic Score40—was
used to identify patients with AD who also had concurrent vascular risk factors,
focal neurological symptoms or signs suggestive of prior stroke, or a history
of strokes. Patients with an MMSE score from 10 to 26 were randomly assigned
to high-dose rivastigmine (6-12 mg/d), low-dose rivastigmine (1-4 mg/d), or
placebo and were followed-up for 26 weeks. Among the observed cases (ie, “randomized
patients with at least one evaluation while on study medication at designated
assessment times”23), patients treated
with 6 to 12 mg/d of rivastigmine showed significantly less decline in their
ADAS-cog than those taking placebo (P<.001). An
intention-to-treat analysis was not reported.
Donepezil. Randomized controlled trials of
donepezil have shown treatment benefits for patients with mild to moderate
AD24 and for patients with VaD,29 but
we found no donepezil trials specifically for patients with mixed dementia
or AD with concurrent cerebrovascular disease. Both AD and VaD trials showed
similar modest treatment benefits (Table 1).
A Cochrane review of donepezil for VaD concluded that it is safe and that
it has some efficacy.41
The recently published AD2000 trial also found statistically significant
benefits of donepezil treatment (5 or 10 mg/d) for cognitive function and
independent performance of activities of daily living (ADLs) in a sample of
patients with mild to moderate AD.25 However,
there were no treatment benefits after 3 years of follow-up for the study’s
2 primary outcomes—institutionalization and progression of disability
in ADLs, leading the authors to conclude that the small but statistically
significant benefits in cognition and ADL performance associated with donepezil
treatment did not lead to clinically meaningful benefits for patients or their
caregivers, and therefore that donepzil did not reach conventional levels
of cost-effectiveness. Sixteen percent of AD patients included in the study
also had VaD (ie, mixed dementia); a subgroup analysis suggested more significant
cognitive improvement among those with mixed dementia treated with donepezil
compared with those lacking VaD (P = .02).
Memantine. Memantine—an antagonist of
the N-methyl-D-aspartate (NMDA) receptor—has
a different mechanism of action than the cholinesterase inhibitors (ChIs)
raising the possibility of an additive or even synergistic treatment effect
for this class of medications.27 We found separate
RCTs of memantine for patients with AD26,27 and
VaD,30 as well as a trial that included patients
with either AD or VaD,31 but none specifically
for patients with mixed dementia. Two 28-week RCTs found a beneficial treatment
effect for memantine (20 mg/d) in patients with moderate to severe AD (MMSE
scores of 3-14), when used alone26 or in combination
with donepezil.27 In patients with mild to
moderate VaD (MMSE scores 12-20), memantine treatment was associated with
a beneficial 2-point treatment difference on the ADAS-cog (P<.01) but no significant difference in the Clinician’s Interview
Based Impression of Change plus Caregiver Input (CIBIC-plus) rating scale.
A trial that included severely demented nursing home patients with either
AD or VaD (MMSE scores <10) also found a benefit after 12 weeks of memantine
treatment.31 A subgroup analysis found a similar
treatment response for patients with either AD or VaD.
Cardiovascular and Other Agents
Antihypertensives. A number of observational
studies have shown a relationship between hypertension and an increased risk
for cognitive impairment,42,43 as
well as a protective effect of antihypertensive therapy for preventing cognitive
decline.44 Consistent with these observations,
the Systolic Hypertension in Europe (Syst-Eur) RCT found the incidence of
dementia decreased 50% from 7.7 to 3.8 cases per 1000 patient-years during
2 years of observation (P = .05) in patients
treated with the long-acting calcium-channel blocker nitrendipine.35 A 2-year open-label extension of the trial showed
similar results, with a 55% reduction in dementia incidence for those receiving
long-term therapy (P<.001).36 Antihypertensive
treatment was associated with a decrease in the incidence of AD as well as
VaD or mixed dementia.
Statins. Observational studies have found an
association between elevated serum cholesterol at middle age and increased
risk of mild cognitive impairment45 and AD.43 Some observational studies also have shown that statin
therapy is associated with a decreased risk for cognitive impairment46 and dementia47-49 although
more recent studies have not.50 The APOE ε4 genotype may modulate the impact of hypercholesterolemia
on cognitive decline, as individuals with evidence of atherosclerosis and
the APOE ε4 allele showed more significant
cognitive decline than those without the allele over 5 to 7 years of follow-up
in the Cardiovascular Health Study.20 One study
has suggested that persons with the APOE ε4
allele may be the subgroup that receives a cognitive protective benefit from
statins.50
Randomized controlled trials have not confirmed that statin therapy
reduces the incidence of cognitive decline37-39 or
AD.51 In the Prospective Study of Pravastatin
in the Elderly at Risk (PROSPER) trial,37 individuals
aged 70 to 82 years at risk for vascular disease with MMSE scores of at least
24 at baseline were randomized to receive either 40 mg/d of pravastatin or
placebo and were followed up for an average of 3.2 years. Although there were
significant cardiovascular benefits for treated patients, there were no significant
differences in cognitive decline during the 3-year follow-up as measured by
the MMSE and other cognitive tests. Similarly, the Heart Protection Study38 found significant cardiovascular and cerebrovascular
benefits over 5 years of follow-up for patients with a history of, or risk
factors for, coronary or cerebrovascular disease who were treated with 40
mg/d of simvastatin, but no evidence for a decreased incidence of cognitive
impairment or dementia.38,39 The
relatively short follow-up period of these 2 trials may have limited their
power to detect significant beneficial cognitive outcomes.19
Aspirin. An observational study of elderly
individuals in Sweden showed an association between aspirin use and a decreased
risk of AD and all-cause dementia,52 but no
RCTs of aspirin have been reported for the treatment of mixed dementia, AD,
or VaD. A Cochrane review of aspirin for VaD also found no eligible RCTs.53 The AD2000 RCT of donepezil25 included
an assessment of the potential benefits of aspirin for AD, but these results
for aspirin have not been published yet.
Vitamin E. An RCT of vitamin E, selegeline,
or both, for patients with moderate AD found a treatment benefit associated
with 2000 IU per day of vitamin E.28 After
adjusting for a significant baseline difference in MMSE score across the vitamin
E and placebo groups, those taking vitamin E had a significant delay to the
combined end point of death, institutionalization, loss of ability to perform
at least 2 of 3 ADLs, or progression to severe dementia. The median time to
this end point was 670 days in the vitamin E group vs 440 days in the placebo
group (P = .001). Therefore the estimated
increase in median time to end point was 230 days (RR, .47). Significantly
fewer patients taking vitamin E were institutionalized during the study period
(26% vs 39%, P = .003; RR, .42). However,
no benefit from vitamin E was found for cognitive function as measured by
the MMSE, the ADAS-Cog, or the Blessed Dementia Scale (BDS). Although some
reviews have interpreted these results as supporting vitamin E treatment to
slow institutionalization in AD patients,54 a
Cochrane systematic review concluded that there is currently insufficient
evidence to recommend vitamin E treatment.55
Ginkgo Biloba. Evidence of benefit for the
use of the plant extract of the Ginkgo biloba tree (EGb 761) for treatment
of cognitive impairment and dementia has been mixed. While we found no RCTs
specifically testing ginkgo in patients with mixed dementia, 2 trials that
included patients with AD and VaD (“multi-infarct dementia”),32,34 and 1 trial that included patients
with AD, VaD, and mixed dementia33 were identified.
The former RCTs found statistically significant improvements in measures of
cognition and global clinical impression among patients with AD or VaD who
took 120 mg/d53 or 240 mg/d54 of EGb 761. The latter
RCT found no benefits from treatment with 160 or 240 mg/d.33 This
conflicting evidence, as well as concerns with how one of the positive trials34 accounted for patients who did not complete the trial,
led a recent Cochrane review to conclude that while there is “promising
evidence” of benefit from ginkgo, further trials are required before
a treatment benefit can be confirmed.56
Clinical Significance and Appropriate Treatment Goals for Mixed Dementia
Our literature review found evidence from RCTs that treatment with the
ChIs galantamine and rivastigmine has modest beneficial effects on cognitive
and functional outcomes in patients with mixed dementia. In addition, memantine
has shown modest treatment benefits in separate trials for patients with AD
and VaD, suggesting that this agent would also prove beneficial for mixed
dementia.
Do the statistically significant differences in the measures of cognition
and function found in these trials translate into clinically meaningful results
for patients and caregivers? There continue to be differing interpretations
of these medication trial results, with some clinicians interpreting them
as showing clinical benefit and recommending treatment for all patients with
dementia, and other clinicians interpreting them much more cautiously.57 A 2001 evidenced-based review on the management of
dementia from the American Academy of Neurology stopped short of recommending
treatment with ChIs, instead recommending that the medications be “considered
in patients with mild to moderate AD, although studies suggest a small average
degree of benefit.”54 On the other hand,
some observers have interpreted the recent negative findings of the AD2000
trial involving more “typical” patients as calling into question
any meaningful clinical benefit from ChI treatment, and have recommended additional
placebo-controlled trials of ChIs to better inform future treatment of patients
with dementia.58
One reason for the continued controversy among physicians in defining
the clinical significance of dementia treatments is likely the simple fact
that desired treatment goals vary significantly across families and likely
continue to change as the severity of the patient’s cognitive impairment
increases. Additional complexity arises because both the patients and the
caregivers may derive benefit (and potential harm) from treatment and because
caregivers may be the primary decision makers due to the patients’ declining
cognitive abilities.59 Clinicians, therefore,
often need to solicit, interpret, and synthesize the treatment preferences
of multiple individuals who may have very different assessments of: (1) the
patient’s current severity of cognitive impairment, (2) the potential
benefits and harms of treatment, and (3) the most important treatment goals
(eg, improved patient quality of life, decreased caregiver burden, delay to
nursing home placement, or, as dementia severity advances, achieving a peaceful
death60).
Conclusions and personal perspectives
What Should Clinicians Do For Patients With Mixed Dementia?
Medications to Treat Mixed Dementia. Our review
of medication therapy for mixed dementia shows that the cognitive and functional
treatment benefits of ChIs and memantine in patients with mixed dementia or
VaD are of a similar magnitude to those previously reported for the treatment
of AD. Regarding cognitive function, the mean treatment effect across ChI
studies for both AD and mixed dementia (about 3 points on the ADAS-Cog) has
been described as equivalent to a 4- to 6-month delay in cognitive decline.61 However, clinicians should discuss with patients
and families that current evidence suggests that response to ChIs may be quite
variable, with a significant number of treated individuals (30% to 50%61,62) showing no improvement, and a smaller
proportion (perhaps up to 20%63) showing a
greater than average response (≥7-point ADAS-cog improvement). Given this
significant variability in response to ChIs, clinicians, patients, and caregivers
should monitor for either treatment-related improvement, or stabilization
of the patient’s decline, in cognitive, ADL, and behavioral domains
over the initial 8 to 12 weeks of treatment and should discuss the appropriate
definition of a meaningful benefit (eg, increased independence, alertness,
or the ability to communicate with family members) from ChI treatment.62 Given that the current monthly out-of-pocket cost
of ChI therapy is approximately $150 and combination ChI and memantine treatment
is approximately $300, discussions with patients and caregivers regarding
concerns about out-of-pocket costs and the value of treatment benefits, while
often uncomfortable, are likely to be appreciated by families.64
Cardiovascular Risk Factor Control and Stroke Prevention. Given the growing epidemiological6 and
clinical3 evidence for the coexistence of AD
and VaD and the potential common pathway leading from cerebral ischemia to
both conditions,4,19,65 aggressive
identification and treatment of cardiovascular risk factors in middle-aged
and older individuals may represent an important strategy for decreasing the
incidence of dementia and for slowing the progression of cognitive decline.43,65 Clinicians should address treatment
and/or lifestyle changes for the risk factors of hypertension, hyperlipidemia,
diabetes, and physical inactivity for patients with early AD, VaD, or mixed
dementia as a potential strategy for improving quality of life and delaying
the progression of cognitive decline. Even though the Heart Protection Study
did not show a statistically significant effect of statins on cognitive decline
(perhaps due to a limited follow-up period), the strong evidence for statin-related
stroke prevention at least suggests that statin therapy may reduce the incidence
and progression of VaD and mixed dementia.39 In
addition, prevention of recurrent strokes through the identification and treatment
of atrial fibrillation and carotid vascular occlusive disease, as well as
the appropriate use of anticoagulation for thromboembolic disease, will also
likely reduce the incidence or progression of VaD and mixed dementia.
Additional Considerations
In addition to discussions of medications and their usage, we believe
it is important to address a range of consequential medical, financial, legal,
long-term care, and prognosis issues early in a patient’s course (Box). Seeking assistance from social
workers, home care services, support groups, and community-based services
can help patients and families access the wide range of information and counseling
available and can help develop an “activated” family that can
proactively address issues as they arise over the progressive course of the
disease. In addition, continuing physician care can aid in the early recognition
and treatment of the complications often seen in mixed dementia, such as behavioral
disturbances and delirium from medical illnesses. Because, as noted above,
the definition of therapeutic success may change from both the patient’s
and family’s perspective as dementia progresses, clinicians should discuss
treatment goals with patients and families at the time of diagnosis and periodically
thereafter.67
Box Section Ref IDBox. Information and Counseling for Patients With a Recent Diagnosis
of Dementia and Their Families
Prognosis regarding expected time course of cognitive
decline and life expectancy66
Patient and family preferences for specific goals
of treatment tailored to patient’s current level of cognitive and physical
impairment
Medical advance directives, including living will,
durable power of attorney for health care, and preferences for end-of-life
interventions such as “do not attempt resuscitation” orders and
hospice care
Review of finances and powers of attorney
Driving safety and eventual need for driving cessation
Recommendations for social engagement and physical
activity
Home safety issues including kitchen safety, firearms,
poisons, and potential fall risks
Potential for wandering and the availability of the
Safe Return Program through the Alzheimer’s Association (information
available at: http://www.alz.org/Services/SafeReturn.asp)
Potential need for long-term care (LTC) services
and financial issues surrounding LTC
Identifying family resources for caregiving
Resources for patient and caregiver information and
support including the Alzheimer’s Association, Alzheimer Disease Education
and Referral Center, American Bar Association Commission on Legal Problems
of the Elderly63
Plan for follow-up and assurance that physician and
other members of health care team will be available to provide education and
information during the course of illness
Current Deficiencies in Knowledge
The growing evidence that AD and cerebrovascular disease commonly coexist
and interact in the brains of older individuals is an example of how Occam’s
razor, or parsimony of diagnosis, may lead clinicians astray when evaluating
and treating older patients.68,69 An
inclusive clinical perspective that considers both AD pathology and VaD pathology
as causes for cognitive decline will become increasingly appropriate as physicians
see proportionately more older patients at higher risk for multiple coexisting
chronic conditions in the coming decades.
To better guide the treatment of patients with mixed dementia, future
studies should similarly broaden their criteria to include patients with evidence
for mixed causes of dementia, rather than identifying only pure AD and VaD.
Similarly, population-based studies that can provide more generalizable information
on real-world patients—including better identification of the risk factors,
prevalence, trajectory of cognitive decline, and survival in patients with
mixed dementia—will be important for informing clinicians, patients,
and families. However, even given better information on the clinical course
of patients with coexisting AD and VaD, the difficult family decisions regarding
appropriate treatment goals for patients with dementia, and how these goals
should change as cognitive decline progresses, will remain. Additional research
into patient and family attitudes will help physicians better use medications
to meet realistic treatment goals in mixed dementia.
Corresponding Author: Kenneth M. Langa,
MD, PhD, Division of General Medicine, University of Michigan Health System,
300 North Ingalls Bldg, Room 7E01, Box 0429, Ann Arbor, MI 48109-0429 (klanga@umich.edu).
Author Contributions: Dr Langa had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Langa, Foster, Larson.
Acquisition of data: Langa.
Analysis and interpretation of data: Langa,
Foster.
Drafting of the manuscript: Langa.
Critical revision of the manuscript for important
intellectual content: Langa, Foster, Larson.
Statistical analysis: Langa.
Obtained funding: Langa.
Administrative, technical, or material support:
Foster, Larson.
Study supervision: Larson.
Funding/Support: Dr Langa was supported by
a Career Development Award from the National Institute on Aging (K08 AG19180),
a New Investigator Research grant from the Alzheimer’s Association,
a Paul Beeson Physician Faculty Scholars in Aging Research award, and a John
A. Hartford Foundation grant to the Society of General Internal Medicine (2002-0013).
Dr Foster was supported in part by National Institutes of Health grant P50
AG08671. Dr Larson was supported in part by National Institutes of Health
grant U01 AG06781.
Role of the Sponsor The NIA, Alzheimer’s
Association, and Paul Beeson Physician Scholars Program had no role in the
conduct of the study nor in the decision to publish the results.
1.Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A population-based study of dementia in 85-year-olds.
N Engl J Med. 1993;328:153-1588417380
Google ScholarCrossref 2.Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment.
J Am Geriatr Soc. 2002;50:1431-143812165002
Google ScholarCrossref 3.Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease:
the Nun Study.
JAMA. 1997;277:813-8179052711
Google ScholarCrossref 4.de la Torre JC. Vascular basis of Alzheimer's pathogenesis.
Ann N Y Acad Sci. 2002;977:196-21512480752
Google ScholarCrossref 5.Roman GC. Vascular dementia: distinguishing characteristics, treatment, and prevention.
J Am Geriatr Soc. 2003;51:S296-S30412801386
Google ScholarCrossref 6.Lim A, Tsuang D, Kukull W.
et al. Clinico-neuropathological correlation of Alzheimer's disease in
a community-based case series.
J Am Geriatr Soc. 1999;47:564-56910323650
Google Scholar 7.Massoud F, Devi G, Stern Y.
et al. A clinicopathological comparison of community-based and clinic-based
cohorts of patients with dementia.
Arch Neurol. 1999;56:1368-137310555657
Google ScholarCrossref 8.Neuropathology Group of the Medical Research Council Cognitive Function
and Ageing Study (MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based
population in England and Wales.
Lancet. 2001;357:169-17511213093
Google ScholarCrossref 9.Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A. The Consortium to Establish a Registry for Alzheimer's Disease
(CERAD), X: neuropathology confirmation of the clinical diagnosis of Alzheimer's
disease.
Neurology. 1995;45:461-4667898697
Google ScholarCrossref 10.Tangarorang G, Kerins G, Besdine R. Clinical approach to the older patient: an overview, in Cassel C, Leipzig
R, Cohen H, Larson E, Meier D, eds: Geriatric Medicine. New York, NY: Springer-Verlag; 2003:149-162
11.Hachinski VC, Iliff LD, Zilhka E.
et al. Cerebral blood flow in dementia.
Arch Neurol. 1975;32:632-6371164215
Google ScholarCrossref 12.World Health Organization. The ICD-10 Classification of Mental and Behavioral
Disorders: Diagnostic Criteria for Research. Geneva, Switzerland: World Health Organization; 1993
13.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition. Washington, DC: American Psychiatric Association; 1994
14.McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop:
diagnosis and treatment. Consortium on Dementia with Lewy Bodies.
Neurology. 1999;53:902-90510496243
Google ScholarCrossref 15.Riekse R, Leverenz J, McCormick W.
et al. Effect of vascular lesions on cognition in Alzheimer's disease:
a community-based study.
J Am Geriatr Soc. 2004;52:1442-144815341544
Google ScholarCrossref 16.Wolfe N, Babikian VL, Linn RT, Knoefel JE, D'Esposito M, Albert ML. Are multiple cerebral infarcts synergistic?
Arch Neurol. 1994;51:211-2158304847
Google ScholarCrossref 17.Hachinski V. Preventable senility: a call for action against the vascular dementias.
Lancet. 1992;340:645-6481355217
Google ScholarCrossref 18.Honig L, Tang M-XAS, Costa R.
et al. Stroke and the risk of Alzheimer disease.
Arch Neurol. 2003;60:1707-171214676044
Google ScholarCrossref 19.Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease: inflammation,
cholesterol, and misfolded proteins.
Lancet. 2004;363:1139-114615064035
Google ScholarCrossref 20.Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors
for cognitive decline in elderly persons.
JAMA. 1999;282:40-4610404910
Google ScholarCrossref 22.Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's
disease combined with cerebrovascular disease: a randomised trial.
Lancet. 2002;359:1283-129011965273
Google ScholarCrossref 23.Kumar V, Anand R, Messina J, Hartman R, Veach J. An efficacy and safety analysis of Exelon in Alzheimer's disease
patients with concurrent vascular risk factors.
Eur J Neurol. 2000;7:159-16910809936
Google ScholarCrossref 24.Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients
with Alzheimer's disease.
Neurology. 1998;50:136-1459443470
Google ScholarCrossref 25.Courtney C, Farrell D, Gray R.
et al. Long-term donepezil treatment in 565 patients with Alzheimer's
disease (AD2000): randomised double-blind trial.
Lancet. 2004;363:2105-211515220031
Google ScholarCrossref 26.Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease.
N Engl J Med. 2003;348:1333-134112672860
Google ScholarCrossref 27.Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease
already receiving donepezil: a randomized controlled trial.
JAMA. 2004;291:317-32414734594
Google ScholarCrossref 28.Sano M, Ernesto C, Thomas RG.
et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment
for Alzheimer's disease: the Alzheimer's Disease Cooperative Study.
N Engl J Med. 1997;336:1216-12229110909
Google ScholarCrossref 29.Wilkinson D, Doody R, Helme R.
et al. Donepezil in vascular dementia: a randomized, placebo-controlled study.
Neurology. 2003;61:479-48612939421
Google ScholarCrossref 30.Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate
vascular dementia: a randomized, placebo-controlled trial (MMM 300).
Stroke. 2002;33:1834-183912105362
Google ScholarCrossref 31.Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit
and efficacy in severely demented patients during treatment with memantine).
Int J Geriatr Psychiatry. 1999;14:135-14610885864
Google ScholarCrossref 32.Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses
of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial.
Pharmacopsychiatry. 2003;36:297-30314663654
Google ScholarCrossref 33.van Dongen M, van Rossum E, Kessels A, Sielhorst H, Knipschild P. Ginkgo for elderly people with dementia and age-associated memory impairment:
a randomized clinical trial.
J Clin Epidemiol. 2003;56:367-37612767414
Google ScholarCrossref 34.Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract
of Ginkgo biloba for dementia.
JAMA. 1997;278:1327-13329343463
Google ScholarCrossref 35.Forette F, Seux ML, Staessen JA.
et al. Prevention of dementia in randomised double-blind placebo-controlled
Systolic Hypertension in Europe (Syst-Eur) trial.
Lancet. 1998;352:1347-13519802273
Google ScholarCrossref 36.Forette F, Seux ML, Staessen JA.
et al. The prevention of dementia with antihypertensive treatment: new evidence
from the Systolic Hypertension in Europe (Syst-Eur) study.
Arch Intern Med. 2002;162:2046-205212374512
Google ScholarCrossref 37.Shepherd J, Blauw GJ, Murphy MB.
et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial.
Lancet. 2002;360:1623-163012457784
Google ScholarCrossref 38.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin
in 20536 high-risk individuals: a randomised placebo-controlled trial.
Lancet. 2002;360:7-2212114036
Google ScholarCrossref 39.Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other
major vascular events in 20536 people with cerebrovascular disease or other
high-risk conditions.
Lancet. 2004;363:757-76715016485
Google ScholarCrossref 40.Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias.
Ann Neurol. 1980;7:486-4887396427
Google ScholarCrossref 41.Malouf R, Birks J. Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev. 2004; CD004395
42.Glynn RJ, Beckett LA, Hebert LE, Morris MC, Scherr PA, Evans DA. Current and remote blood pressure and cognitive decline.
JAMA. 1999;281:438-4459952204
Google ScholarCrossref 43.Kivipelto M, Helkala EL, Laakso MP.
et al. Midlife vascular risk factors and Alzheimer's disease in later
life: longitudinal, population based study.
BMJ. 2001;322:1447-145111408299
Google ScholarCrossref 44.Murray M, Lane K, Gao S.
et al. Preservation of congnitive function with antihypertensive medications.
Arch Intern Med. 2002;162:2090-209612374517
Google ScholarCrossref 45.Kivipelto M, Helkala E, Hanninen T.
et al. Midlife vascular risk factors and late-life mild cognitive impairment.
Neurology. 2001;56:1683-168911425934
Google ScholarCrossref 46.Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum lipoprotein levels, statin use, and cognitive function in older
women.
Arch Neurol. 2002;59:378-38411890840
Google ScholarCrossref 47.Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia.
Lancet. 2000;356:1627-163111089820
Google ScholarCrossref 48.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;57:1439-144311030795
Google ScholarCrossref 49.Rockwood K, Kirkland S, Hogan DB.
et al. Use of lipid-lowering agents, indication bias, and the risk of dementia
in community-dwelling elderly people.
Arch Neurol. 2002;59:223-22711843693
Google ScholarCrossref 50.Li G, Higdon R, Kukull W.
et al. Statin therapy and risk of dementia in the elderly: a community-based
prospective cohort study.
Neurology. 2004;63:1624-1628
Google ScholarCrossref 51.Scott HD, Laake K. Statins for the prevention of Alzheimer's disease. Cochrane Database Syst Rev. 2001;(4):CD00316011687176
52.Nilsson SE, Johansson B, Takkinen S.
et al. Does aspirin protect against Alzheimer's dementia? a study in
a Swedish population-based sample aged > or =80 years.
Eur J Clin Pharmacol. 2003;59:313-31912827329
Google ScholarCrossref 53.Williams PS, Rands G, Orrel M, Spector A. Aspirin for vascular dementia. Cochrane Database Syst Rev. 2000;(4):CD00129611034710
54.Doody RS, Stevens JC, Beck C.
et al. Practice parameter: management of dementia (an evidence-based review):
report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2001;56:1154-116611342679
Google ScholarCrossref 55.Tabet N, Birks J, Grimley Evans J. Vitamin E for Alzheimer's disease. Cochrane Database Syst Rev. 2000;(4):CD00285411034775
56.Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2002;(4):CD00312012519586
57.Grady D. Minimal benefit is seen in drugs for Alzheimer's. New York Times. April 7, 2004:1A
59.Karlawish JH, Casarett DJ, James BD, Tenhave T, Clark CM, Asch DA. Why would caregivers not want to treat their relative's Alzheimer's
disease?
J Am Geriatr Soc. 2003;51:1391-139714511158
Google ScholarCrossref 60.Sachs GA. Dementia and the goals of care.
J Am Geriatr Soc. 1998;46:782-7839625199
Google Scholar 61.Cummings J. Use of cholinesterase inhibitors in clinical practice.
Am J Geriatr Psychiatry. 2003;11:131-14512611743
Google Scholar 62.Clark C, Karlawish J. Alzheimer disease: current concepts and emerging diagnostic and therapeutic
strategies.
Ann Intern Med. 2003;138:400-41012614093
Google ScholarCrossref 63.Grossberg G, Desai A. Management of Alzheimer's disease.
J Gerontol A Biol Sci Med Sci. 2003;58A:331-35312663697
Google ScholarCrossref 64.Alexander GC, Casalino LP, Meltzer DO. Patient-physician communication about out-of-pocket costs.
JAMA. 2003;290:953-95812928475
Google ScholarCrossref 65.Haan MN, Wallace R. Can dementia be prevented? brain aging in a population-based context.
Annu Rev Public Health. 2004;25:1-2415015910
Google ScholarCrossref 66.Larson EB, Shadlen MF, Wang L.
et al. Survival after initial diagnosis of Alzheimer disease.
Ann Intern Med. 2004;140:501-50915068977
Google ScholarCrossref 67.Phelan EA, Anderson LA, LaCroix AZ, Larson EB. Older adults' views of “successful aging”—how
do they compare with researchers' definitions?
J Am Geriatr Soc. 2004;52:211-21614728629
Google ScholarCrossref 68.Drachman DA. Occam's razor, geriatric syndromes, and the dizzy patient.
Ann Intern Med. 2000;132:403-40410691591
Google ScholarCrossref 69.Hilliard AA, Weinberger SE, Tierney LM Jr, Midthun DE, Saint S. Clinical problem-solving. Occam's razor versus Saint's triad.
N Engl J Med. 2004;350:599-60314762188
Google ScholarCrossref