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Biomarkers of Alzheimer's disease and exercise One step closer to prevention.

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Biomarkers of Alzheimer’s Disease and
Exercise: One Step Closer to Prevention
he prevalence of dementia is expected to rise dramatically in the upcoming decades, and interventions
that decrease or delay cognitive impairment are critical to
identify. However, to date, the identification of these interventions has been elusive. Physical activity has recently
emerged as one of the most promising strategies for dementia prevention.1 Numerous studies have reported that
people who are physically active in mid-life and late-life
have a lower risk of developing cognitive impairment and
dementia in later life. In addition, physically active elderly
people have slower rates of cognitive decline than those
who are inactive. Several randomized controlled trials confirm that exercise can improve cognition including in people with mild cognitive impairment, but results are less
consistent than observational associations.2
There are several mechanisms that may underlie the
association between physical activity and reduced risk of
cognitive decline and dementia. These include reductions in
vascular disease, inflammation, and insulin resistance, all of
which are inter-related and have been associated with risk of
cognitive impairment. Physical activity has been shown to
increase neurogenesis and synaptic plasticity in rodent models and to favorably modify amyloid-b (Ab) deposition and
tau hyperphosphorylation in transgenic mouse models of
Alzheimer’s disease (AD).3,4 This existence of plausible biological mechanisms provides further evidence in support of
a causal association between physical activity and reduced
risk of dementia. However, establishing a causal association
is the Sisyphean task of observational studies and several
equally promising strategies to prevent dementia have failed
in large primary prevention trials.5
In this setting, the investigation by Liang and colleagues6 is a welcome addition. The investigators explore
the association between physical activity and biomarkers
of AD, specifically cerebrospinal fluid (CSF) level of
amyloid-b (Ab) 42, tau, and phosphorylated tau (ptau)
181, and Pittsburgh Compound B (PIB) binding on
positron emission tomography (PET) scans. The study
included 69 nondemented elders, as determined with the
Clinical Dementia Rating (CDR) scale, who received
PET scans and CSF analysis for biomarker measurement.
The AD biomarkers were dichotomized into ‘‘at risk’’ or
‘‘normal’’ levels. After an average of several years, the participants were interviewed with a telephone assessment of
exercise including past 10-year participation in walking,
running, and jogging. Two primary analyses were conducted. In 1, older adults with ‘‘at risk’’ profiles of PIB
binding demonstrated significantly lower mean exercise
levels. The other analysis reversed predictor and outcome
and found that adults meeting American Heart Association recommendations for weekly exercise had lower continuous measurement of PIB binding and higher CSF Ab
42 level compared to those not meeting criteria recommendations. CSF tau and ptau levels did not differ across
activity groups.
While compelling, several issues challenge the conclusion that physical activity results in lower biomarkers
of AD. The authors describe this as a cross-sectional
study, but unusually, physical activity assessment was
conducted an average of several years after biomarker
evaluation (time range not provided), possibly resulting
in misclassification of exercise level at the time of biomarker measurement. However, this would most likely
lead to a bias toward the null and recent evidence suggests that the effects of physical activity on late-life cognitive function operate across the life course.7 It is notable that many types of physical activity and all
nonvoluntary activity were not assessed.
The authors report no statistically significant differences between many characteristics of the physically active
group compared to the nonactive group and therefore performed limited covariate adjustment. Yet the sample size is
small (10–11 in the active group) and several differences,
assumingly not statistically significant, are notable. The
importance of these differences is unclear, but many of the
variables have been associated with AD biomarker level.
These include education, age, apolipoprotein E e4, body
mass index, and several cardiovascular risk factors such as
hypertension and heart disease. After only controlling for
basic demographics, some of the unadjusted findings
between the ‘‘at risk’’ profile and exercise became nonsignificant; one wonders if residual confounding remains.
C 2010 American Neurological Association
of Neurology
Another important question is the nature of the
association between physical activity and AD biomarker
profile. The authors assume a cause-effect relationship
with those less active having greater biomarkers. Yet it
is possible that an ‘‘effect-cause’’ association exists. The
use of the CDR as the sole measure of cognitive status
is problematic and it is possible, especially given the
time lag, that those participants who developed minor
cognitive deficits were subsequently less active. This
possibility is not helped by the fact that the investigators flipped predictor and outcome in their 2 primary
analyses. While those who exercised regularly had more
favorable biomarker profiles, the authors also conclude,
‘‘individuals potentially at greater risk for AD engaged
in less exercise.’’ It is hard to imagine the mechanism
for this unless mediated by changes in cognition or
These issues notwithstanding, the study by Liang
and colleagues6 is a model for future investigations of dementia prevention strategies. Before large and very expensive randomized controlled trials can be undertaken, evidence of biomarker reduction associated with a candidate
agent from observational or small interventional studies
is critical. This proof of concept strategy should be conducted for promising interventional agents. In the case of
physical activity, this study moves us closer to a clear biological pathway, less amyloid-b accumulation, that most
likely underlies the important emerging evidence that
physical activity can prevent dementia.
Potential Conflicts of Interest
Nothing to report.
Kristine Yaffe, MD1,2
Departments of Psychiatry, Neurology, and Epidemiology and
Biostatistics, University of California, San Francisco, San Francisco, CA
Department of Psychiatry, Veterans Affairs Medical Center,
San Francisco, CA
Middleton LE, Yaffe K. Promising strategies for the prevention of
dementia. Arch Neurol 2009;66:1210–1215.
Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 2008;300:1027–1037.
Adlard PA, Perreau VM, Pop V, Cotman CW. Voluntary exercise
decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci 2005;25:4217–4221.
Leem Y, Lim H, Shim S, et al. Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse
model of tauopathies. J Neurosci Res 2009;87:2561–2570.
Coley N, Andrieu S, Gardette V, et al. Dementia prevention:
methodological explanations for inconsistent results. Epidemiol
Rev 2008;30:35–66.
Liang K, Mintun M, Fagan A, et al. Exercise and Alzheimer’s disease biomarkers in cognitively normal older adults. Ann Neurol
Middleton L, Barnes D, Lui LY, Yaffe K. Physical activity over the
life course and its association with cognitive performance and
impairment in old age. J Am Geriatr Soc 2010;58:1322–1326.
DOI: 10.1002/ana.22143
Volume 68, No. 3
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step, closer, exercises, one, biomarkers, disease, prevention, alzheimers
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