Trials and Treatments for Vascular Brain Health: Risk Factor Modification and Cognitive Outcomes - FINGERS ...
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Stroke
FOCUSED UPDATES: BRAIN HEALTH
Trials and Treatments for Vascular Brain Health:
Risk Factor Modification and Cognitive Outcomes
Miia Kivipelto , MD, PhD; Katie Palmer , PhD; Tina D. Hoang, MPH; Kristine Yaffe , MD
ABSTRACT: There is robust evidence linking vascular health to brain health, cognition, and dementia. In this article, we present
evidence from trials of vascular risk factor treatment on cognitive outcomes. We summarize findings from randomized controlled
trials of antihypertensives, lipid-lowering medications, diabetes treatments (including antidiabetic drugs versus placebo, and
intensive versus standard glycemic control), and multidomain interventions (that target several domains simultaneously such as
control of vascular and metabolic factors, nutrition, physical activity, and cognitive stimulation etc). We report that evidence on
the efficacy of vascular risk reduction interventions is promising, but not yet conclusive, and several methodological limitations
hamper interpretation. Evidence mainly comes from high-income countries and, as cognition and dementia have not been the
primary outcomes of many trials, evaluation of cognitive changes have often been limited. As the cognitive aging process occurs
over decades, it is unclear whether treatment during the late-life window is optimal for dementia prevention, yet older individuals
have been the target of most trials thus far. Further, many trials have not been powered to explore interactions with modifiers
such as age, race, and apolipoprotein E, even though sub-analyses from some trials indicate that the success of interventions
differs depending on patient characteristics. Due to the complex multifactorial etiology of dementia, and variations in risk factors
between individuals, multidomain interventions targeting several risk factors and mechanisms are likely to be needed and the
long-term sustainability of preventive interventions will require personalized approaches that could be facilitated by digital health
tools. This is especially relevant during the COVID-19 pandemic, where intervention strategies will need to be adapted to the
new normal, when face-to-face engagement with participants is limited and public health measures may create changes in
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lifestyle that affect individuals’ vascular risk profiles and subsequent risk of cognitive decline.
Key Words: alzheimer dementia ◼ antihypertensive agents ◼ brain ◼ cognition ◼ dementia ◼ glycemic control ◼ lipids
T
here is robust evidence linking vascular health to brain Hypertension, hypercholesterolemia, and diabetes are
health including for cognitive decline and risk of demen- associated with increased inflammation, cerebrovascu-
tia. It is estimated that over 50 million adults are living lar injury, damage to white matter integrity8–10 as well as
with dementia worldwide,1 and in the next 50 years, that greater amyloid burden.11–13 These risk factors are also
prevalence is projected to triple.2 Thus, intervention strate- linked with atherosclerosis which can contribute to reduced
gies to delay or reduce cognitive impairment could have a cerebral blood flow and hypoxia and further disrupt amyloid
significant impact on the global burden of disease.3,4 Criti- clearance.14,15 This suggests that treatment of vascular risk
cally, vascular risk factors including hypertension, high cho- factors could have a role in prevention of AD and vascular
lesterol, and diabetes are both common and modifiable.5,6 dementia. In addition, less than a third of clinical AD patients
have pure AD pathology16; many people diagnosed with
clinical dementia, including AD, demonstrate mixed pathol-
See related articles, pages 391, 394, 404, 416, 427, 437, 444 ogy often with a vascular component.17–21 Among vulner-
able populations, including Black and Hispanic older adults
as well as the oldest old, the prevalence of mixed pathol-
Vascular risk factors have been linked to pathological ogy is even greater.22–26 Treatment of vascular risk factors
markers of both vascular dementia and Alzheimer dis- could, therefore, target multiple pathways affecting cogni-
ease (AD),7 the 2 most common subtypes of dementia. tive health and dementia mechanisms.
Correspondence to: Miia Kivipelto, MD, PhD, Karolinska Institute, Karolinska Universitetssjukhuset, Karolinska Vägen 37 A, QA32, 171 64 Solna, Sweden. Email miia.
kivipelto@ki.se
For Sources of Funding and Disclosures, see page 453.
© 2022 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str
444 February 2022 Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614Kivipelto et al Interventions to Prevent Cognitive Decline
Nonstandard Abbreviations and Acronyms SMARRT Systematic Multi-Domain
FOCUSED UPDATES
Alzheimer’s Risk Reduction Trial
ACCORD MIND Action to Control Cardio- SPRINT MIND Systolic Blood Pressure
vascular Risk in Diabetes Intervention Trial Memory
Memory in Diabetes and Cognition in Decreased
ACCORDION MIND Action to Control Cardiovas- Hypertension
cular Risk in Diabetes Follow- Syst-Eur Systolic Hypertension in Europe
On Memory in Diabetes TICSm modified Telephone Interview
ACE angiotensin-converting enzyme for Cognitive Status
AD Alzheimer disease TRANSCEND Telmisartan Randomized
ADVANCE Action in Diabetes and Vas- Assessment Study in ACE
cular Disease: Preterax and Intolerant Subjects With Car-
Diamicron Modified Release diovascular Disease
Controlled Evaluation TRIPOD transparent reporting of a mul-
AHEAD Action for Health in Diabetes tivariable prediction model for
individual prognosis or diagnosis
APOE apolipoprotein E
BP blood pressure
CAIDE Cardiovascular Risk Factors, Observational cohort studies have also shown that vas-
Aging and Dementia cular factors are among the most critical risk factors for
CSF cerebrospinal fluid cognitive decline and dementia.27–29 The findings are most
consistent for hypertension and high blood pressure (BP),
CVD cardiovascular disease
particularly in population-based studies of midlife exposure
FINGER Finnish Geriatric Intervention
and late-life cognitive outcomes.14,29,30 Results for high cho-
Study to Prevent Cognitive
Impairment and Disability lesterol also highlight the importance of midlife exposure.31
Diabetes is also associated with an increased risk of cogni-
HATICE Healthy Ageing Through
Internet Counselling in the tive decline, dementia, and AD,32–34 estimated to be a 1.25-
Elderly to 1.91-fold excess risk for cognitive disorders (cognitive
HOPE-3 Heart Outcomes Prevention impairment, mild cognitive impairment [MCI], and demen-
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Evaluation-3 tia),33 and an association is also seen for both prediabe-
HYVET-Cog Hypertension in the Very tes and changes in glucose metabolism.33,35 Meta-analyses
Elderly Trial Cognitive Func- of antihypertensive and statin use in observational studies
tion Assessment further support a beneficial relationship between vascular
LIFE Lifestyle Interventions and risk factor treatment and lowered risk of developing demen-
Independence for Elders tia.36,37 In addition, trend data from multiple studies suggest
MAPT Multidomain Alzheimer Pre- that the incidence of dementia has decreased over the last
ventive Trial few decades38–40; mostly observed in high-income coun-
MCI mild cognitive impairment tries.40 Interestingly, these declines in dementia incidence
MIND Memory in Diabetes coincide with improvements in education but also with
advances in cardiovascular treatment including medications,
MMSE Mini-Mental State Examination
public awareness, and stricter treatment guidelines.41–43
ONTARGET Ongoing Telmisartan Alone
Cumulatively, these data provide compelling evidence to
and in Combination With
Ramipril Global End Point Trial support clinical trials of vascular risk factor treatment to
prevent or delay cognitive decline and dementia.
ORIGIN The Outcome Reduction With
an Initial Glargine Intervention In this article, we present evidence from trials of vascular
risk factor treatment on cognitive outcomes. We summarize
preDIVA Prevention of Dementia by
Intensive Vascular Care findings from randomized controlled trials (RCTs) of anti-
hypertensives, lipid-lowering medications, diabetes treat-
PROSPER Prospective Study of Pravas-
tatin in the Elderly at Risk ments, and multidomain interventions; discuss limitations of
the current evidence; and outline next steps to advance the
RCT randomized controlled trial
field of vascular risk factor treatment for cognitive health.
SCOPE Study on Cognition and Prog-
nosis in the Elderly
SHEP Systolic Hypertension in the
Elderly Program ANTIHYPERTENSIVE TRIALS
While the results are promising, trials of antihyperten-
sive treatment that have evaluated effects on cognitive
Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614 February 2022 445Kivipelto et al Interventions to Prevent Cognitive Decline
outcomes have not uniformly demonstrated benefits on examined the effects of a diuretic (indapamide) with the
cognition. Most early trials with short follow-up (between option of an ACE (angiotensin-converting enzyme) inhib-
FOCUSED UPDATES
9 and 12 months) have reported no benefits for cog- itor (perindopril) compared with placebo in 3336 adults
nitive outcomes,44,45 while results from RCTs with more at least 80 years and older with hypertension.49 Investi-
extended follow-up periods, between 2 and 5 years, as gators found no significant difference in risk of develop-
well as those trials with large samples sizes have reported ing dementia, defined as Mini-Mental State Examination
both positive effects and no effects on cognitive out- (MMSE) scoreKivipelto et al Interventions to Prevent Cognitive Decline
at baseline; n=1626 with follow-up cognitive testing), the a statin compared with placebo.59,60 Another RCT of
antihypertensive treatment group was not significantly dif- adults aged 35 to 70 years old with hypercholesterol-
FOCUSED UPDATES
ferent from the placebo group on changes in psychomotor emia reported greater cognitive decline, albeit a modest
speed, attention, and global cognition (modified Montreal amount, in the treatment group compared with placebo
Cognitive Assessment) after 5 years of follow-up. over 6 months, but baseline differences in cognitive test-
ing may have explained this finding.61
Intensive BP Control
SPRINT MIND Trial
More recently, the SPRINT MIND trial (Systolic Blood Evidence From Large-Scale RCTs
Pressure Intervention Trial Memory and Cognition in The Heart Protection Study
Decreased Hypertension) targeted intensive BP control, The Heart Protection Study randomized 20 536 adults,
a goal of 120 mm Hg, and compared this to the standard aged 40 to 80, with CVD and diabetes to simvastatin or
goal of 140 mm Hg among older adults with hypertension to placebo. The primary outcomes of interest were cardio-
and increased cardiovascular risk.54 Treatment regimens vascular events and mortality. After 5 years of follow-up,
were not standardized, but investigators recommended there were no differences between the statin treatment
thiazide-type diuretics as the primary agent. Cogni- group and placebo on cognitive decline as determined
tive function was assessed with tests of global cogni- by the modified Telephone Interview for Cognitive Status
tion, learning and memory, and processing speed while Questionnaire.62
evaluation of MCI and dementia included more extensive
screening and an adjudication process prompted by low Prospective Study of Pravastatin in the Elderly at
cognitive performance. The trial was terminated early at Risk
3.3 years due to the benefits for the primary outcome PROSPER (Prospective Study of Pravastatin in the
of cardiovascular events, but follow-up extended to 5.1 Elderly at Risk),63 a RCT of 5804 adults aged 70 to 82
years. Participants in the intensive BP treatment group years old with vascular disease or high vascular risk,
were less likely to develop MCI/dementia; however, compared treatment with pravastatin to placebo for the
there were no domain specific differences on cognition.55 prevention of cardiovascular events. Global cognition,
Early studies of antihypertensives with short treatment, executive function, and processing speed were assessed
short follow-up, and measures of cognitive outcomes over time. After 3 years, no difference in cognitive decline
with low sensitivity often did not report reductions in risk. on any domain was observed between the treatment and
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Studies with longer follow-up and more sensitive assess- placebo groups.
ments of cognitive outcomes have suggested some ben- Heart Outcomes Prevention Evaluation-3
efits for dementia and MCI. Meta-analyses of trial data HOPE-3 also randomized participants with CVD to a
have reported generally protective associations, ≈10% statin treatment arm for the prevention of cardiovascular
reduction in dementia risk, but often not reaching the events. The cognitive substudy reported no significant
level of significance,49,56–58 likely due to heterogeneity in difference comparing statin treatment to the placebo
design, populations, treatments, and outcomes. An early group on changes in psychomotor speed, attention, and
meta-analysis of antihypertensive treatment and risk of global cognition after 5.7 years.64
dementia included 4 trials: Syst-Eur, PROGRESS (Per- Despite the interest in statins and lipids as prevention
indopril Protection Against Recurrent Stroke Study), strategies for cognitive impairment and dementia, random-
SHEP, and HYVET and reported a pooled Relative Risk ized trials, to date, have not shown any benefits for cognitive
of 0.87 (95% CI, 0.76–1.00; P=0·045).49 A more recent outcomes. There are fewer meta-analyses of lipid-lowering
and expanded meta-analysis of twelve RCTs including RCTs due to the limited number of studies, but a Cochrane
SPRINT MIND (n=92 135), found that antihypertensive review in 2016 identified four RCTs of statins with no ben-
treatment was associated with a significant reduction in efits for brain health as assessed by the Alzheimer Disease
risk of dementia or cognitive impairment compared with Assessment Scale—Cognitive Subscale (mean difference,
controls (odds ratio, 0.93 [95% CI, 0.88–0.98]) with −0.26 [95% CI, −1.05 to 0.52]) or on MMSE (mean differ-
a similar reduction in risk of cognitive decline (8 trials, ence, −0.32 [95% CI, −0.71 to 0.06]).65
n=67 476; odds ratio, 0.93 [95% CI, 0.88-0.99]).56
DIABETES TREATMENT TRIALS
LIPID-LOWERING TRIALS Trials aiming to prevent cognitive decline and dementia
There are fewer RCTs of lipid-lowering treatment with in persons with diabetes have mainly focused on three
cognitive outcomes. Two small studies, one of older types of interventions: antidiabetic treatments versus
adults and another of adults 25 to 60 years, both with placebo, intensive versus standard glycemic control, and
high lipid levels and normal cognition, reported no dif- dietary or physical activity interventions. Currently, there
ference in cognition after 6 months of treatment with is no high-quality trial evidence to show that medications
Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614 February 2022 447Kivipelto et al Interventions to Prevent Cognitive Decline
for glycemic control have an effect on cognitive decline it was concluded that the intensive glycemic, BP or lipid
or incidence of dementia.66,67 Indeed, a meta-analyses interventions in diabetes patients had no long-term effect
FOCUSED UPDATES
on 24 297 diabetes patients from 5 RCTs concluded on cognition or brain structure outcomes in this trial.
that intensive glycemic control was not associated with
The Outcome Reduction With an Initial Glargine
a slower rate of cognitive decline than standard man-
Intervention
agement.68 Another review reported that there is some
The ORIGIN trial (Outcome Reduction With an Initial
evidence for improvement in cognitive functioning in
Glargine Intervention)74 was initiated to examine whether
patients with diabetes undergoing physical activity inter-
targeting normal fasting glucose levels with insulin
ventions, though studies were few and mainly had small
reduces CVD events in persons aged 50 or over with
sample sizes.69 Details from some of the larger studies
dysglycemia and HbA1cKivipelto et al Interventions to Prevent Cognitive Decline
However, patterns differed according to baseline health renin system inhibitors did not confer a benefit.85 A sec-
factors; participants who were overweight but not obese ond meta-analysis of observational studies also found
FOCUSED UPDATES
or had a history of CVD at the start of the trial showed the that calcium channel blockers and angiotensin receptor
most benefits.81 Although the trials on physical activity in blockers were associated with lower risk of dementia.86
diabetes have shown some positive results on slowing Aside from direct effects through vascular mechanisms,
cognitive decline, discrepancies between epidemiologi- calcium channel blockers and angiotensin receptor block-
cal and clinical trial evidence should be considered. Epi- ers may also interact with amyloid clearing pathways.87
demiological data showing the risk of reduced physical Statins may also vary in effectiveness due to differences
activity on both diabetes and cognitive decline likely in lipophilicity and blood brain barrier permeability.88,89 A
reflect life-long exercise habits whereas short-term trials clearer understanding of dose response effects for each
aimed at increasing physical activity in persons who were treatment is also needed.90,91
sedentary during, for example, midlife, might not be suf- Previous trials have focused almost exclusively on older
ficient to modify cognitive outcomes in diabetes patients. adults, with most participants in their late sixties and early
There is a discrepancy between research from epi- seventies. Given that the cognitive aging process occurs
demiological studies and results from intervention trials. over decades, it is unclear whether treatment during the
Although diabetes has consistently been shown to be late-life window is optimal for the prevention of cogni-
associated with an increased risk of dementia and cogni- tive decline and dementia. Observational data suggests
tive impairment,32,33 so far there is no clear evidence from that the association between vascular health and cogni-
the above trials that intensive glycemic control in diabe- tive outcomes is most consistent for midlife exposures. In
tes modifies cognitive decline or dementia incidence. addition, many previous trials focused on preventing cog-
nitive decline in people with an already existing hyperten-
sion, hypercholesteremia, or diabetes diagnosis, but this
LIMITATIONS OF PRIOR might not be the most efficacious moment to initiate pre-
ventative strategies. It is plausible that the mechanisms
ANTIHYPERTENSIVE, LIPID-LOWERING, linking vascular risk factors to dementia may be more
AND DIABETES TREATMENT TRIALS difficult to reverse once a diagnosis has occurred and,
While there are encouraging results from treatment trials therefore, interventions do not generate the same effect
of vascular risk factors, more rigorous data are needed if they are initiated before the threshold of vascular dis-
in several areas.82 Cognitive decline and dementia have ease diagnosis is met when the underlying mechanisms
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not been the primary or even the secondary outcomes of that are linked to subsequent cognitive impairment may
previous trials, and evaluation of cognitive changes have already be ongoing for decades.
often been limited with some studies lacking baseline Unfortunately, many trials have not been powered
cognitive function.83 Cognitive outcomes have tended to explore interactions with critical modifiers such as
to use screening tests with low sensitivity which may age, race, and APOE (apolipoprotein E), even though
limit the ability to detect more subtle or domain spe- sub-analyses from some trials indicate different effects
cific effects. Prior studies may have also had insufficient depending on patient characteristics. Therefore, it will be
power to detect cognitive decline over time.84 Because essential to adequately power studies so that it is pos-
antihypertensive and statin therapy provide clear ben- sible to stratify according to specific factors to verify
efit for the primary treatment of CVD, RCTs that with- the heterogenous response that individuals may have
hold standard care in high risk populations would not be to specific interventions. The focus on a population with
ethical. Thus, meta-analysis of existing trials currently genetic susceptibility for dementia is of particular impor-
provide the best evidence. To further advance the field, tance, for example, since within individuals who carry the
future trials of antihypertensive and statin treatment APOE ε4 allele, dementia incidence is almost 4 times
could incorporate more comprehensive cognitive bat- higher in persons with diabetes compared to those with-
teries, assessing a range of cognitive domains, using out diabetes.92
reliable and validated measures, with more extensive
evaluation of dementia (including differentiation of AD
and vascular types).67 Measurement of imaging and fluid MULTIDOMAIN INTERVENTIONS FOR
biomarkers of dementia as outcomes could also improve PREVENTING COGNITIVE DECLINE AND
assessments of vascular treatment efficacy. DEMENTIA
There is evidence to suggest that different types of
antihypertensives or statins may have varying effects Evidence From Large-Scale RCTs
on cognitive outcomes but, currently, there is a lack of The 2020 Dementia prevention, intervention, and care
comparative data. One meta-analysis of 5 RCTs found report of the Lancet Commission has estimated that
that diuretics and calcium channel blockers were associ- 40% of dementias worldwide might be delayed or pre-
ated with a small reduction in risk of dementia; whereas, vented through the modification of twelve risk factors,
Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614 February 2022 449Kivipelto et al Interventions to Prevent Cognitive Decline
namely, low education, midlife hypertension and obe- The multidomain intervention (cognitive training, physical
sity, diabetes, smoking, excessive alcohol use, physical activity, and nutrition, and 3 preventive consultations) was
FOCUSED UPDATES
inactivity, depression, low social contact, hearing loss, assessed alone or in conjunction with omega 3 polyunsat-
traumatic brain injury, and air pollution.93 This provides urated fatty acid supplementation. The multidomain inter-
the foundation for prevention potential and several pos- vention alone had no significant effects on 3-year change
sible targets and time windows for the interventions. in a composite score of cognitive tests,98 and the results
Though several intervention trials have aimed to modify did not differ between participants with or without frailty.99
separate risk factors, these do not take into account the In post hoc analyses, when pooling participants from the
multifactorial etiology of dementia syndromes. There- 2 multidomain intervention groups (ie, with and without 3
fore, in recent years there has been a focus on multi- polyunsaturated fatty acid supplementation), the interven-
domain interventions that simultaneously target several tion had beneficial effects; decline in the composite cog-
risk factors, which may have better efficacy to pre- nition score and MMSE orientation items was less than in
vent cognitive impairment and dementia and increase persons who did not receive this intervention. Further, in
healthy brain ageing. Below, we summarize the com- persons with an increased risk of dementia (CAIDE score
pleted large-scale multidomain RCTs aiming to prevent ≥6) cognitive decline was less in the combined interven-
or postpone cognitive impairment and dementia. tion group than in the placebo group.
The Finnish Geriatric Intervention Study to Prevention of Dementia by Intensive Vascular
Prevent Cognitive Impairment and Disability Care
One of the first, large RCTs to assess the efficacy of The Dutch preDIVA trial (Prevention of Dementia by
a multidomain lifestyle intervention to prevent cognitive Intensive Vascular Care) is a 6-year, multidomain car-
decline is the FINGER study (Finnish Geriatric Interven- diovascular intervention aimed at preventing dementia
tion Study to Prevent Cognitive Impairment and Dis- in 3526 community-dwelling participants aged 70 to 78
ability).94 It included a 2-year multidomain intervention years.100 The nurse-led intervention consisted of indi-
consisting of nutritional guidance, exercise, cognitive vidually tailored lifestyle advice and drug treatment for
training and social activities, and monitoring and man- cardiovascular risk factors versus usual care. Although
agement of metabolic and vascular risk factors. FIN- there was no significant effect of the intervention on
GER included 1260 older individuals (age 60–77 years) overall dementia incidence, AD, or cognition (MMSE),
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from the general population who were at risk of cog- there was a reduced risk of non-AD dementia in the
nitive decline (measured with the Cardiovascular Risk intervention group. Specifically, the hazard ratio of non-
Factors, Aging and Dementia (CAIDE) Dementia Risk AD dementia, which included mostly vascular dementia
Score, which includes age, sex, education, hypertension, was 0.37, but numbers were low so this result should be
hypercholesterolemia, obesity, and physical inactivity95). interpreted with caution. Further sub-analyses revealed
After 2 years, the intervention showed beneficial effects a reduced risk of dementia in participants with untreated
on global cognition and for the prespecified cognitive baseline hypertension who adhered to the intervention.
sub-domains; executive functioning and processing Although the intervention did not prevent white matter
speed. For complex memory, there was higher improve- hyperintensity progression, there were greater inter-
ment in the intervention group and the risk of cognitive vention effects with increasing baseline white matter
decline was significantly higher in the control group.96 hyperintensity volumes.101
Furthermore, APOE ε4 carriers were shown to ben-
efit from the intervention suggesting that healthy life-
Evidence From Other Multidomain Intervention
style changes may be beneficial for cognition even in
the presence of APOE-related genetic susceptibility to Trials
dementia.97 Extended FINGER follow-ups (currently up In addition to these larger trials, several smaller studies
to 7 years; 11-years in planning) will provide crucial new (ie,Kivipelto et al Interventions to Prevent Cognitive Decline
decline can be prevented. Although there were no sig- is that many dementia syndromes have a long, progressive
nificant effects on MMSE or a composite of 7 cognitive onset, and often require complex assessment methods (eg,
FOCUSED UPDATES
tests, the intervention has been shown to lead to modest neuroimaging, CSF). Most of the currently available trials have
improvements in cardiovascular risk profiles (composite been designed to look at changes in cognitive function as a
primary outcome, and extended follow-ups to evaluate lon-
score of systolic BP, LDL cholesterol, and body mass
ger term outcomes are important. Most studies use a clinical
index).106 Given the recent COVID-19 pandemic and
diagnosis of dementia or changes in neuropsychological test
the need to postpone many research trials and reduce performance as outcomes, without any objective evidence of
face-to-face nonurgent medical services including pre- disease pathology. This makes it challenging to imply any cause
vention programs, initiatives that provide remote support or effect on disease mechanisms. Studies that include biomark-
to older persons to self-manage cardiovascular risk fac- ers (imaging, CSF etc) as outcomes are needed to investigate
tors will become increasingly important. Due to public what effect interventions have in terms of changing or slow-
health measures such as social distancing recommen- ing disease pathology. At the same time, it is becoming clear
dations and lockdowns, many older people are already that dementia is not a feasible outcome in the shorter term. It
experiencing changes in lifestyles that may subsequently has been reported that a cognitively unimpaired, preclinical AD
affect their cardiovascular risk and cognitive function- population (eg, persons with amyloid positivity without cognitive
impairment) declines to the cognitive performance of an early
ing. A remote survey conducted during the first wave of
MCI population in 6 years.110 The observation that clinically
the pandemic on participants from the FINGER study
meaningful decline is reached within 6 years underlines the
showed that physical activity levels reduced in about need to use a cognitive composite in trials that are shorter than
one-third of people and many experienced a reduction in 6 years, since short-term cognitive decline can be conceptual-
social and cognitive activities.107 We cannot yet estimate ized as a proxy for downstream functional changes. With mean-
what long-term affect this will have on vascular risk fac- ingful continuous cognitive changes occurring before a MCI
tors for cognitive impairment in individuals. We currently diagnosis, these results argue against the use of a time-to-MCI
do not know how long the pandemic will continue and end point in preclinical AD trials. Thus, early interventions and
whether vaccinations will provide long-term solutions for surrogate outcomes for the onset of clinically significant cogni-
wide-spread reduction of SARS-CoV-2 infection and, tive impairment and dementia onset should be developed and
therefore, older individuals may need to continue with tested. As an example, the FINGER multidomain intervention
reduced the overall dementia risk according to both Lifestyle
social distancing measures. Remote interventions that
for Brain Health and CAIDE dementia risk scores.111
can effectively enhance their nutritional, physical, cog-
Another important perspective will be to examine a combi-
nitive, and cardiovascular health will be a vital part of
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nation of factors in multidomain interventions that target both
ensuring that preventative programs can be delivered to lifestyle factors and vascular treatments. Two such trials are
at-risk individuals. ongoing, which combine intensive, multidomain lifestyle inter-
ventions with metformin treatment. One targets older, Chinese
adults with MCI and prediabetes or diabetes, while the 2-year
Limitations and Challenges MET-FINGER trial, currently under development, will test the
Limited Evidence From Different Economic Settings efficacy of a multimodal lifestyle intervention, including a phase
Much of the current evidence on multidomain interven- IIB proof of concept metformin trial within trial, in an at-risk
tions comes from Europe and high-income countries. population (ie, APOE e4 enriched). The focus on a population
with genetic susceptibility for dementia is of particular impor-
Future trials in low-income and middle-income countries
tance since within individuals who carry the APOE ε4 allele,
are essential, because it is expected that the largest
dementia incidence is nearly four times higher in persons with
dementia reductions will be possible in low-income and diabetes compared with those without.92
middle-income countries due to the ongoing increase in An additional ongoing multidomain trial in the United
population aging and the high frequency of potentially States, SMARRT (Systematic Multi-Domain Alzheimer’s Risk
modifiable risk factors in these countries.93 The FINGER Reduction Trial) is targeting vascular treatment as well as life-
intervention model is currently being adapted, assessed, style factors and other medical risk factors.112 SMARRT has
and optimized in a diverse range of settings in >30 coun- completed enrollment of adults aged 70 and older with low/
tries as part of World-Wide FINGERS.108,109 Crucially, the normal cognitive performance and at least 2 modifiable risk
network includes research groups from a range of eco- factors. Participants have been randomized to a tailored mul-
nomic and cultural settings that will help establish the tidomain intervention (SMARRT) or to a health education con-
trol group. The SMARRT treatment group will work closely with
optimum methods for multimodal prevention strategies
a behavioral health coach or nurse to develop a personalized
in different populations.
plan aimed at reducing dementia risk factors including hyper-
tension, diabetes, depressive symptoms, poor sleep quality,
contraindicated medications, physical inactivity, low cognitive
METHODOLOGICAL ISSUES stimulation, social isolation, poor diet, and smoking. SMARRT
The interpretation of results from RCTs on multidomain interven- and other ongoing or recently completed trials such as those
tions for preventing cognitive decline and dementia are limited in the World-Wide FINGERS network,108 including for example,
by several methodological challenges. One major complication US-POINTER (United States), MIND-China (China), SINGER
Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614 February 2022 451Kivipelto et al Interventions to Prevent Cognitive Decline
(Singapore), Maintain Your Brain (Australia), J-MINT (Japan), the relevance both of dementia and the potential impor-
Superbrain (Korea), Goiz-Zaindu and Pensa (Spain), AgeWell tance of preventative strategies for them to be effec-
FOCUSED UPDATES
(Germany), and MIND-AD (Sweden, Finland, Germany, and tively implemented. It is also important to consider how
France) will help to further our knowledge on potential person- to actively engage people in preventative interventions
alized approaches to dementia prevention.
and increase adherence to the program. Research has
Further, the timing of interventions is also important in
shown that adherence to multidomain interventions dif-
terms of identifying the most relevant target population who
will benefit most. It is thought that the pathophysiological fers according to the complexity and intensity117 with
process of AD begins many years before the diagnosis of higher adherence levels found for cardiovascular moni-
AD dementia and in 2011 the National Institute on Aging- toring and nutritional counseling and lower for unsuper-
Alzheimer’s Association workgroups created separate diag- vised computer-based cognitive training. Older adults
nostic recommendations for each stage of the disease have expressed strong interest in dementia risk factor
continuum—preclinical, MCI, and dementia,113–115 highlighting reduction.118 In addition, studies suggest they want to
that the long preclinical phase of AD can provide a critical know their personal risk factors and can be highly moti-
opportunity for intervention. Though the most effective time vated to make healthy lifestyle changes to lower demen-
to prevent dementia may be in midlife, there are inherent tia risk. Such findings suggest that future interventions
challenges in designing trials that have enough resources
can be improved by ensuring that technological tools are
and power to effectively follow-up participants to older ages
suitable for older individuals and taking into account par-
where dementia incidence is highest. In the FINGER trial, par-
ticipants were selected using the CAIDE Dementia Risk Score ticipant characteristics, preferably by using individually
identifying persons who have elevated dementia risk during tailored approaches to increase adherence to different
the following 20 years and modifiable risk factors (eg, hyper- components of the multidomain intervention.
tension, hypercholesterolemia, obesity, and physical inactiv-
ity).96 Interestingly, significant benefits on cognition were also
reported among participants in the MAPT trial with a high CONCLUSIONS AND RECOMMENDATIONS
CAIDE score.98 Post hoc analysis of preDIVA revealed that In summary, there is increasing evidence linking vascu-
the intervention was more effective in persons with untreated lar and metabolic risk factors for cognitive impairment
hypertension, further supporting the role of targeted preven-
and dementia later in life. The life-course perspective is
tative strategies in older, at-risk individuals. Further work is
important when addressing this topic since the relevance
needed to develop and validate risk scores or algorithms to
select the most appropriate at-risk groups to the right inter- of these risk factors and conditions may vary at midlife
and late-life. While in general, there is support for the
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ventions (eg, for multidomain lifestyle interventions the risk
score should select individuals with the type of risk profile that notion that “what is good for the heart is good for the
the intervention aims to modify as in the SMARRT trial). In brain,” more evidence is needed concerning optimal
addition, it is important to promote standardized and transpar- interventions (eg, what symptoms or behaviors to target
ent reporting to support appropriate selection risk estimation and which drugs to use), in which people (eg, which cut-
tools for specific purposes, such as the TRIPOD statement offs and tools should be used to defined people at-risk),
(Transparent Reporting of a Multivariable Prediction Model for and how the effect of interventions differs at various life
Individual Prognosis or Diagnosis).116 stages, especially among the oldest old population.
From Knowledge About Risk Factors to Sustainable Given that AD pathology usually co-occurs with vas-
Implementations cular pathology, and that many vascular risk factors are
When moving from research to implementation, several linked to AD risk itself, vascular risk factors are the major
practical considerations should be taken into account. preventable and treatable component of dementia. How-
In 2019, the World Health Organization published the ever, there are several possible mechanisms that may play
first guidelines for Risk Reduction of Cognitive Decline a role in cognitive decline and dementia, including vas-
and Dementia. The guidelines were developed to provide cular, inflammation, oxidative stress, neurodegeneration,
evidence-based recommendations on interventions and brain plasticity, and cognitive reserve; this offers a range
to support implementation. The recommendations under- of potential targets for interventive strategies. Although
line the importance of interventions that are related to the level of evidence for some interventions to reduce
the management of CVD and diabetes and, thus, rec- risk factors for dementia and cognitive decline still needs
ommend that implementation should be combined with to be strengthened, interventions addressing certain risk
ongoing prevention programs because preventative factors such as high BP or glucose are anyway relevant
effects may be optimized by addressing multiple risk for other health benefits, highlighting the importance of
factors at the same time. However, the success of such integrated interventions that might have an effect on
programs relies on the engagement of healthcare provid- several noncommunicable diseases (eg, stroke, CVD,
ers. Though the importance of prevention for CVD and dementia). Indeed, the 2019 World Health Organiza-
diabetes may be clearer because outcomes are more tion guidelines for dementia prevention drew on existing
immediate and clearly identifiable (eg, change in glucose World Health Organization guidelines for the prevention
levels, BP etc) healthcare providers need to understand of other chronic diseases and, as dementia shares many
452 February 2022 Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614Kivipelto et al Interventions to Prevent Cognitive Decline
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454 February 2022 Stroke. 2022;53:444–456. DOI: 10.1161/STROKEAHA.121.032614You can also read
