Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

Jensen, Christer; Portelius, Erik; Siersma, Volkert; Høgh, Peter; Wermuth, Lene; Blennow, Kaj; Zetterberg, Henrik; Waldemar, Gunhild; Hasselbalch, Steen G.; Simonsen, Anja Hviid

doi:10.1159/000449408

Cited by 49 publications

(44 citation statements)

References 43 publications

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“…This was observed for whole brain as well as for regional CBF in the frontal precuneus. The absence of detectable changes induced by the 16-week exercise intervention is in line with results from other modalities in this study ( Hoffmann et al, 2016 ; Sobol et al, 2016 ; Steen Jensen et al, 2016 ). Yet, an effect of exercise has been reported on several neuropsychological and physical function tests in the ADEX trial ( Hoffmann et al, 2016 ; Sobol et al, 2016 ).…”

Section: Discussionsupporting

confidence: 91%

The effect of physical exercise on cerebral blood flow in Alzheimer's disease

Kleij

Petersen

Siebner

et al. 2018

NeuroImage: Clinical

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In recent years there has been an increasing focus on the relation between cerebrovascular health, physical exercise and Alzheimer's disease. The aim of the current study was to determine the effect of moderate-to-high-intensity aerobic exercise on cerebral blood flow in patients with mild to moderate Alzheimer's disease. Fifty-one patients were randomized to either usual care or moderate-to-high intensity aerobic exercise for 16 weeks. Exercise had no consistent effect on whole brain or regional cerebral blood flow. Sixteen weeks of exercise are, therefore, not sufficient to produce a consistent increase in cerebral blood flow in a relatively small sample of Alzheimer's patients.

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Section: Discussionsupporting

confidence: 91%

The effect of physical exercise on cerebral blood flow in Alzheimer's disease

Kleij

Petersen

Siebner

et al. 2018

NeuroImage: Clinical

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“…In addition, other studies showed no effects of exercise on Aβ levels in mouse models of AD 41,42 . Further, a patient study with exercise intervention found no effects on Aβ levels in CSF 43 , similar to what we observed in CSF from our 5xFAD mice. Hence, the clinical benefits regarding the effect of exercise on Aβ pathology in AD indicated in other experimental studies can be questioned.…”

Section: Discussionsupporting

confidence: 89%

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease

Svensson

Andersson

Manouchehrian

et al. 2020

Sci Rep

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Physical exercise has been suggested to reduce the risk of developing Alzheimer's disease (AD) as well as ameliorate the progression of the disease. However, we recently published results from two large epidemiological studies showing no such beneficial effects on the development of AD. In addition, long-term, voluntary running in the 5xFAD mouse model of AD did not affect levels of soluble amyloid beta (Aβ), synaptic proteins or cognitive function. In this follow-up study, we investigate whether running could impact other pathological aspects of the disease, such as insoluble Aβ levels, the neuroinflammatory response and non-cognitive behavioral impairments. We investigated the effects of 24 weeks of voluntary wheel running in female 5xFAD mice (n = 30) starting at 2-3 months of age, before substantial extracellular plaque formation. Running mice developed hindlimb clasping earlier (p = 0.009) compared to sedentary controls. Further, running exacerbated the exploratory behavior in Elevated plus maze (p = 0.001) and anxiety in Open field (p = 0.024) tests. Additionally, microglia, cytokines and insoluble Aβ levels were not affected. Taken together, our findings suggest that voluntary wheel running is not a beneficial intervention to halt disease progression in 5xFAD mice.Alzheimer's disease (AD) is the most common form of dementia, affecting around 30 million people worldwide (WHO 2016). Even though cognitive dysfunction is a hallmark of AD, a majority of AD patients also suffer from other, non-cognitive symptoms such as depression and anxiety 1,2 . AD is characterized by accumulation of extracellular amyloid-beta (Aβ) plaques and progressive neurodegeneration. Further, the inflammatory response is also altered in the AD brain 3 . Postmortem studies using AD brains have revealed than pro-inflammatory cytokines, such as IL-1β and IL-6, accumulate around Aβ plaques 4,5 . In addition, microglial activation is increased 6 and correlates with the Aβ deposition 7,8 . Recently, a genome-wide association study revealed that genetics variants related to increased risk of developing AD are specifically enriched in enhancers of myeloid cells 9 . Interestingly, microglia are capable of phagocytosing Aβ aggregates and, thereby, facilitate Aβ clearance 10 . Contrastingly, neuronal Aβ production can induce cytokines in microglia and this can up-regulate the expression and enzymatic activity of β-secretase, thereby enhancing Aβ production 11 . Thus, it is likely that the microglial response in the AD brain contribute with both protective and harmful effects. Hence, future therapeutic interventions may focus on modulating different aspects of these responses.Several studies suggest that physical exercise is beneficial by reducing the risk of AD and slowing the progression of the pathology 12-14 . Exercise intervention may improve cognition 15,16 and ameliorate Aβ levels in patients 17 . Moreover, exercise was associated with larger gray matter volumes in cortex and hippocampus and improved cortical connectivity of cognitive netwo...

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“…However, we found no significant effect of EXE on our selected biomarkers. In a previous study, we also did not find effect on Ab species and tau/p-tau [9]. These markers, however, may provide novel insight into AD pathology and its progression [16,18,26].…”

Section: Discussioncontrasting

confidence: 44%

“…All subjects donated a blood sample before and after intervention and were tested at baseline and at 16 week follow-up with a comprehensive battery of tests of CF, activities of daily function, quality of life, physical activity, and neuropsychiatric symptoms. For details of inclusion and exclusion criteria, methods for inclusion, and cognitive and physical tests, see Steen Jensen et al [9]. A subgroup of 56 subjects recruited from three of eight centers had a lumbar puncture performed to collect CSF samples before and after intervention.…”

Section: Study Populationmentioning

confidence: 99%

“…Furthermore, in an effort to arrest the decline in cognitive function (CF) and loss of activities of daily living, nonpharmacological approaches have been investigated. In the randomized clinical trial "Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study," we analyzed the effect of 16 weeks moderate-to high-intensity physical exercise (EXE) in patients with AD on a cognitive [7], functional [8], and molecular level [9]. Despite some effect on clinical symptoms such as processing speed and neuropsychiatric symptoms [7], we found no effect of EXE on levels of Ab, tau, and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) [9].…”

Section: Introductionmentioning

confidence: 99%

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[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

Jensen

Portelius

Høgh

et al. 2017

Alzheimer's & Dementia

Self Cite

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Introduction: Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid b and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity. Methods: Cerebrospinal fluid (CSF) from 51 AD subjects who participated in the randomized controlled trial Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) was analyzed for the concentration of neurofilament light (NFL), neurogranin (Ng), visinin-like protein-1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Participants were subjected to either 16 weeks of moderate-to highintensity exercise (n 5 25) or treatment as usual (control group, n 5 26), and CSF was collected before and after intervention. Results: No significant differences in CSF concentrations of VILIP-1, YKL-40, NFL, and Ng were observed when comparing mean change from baseline between the exercise and control groups. Similarly, when classifying subjects based on their exercise levels, no significant changes were observed for the biomarkers in the control group compared with the high-exercise group (attending 80% of the exercise sessions with an intensity of 70% of maximum heart rate or above). Discussion: These results are not supportive of a modulatory effect of physical exercise on the selected biomarkers of neuronal and synaptic integrity in patients with AD.

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Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

Cited by 49 publications

References 43 publications

The effect of physical exercise on cerebral blood flow in Alzheimer's disease

The effect of physical exercise on cerebral blood flow in Alzheimer's disease

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

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