

































Association between IL-6 and 
Caregiving for People Living with 
Dementia (PLWD) and Potential 

Interventions
Kush Modi

 
GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

Volume Four
Edition One
Spring 2024

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1Georgetown University, Washington DC, USA 
Email: kmm488@georgetown.edu 
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According to the World Health Organization (WHO), there are approximately 55 million people worldwide 
that are currently diagnosed with dementia.2 Informal caregivers, such as family and friends, of people living 
with dementia (PLWD) cover more than 50% of the total cost of caregiving.2 Apart from the cost, caregivers 
to PLWD also spend a significant amount of time (four hours) every day caring for dementia patients.2 This 
leads to a significant amount of financial, emotional and social stress on a daily basis which has been shown 
to lead to an exaggerated proinflammatory response and increased blood and serum levels of Interleukin-6 
(IL-6), a tightly regulated cytokine. IL-6 binds to the IL-6 receptor, leading to the homodimerization of 
transmembrane gp130 and thus initiating a signaling cascade that eventually leads to a proinflammatory 
response. Excessive proinflammatory markers, such as IL-6, can affect the profibrinolytic and anticoagulant 
effects of endothelial cells, leading to an increased likelihood of cardio-cerebrovascular diseases (CCVDs), 
such as heart failure (HF), myocardial infarction (MI), ischemic stroke (IS), and atherosclerosis. Therefore, 
an intervention for caregivers to PLWD may be helpful in mitigating caregivers’ risk of developing cardio-
cerebrovascular diseases, but further research is necessary to establish causation.  This paper reviews literature 
that explores the association between IL-6 levels and caregiving status of individuals. Topics covered will 
include rates of IL-6 increase in caregivers, persistence of IL-6 increase post-caregiving, and potential 
interventions to reduce IL-6 levels in caregivers to PLWD. 
Keywords: dementia, caregiving, IL-6, cardiovascular, cerebrovascular 
 
IInnttrroodduuccttiioonn    

Dementia is the acquired loss of cognitive 
functioning in multiple cognitive domains that 
interferes with day-to-day activities.1 In 2019, 
dementia cost the global economy approximately 1.3 
trillion US Dollars.2 Of the 1.3 trillion USD, 
approximately 16%  was attributed to direct medical 
costs, 34% was attributed to direct social sector costs, 
and 50% was attributed to informal caregivers (such 
as family and friends) that spend approximately four 
hours per day caring for the dementia patients.3 This 

large toll is partly due to the increasing number of 
dementia cases worldwide. According to the World 
Health Organization (WHO), there are 
approximately 55 million people worldwide that 
have been diagnosed with dementia.2 These 
numbers are predicted to increase exponentially over 
the next few decades as we face an aging population 
worldwide.   
 However, some of the most overlooked problems 
in the field of dementia caregiving are the 
physiological effects that informal caregivers face 

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when caring for dementia patients. Informal 
caregivers are those that provide care to family and 
friends, usually for no payment.  These informal 
caregivers of people living with dementia (PLWD) 
face financial, social, and emotional challenges on a 
daily basis as they care for their loved ones. These 
recurrent stressors may lead to an increased level of 
proinflammatory biomarkers, such as IL-6, which 
can lead to a myriad of health problems. 14% of the 
informal caregivers of PLWD are their elderly 
spouses, further exacerbating the physiological 
health consequences of caregiving due to old age.  
 Interleukin-6 or IL-6 is a tightly regulated 
proinflammatory cytokine that is quantified from 
blood and serum samples. It is usually present in low 
levels in healthy individuals, but is present in high 
levels in those with chronic stress. It is a 
multifunctional glycoprotein that is approximately 
184 amino acids long and weighs 26 kDa.4 It is 
produced by mononuclear macrophages, T helper 2 
cells, B cells, vascular endothelial cells, smooth 
muscle cells and fibroblasts.5 IL-6 binds to the IL-
6R (IL-6 receptor), a cell surface receptor, which 
then starts a signaling cascade. The binding activates 
the gp130 transduction complex, causing gp130 
dimerization.5 This leads to Janus kinase (JAK) 
activation, which then causes phosphorylation of 
signal transducers and activators of transcription 
(STAT).5 gp130 dimerization also causes 
recruitment of SH2-containing protein tyrosine 
phosphatase 2 (SHP2), which activates 
phosphatidylinositol 3-kinase (PI3K) and mitogen-
activated protein kinase (MAPK) pathways.5 These 
lead to a variety of downstream events, including 
acute phase response (response to local or systemic 
disturbances caused in its homeostasis) , infection 
defense and metabolism, including glucose 
homeostasis. Indeed, chronically high levels of IL-6 
have been associated with higher levels of mortality.6 
 Inflammation is one of the main mechanisms 
used by the body to counter infections, tissue injuries 
and stress. However, if the inflammatory response 
becomes prolonged and out of control, it can lead to 
the accumulation of cytokines, releasing toxic 

substances that can lead to cell death. Excessive 
inflammatory responses also affect the anticoagulant 
and profibrinolytic ability of endothelial cells. 
Therefore, high levels of IL-6, a proinflammatory 
cytokine, over long periods of time can lead to a 
range of physiological changes, such as enhanced 
angiogenesis and hypertension.7,8  
 Past research has suggested a strong link 
between higher IL-6 levels and incidence of heart 
failure (HF), myocardial infarction (MI), ischemic 
stroke (IS), atherosclerosis and other cardio-
cerebrovascular diseases (CCVDs).5 CCVDs are 
conditions that involve restricted flow of blood to a 
particular part of the body (usually the heart and 
brain) due to narrowing of the blood vessels, 
formation of clots, or blockage and rupture of blood 
vessels.9 Zhang et al. treated rats with acute 
myocardial infarction (AMI) with simvastatin, a 
drug that reduces IL-6 levels, leading to a reduction 
in collagen deposition in noninfarcted myocardium 
and improvement in cardiac function.10 
Additionally, Biasucci et al. demonstrate that IL-6 
levels are elevated in patients with an unstable 
angina, further suggesting an association between 
IL-6 and CCVDs.11 Research has suggested that this 
link between IL-6 and CCVDs may be mediated by 
increased production of C-reactive protein (CRP) in 
the liver. This, in turn, leads to the recruitment of 
leukocytes and thrombosis which increases the risk 
for developing CCVDs.5  

High IL-6 levels known to be associated with 
many different types of stress. However, for the 
premises of this paper, we will focus only on the 
correlation between high IL-6 levels and caregivers 
to people living with dementia.   

Caring for family members with dementia can 
cause informal caregivers, including family and 
friends, to experience fatigue and chronic stress. 
This may lead to increased levels of IL-6 over long 
periods of time, which, as discussed above, can be 
detrimental to the person’s health. This paper aims 
to describe recent research on the association 
between IL-6 and informal caregiving for dementia 

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patients and to discuss past studies which have 
assessed psychosocial interventions to reduce IL-6 
and potential future directions for the field.   
MMeetthhooddoollooggyy  

The first part of the paper focuses on the 
association between IL-6 levels and caregiving for 
dementia patients. Due to the low number of 
research studies performed specifically on this 
relationship, not many limitations could be applied 
while researching studies relevant to this paper. 
However, only studies conducted in the last 25 years 
were considered for this review. In addition, only 
studies measuring IL-6 levels in caregivers of 
dementia patients were considered. It was also 
ensured that all studies had non-caregivers as the 
control group. The second part of this paper focused 
on discussing research studies that tested 
interventions to reduce IL-6 levels in caregivers to 
dementia patients. Again, due to the lack of much 
research in this field, not too many limitations could 
be applied for this review. Only studies in the last 15 
years (since 2009) were considered for this review. In 
addition, only papers that tested interventions 
specifically on caregivers to dementia patients were 
included in this review. Lastly, only studies that used 
IL-6 levels as a measure of intervention efficacy were 
included in the review.  
11..  AAssssoocciiaattiioonn  ooff  IILL--66  lleevveellss  aanndd  CCaarreeggiivviinngg  ffoorr  
DDeemmeennttiiaa  PPaattiieennttss    
 Past research has suggested a link between 
negative and stressful emotions and production of 
IL-6 levels. Recurrent stressful experiences can cause 
dysregulation of the hypothalamic-pituitary-adrenal 
(HPA) axis, which controls the stress response, and 
leads to an exaggerated production of IL-6. 
Caregivers for dementia patients are expected to 
have higher levels of stress due their caregiving 
activities and the behavioral symptoms of dementia 
patients, such as sleep disturbances and agitation. 
Hence, it is expected that caregivers of dementia 
patients may have significantly higher levels of IL-6 
compared to non-caregivers. In the following 

section, this paper reviews studies that explore the 
association between IL-6 levels and caregiving for 
dementia patients.    
11..11  NNuummbbeerr  ooff  SSttrreessssoorrss  aanndd  CCaarreeggiivviinngg  SSttaattuuss  

Gouin et al. (2012) conducted a cross-sectional 
study that included 53 caregivers and 77 controls 
(non-caregivers).12 It measured the number of daily 
stressors that each participant had experienced over 
the past 24h and collected blood samples to detect 
serum IL-6 and CRP levels.  

Results suggested that caregiving status was 
significantly associated with the report of multiple 
stressors compared to the absence of stressors in the 
past 24h. Approximately 50% of the caregivers 
reported multiple daily stressors compared to 
approximately 25% of non-caregivers.12 However, 
caregiver status was not significantly related to the 
presence of one stressor or no stressors in the past 
24h. This means that caregivers were more likely to 
have reported multiple stressors in the past 24h, but 
not more likely to have reported one stressor or no 
stressor compared to non-caregivers.  

Results also found that the number of daily 
stressors was related to IL-6 levels regardless of 
caregiving status. Those participants that had 
experienced multiple stressors in the past 24h were 
measured by blood samples to have higher IL-6 
levels than those that experienced zero stressors. 
Their IL-6 levels were also higher, although not 
significantly, than those that had reported just one 
stressor in the past 24h. This suggests that IL-6 
levels were, in fact, positively associated with the 
number of stressors.  

However, the study did not show a significant 
association between caregiving status and IL-6 
levels. Caregivers were more likely to report multiple 
daily stressors, yet still did not have significantly 
higher IL-6 levels compared to non-caregivers. This 
is contradictory to the understanding that stress is 
correlated to elevated levels of IL-6 that other 
studies show. For example, Carpenter et al. reported 
that early childhood stress leads to higher IL-6 

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concentrations over time.13 One reason for this 
discrepancy in results may be due to the differences 
in timing of measurement of IL-6 concentrations. In 
this study, the IL-6 levels were only measured over 
24h and a better understanding of the association 
between caregiving status and IL-6 may be yielded 
by measuring proinflammatory marker levels over 
multiple days.  

The study did, however, show a significant 
relationship between caregiving status and CRP 
levels. Caregivers were measured to have higher 
CRP levels than non-caregivers. These results are 
again puzzling because IL-6 stimulates the hepatic 
synthesis of CRP, but this study did not show an 
association between caregiving status and IL-6.14 
This also suggests the need to increase the number 
of IL-6 measurements taken in future studies. 
However, since CRP is a marker of 
atherothrombotic vascular disease, this study does 
support the overarching hypothesis that caregiving 
for dementia patients is associated with higher risk 
of CCVDs in caregivers.  
11..22  EEffffeecctt  ooff  GGeennddeerr  aanndd  DDeemmeennttiiaa  SSeevveerriittyy  oonn  
IILL--66  lleevveellss    
 Mills et al. (2008) explored the effects that 
gender and dementia severity have on IL-6 levels in 
spousal caregivers of dementia patients.15 It aimed to 
examine whether one gender was at a higher risk 
from caregiving and whether caring for a patient 
with more severe dementia led to greater IL-6 levels. 
81 caregivers and 41 non-caregivers were included in 
the study.15  
 Consistent with expectations, dementia 
caregivers reported significantly greater frequency, 
severity and distress from behavioral symptoms of 
dementia patients compared to non-caregivers. 
Results also suggested that dementia caregivers 
caring for spouses with moderate to severe dementia 
reported higher frequency, severity and distress from 
behavioral symptoms compared to caregivers caring 
for spouses with questionable to mild dementia. 
Analyses also suggested that IL-6 levels were higher 
in male and female caregivers for spouses with 

moderate to severe dementia compared to non-
caregivers. 

The study results also showed that females had 
significantly higher levels of role overload stress 
(stress that is caused by one’s perception of the 
demands of caregiving exceeding the available 
resources) compared to males. However, contrary to 
this, IL-6 levels were elevated up to 28 to 38% in 
males caring for spouses with moderate to severe 
dementia (high CDR) compared to other 
caregivers.15 These higher IL-6 levels in males may 
be due to the results found that male caregivers spent 
more time awake after sleep onset than female 
caregivers caring for dementia spouses with 
moderate to severe dementia. This poorer sleep 
outcome in male caregivers may lead to increased 
IL-6 levels and worse physical functioning.16  

This study indicates that more research is needed 
to look at the differences in the coping strategies 
employed for caregiving stress by male and female 
caregivers. This will provide more insight into the 
understanding of role overload stress and IL-6 level 
differences seen in this study between males and 
females. Additionally, only one IL-6 level 
measurement was taken. Future studies should 
include more IL-6 measurements over several days 
to better understand the role that gender and 
dementia severity plays on IL-6 levels in spousal 
caregivers of dementia patients.  
11..33  LLoonnggiittuuddiinnaall  SSttuuddyy  ttoo  EExxpplloorree  AAssssoocciiaattiioonn  ooff  
IILL--66  LLeevveellss  aanndd  CCaarreeggiivviinngg  SSttaattuuss  

  Unlike the studies discussed earlier, Kiecolt-
Glaser et al. (2003) observed the IL-6 levels in 
caregivers over a period of 6 years.17 As mentioned 
before, a longitudinal study enables researchers to 
better understand the pattern of IL-6 in relation to 
the chronic stress due to caregiving. The study 
analyzed IL-6 levels from plasma samples of those 
caregivers that were at least 55 years old and had at 
least two samples across six consecutive years.17 The 
dementia patients of multiple caregivers died over 
the 6 years, which provided new insight in IL-6 
levels after caregiving activity has ceased.  

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 The study used data points to create a model of 
change in IL-6 levels in caregivers and non-
caregivers with age as a predictor of IL-6 levels.17 
Predicted IL-6 levels were modeled to increase in 
caregivers at an average rate that is approximately 
four times greater than that of non-caregivers.17 
Results from the study also suggested that caregivers 
reported higher stress than controls over the 6 years 
compared to non-caregivers.17 This again suggests 
that caregivers of dementia patients suffer from 
higher stress and IL-6 levels, and increases the 
likelihood that there is an association between 
caregiving status and IL-6 levels.  
 IL-6 data was also analyzed between two groups: 
one group included data from current caregivers and 
the other group included post-caregiving data from 
former caregivers (former caregivers are those 
individuals whose spouses with dementia died before 
or during the course of the study). The results found 
that there was no statistically significant difference 
in the absolute levels or average rate of change of IL-
6 levels between former caregivers and current 
caregivers.17 This may be explained by the 
understanding that chronic stress can permanently 
alter the inflammatory response mechanism such 
that subsequent stressors would produce exaggerated 
proinflammatory responses and hence higher 
proinflammatory cytokine levels.17 This suggests 
that even after the caregiving ends upon the death of 
the family member with dementia, the physiological 
downsides of prolonged caregiving remain due to 
prolonged inflammatory responses.  
 The demographic data collected over the course 
of the study also provided some interesting results. 
After controlling for age, males had significantly 
higher levels of IL-6 than females for two out of the 
six years in the study. This increases confidence in 
the results that were discussed in the previous study 
(Mills et al., 2008) and provides a longitudinal look 
at the effect that gender plays on IL-6 levels.15 
Additionally, data also indicated that African 
Americans had significantly higher IL-6 levels than 
non-African Americans for four out of the six years 
of the study. These higher IL-6 levels in African 

Americans can be attributed to the racial and 
economic disparities that exist in healthcare.18  
 Overall, this study provides key longitudinal 
insights into the relationship between caregiving for 
a dementia family member and IL-6 levels. The 
results that IL-6 levels increased at a faster average 
rate in caregivers compared to non-caregivers further 
provides evidence to the understanding that long-
term stress can worsen physiological functioning 
faster than normal aging. Additionally, this study 
highlights key populations that are at higher risk 
from dementia caregiving activities, including males 
and African Americans. Future longitudinal studies 
should attempt to record more IL-6 data over a 
longer period to better understand IL-6 level trends 
over time.  
11..44  IILL--66  lleevveellss  aafftteerr  aaccttiivvaattiioonn  ooff  tthhee  iinnffllaammmmaattoorryy  
rreessppoonnssee  bbyy  vvaacccciinnaattiioonn    
 Segerstrom et al. (2008) looked at how chronic 
stress due to dementia caregiving can lead to reduced 
antibody production and higher IL-6 levels after 
influenza vaccination. The study also looked at how 
repetitive thoughts, which are recurrent and 
prolonged thoughts about oneself and one’s 
experiences, can alter stress outcomes and IL-6 
levels.19 These repetitive thoughts can be negative 
(e.g., worrying) or neutral (e.g., reflection), which 
can alter IL-6 levels in caregivers differently. As 
discussed earlier in the paper, stress activates the 
inflammatory responses and hence leads to higher 
levels of IL-6. Additionally, vaccinations also 
stimulate the immune system, which leads to higher 
IL-6 levels post-vaccination in caregivers than non-
caregivers.20 
 The results suggested that there was no 
significant difference in the levels of negative or 
neutral repetitive thoughts between caregivers and 
non-caregivers. This means that caregivers are not 
more likely to engage in negative repetitive thoughts 
than non-caregivers, despite their higher level of 
daily stress from caregiving.  

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It was found that negative repetitive thoughts 
were associated with higher levels of IL-6 both pre- 
and post-vaccination compared to neutral repetitive 
thoughts, but this was not a significant difference.19 

With increasing levels of neutral repetitive thought, 
controls saw lower levels of IL-6 post-vaccine.19 
However, with increasing levels of neutral repetitive 
thoughts, caregivers saw higher levels of IL-6 post-
vaccine.19 Despite the higher frequency of neutral 
repetitive thoughts, the inflammatory response of 
caregivers due to chronic stress is more prolonged, 
leading to higher IL-6 levels.  

Results also indicated that caregivers had higher 
IL-6 levels pre-vaccination compared to controls, 
although not significantly. After controlling for pre-
vaccination levels, results indicated that caregivers 
had significantly higher IL-6 levels at 4 weeks post-
vaccination compared to non-caregiver controls.19 
This suggests that caregivers had elevations in IL-6, 
due to vaccinations, that were more prolonged than 
non-caregivers, which may be attributable to higher 
chronic stress due to caregiving.19 IL-6 levels in 
caregivers were also seen to be independent of 
depression levels.  

This study was crucial in suggesting the long-
term physiological effect that caregiving stress had 
on caregivers for people living with dementia. 
Caregivers, despite increasing neutral repetitive 
thought, were shown to have higher IL-6 levels 
post- influenza vaccination. This may be because the 
caregivers’ daily stressful environment and the 
repetitive thoughts leads to an inflammatory 
response and, actually, a more prolonged response. 
In addition, this prolonged response leads to IL-6 
levels remaining higher for a longer period of time, 
increasing the risk of cardio- and cerebrovascular 
diseases. This study also clearly shows how the 
repetitive thought pattern of caregivers can be 
improved through future interventions to reduce 
these health risks. Future studies should aim to 
gather post-vaccination IL-6 data more frequently 
for a better understanding of the prolonged immune 
response. 

11..55  SSuummmmaarryy  
The research studies highlighted above have 

been crucial in understanding how daily caregiving 
activities of caregivers for PLWD impact blood IL-
6 levels. Results discussed earlier have indicated that 
caregivers face an increased level of daily stress due 
to their caregiving burdens and responsibilities. For 
example, Gouin et al. (2012) suggested that 
caregivers were more likely to have reported multiple 
stressors in the past 24h compared to non-
caregivers.12 This higher level of stress 
overstimulates the proinflammatory response and 
hence may lead to higher levels of IL-6 in caregivers.  

In the 6-year longitudinal study, it was found 
that the IL-6 levels were increased in caregivers at a 
rate approximately 4 times faster than non-
caregivers.17 Additionally, studies have shown that 
caregivers have an inflammation response that is 
prolonged with the proinflammatory cytokine, IL-6, 
levels remaining elevated for longer. Kiecolt-Glaser 
et al. (2008) showed that there were no significant 
differences in IL-6 levels between current caregivers 
and former caregivers.17 This suggests that the 
effects of caregiving are long-lasting, possibly due to 
the chronic stress permanently altering the 
inflammatory response, prolonging and 
exaggerating it.  

Results from studies on dementia caregivers have 
also suggested that disparities do exist in the extent 
to which caregiving stress affects IL-6 levels. Males 
were reported to have significantly higher levels of 
IL-6 compared to females in two out of the six years 
in a longitudinal study.17 In the same study, African 
Americans were reported to have significantly higher 
IL-6 levels in four out of the six years that were 
studied.17  

The research studies that have been discussed so 
far support the understanding that caregivers for 
people living with dementia are burdened with a 
higher level of stress than non-caregivers, and hence 
have a higher level of IL-6. However, future studies 
should focus on observing the patterns of IL-6 levels 
with more frequent recordings. These results could 

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help develop new interventions to reduce the IL-6 
levels of dementia caregivers and improve long-term 
physiological health outcomes.  
22..  IInntteerrvveennttiioonnss  ffoorr  DDeemmeennttiiaa  CCaarreeggiivveerrss    
  The previous section of the paper reviewed 
research establishing the link between stress and IL-
6. Dementia caregivers, on average, tend to 
experience high daily stress due to their caregiving 
activities, and hence tend to have high IL-6 levels. 
These high IL-6 levels have been linked to various 
physiological consequences for the caregivers. For 
example, a study established that high IL-6 levels in 
dementia caregivers significantly predicted 
emergency department visits during a 15-month 
follow-up from when the IL-6 levels were 
measured.21  
 Due to this higher physiological risk, there is an 
increasing need and urgency to develop an effective 
intervention to reduce IL-6 levels amongst dementia 
caregivers. This section reviews some studies aiming 
to advance the development of an intervention 
program for caregivers of patients with dementia. 
22..11  PPootteennttiiaall  IInntteerrvveennttiioonn  UUssiinngg  CCooppiinngg  SSeellff--
EEffffiiccaaccyy  aass  aa  TTooooll    

 Mausbach et al. (2011) attempted to understand 
the association between coping self-efficacy (CSE) 
and circulating IL-6 levels in caregivers to patients 
with dementia in order to suggest a potential future 
intervention to reduce IL-6 levels.22 Coping self-
efficacy (CSE) is a measure of one’s confidence in 
performing strategies or behaviors necessary to 
confront and respond to challenges.23 Past studies 
have shown that CSE reduces the secretion of 
catecholamines, a class of neurotransmitters and 
hormones. Since IL-6 secretion is known to be 
stimulated by catecholamines, CSE may effectively 
reduce IL-6 levels in caregivers.  
 The results suggests that the relation between 
stress (as measured by The Role Overload scale) and 
IL-6 levels changes with the level of coping self-
efficacy (CSE).22 Stress was found to be significantly 
associated with IL-6 levels when CSE levels were 

low, but not when CSE levels were high.22 When 
CSE was low, the plasma IL-6 levels increase with 
increasing levels of caregiving stress. With higher 
CSE, the plasma IL-6 levels decrease with 
increasing levels of caregiving stress. This is likely 
due to the self-efficacy reducing the sympathetic 
response to stress, hence reducing the IL-6 
concentrations.22 Caregivers with low levels of self-
efficacy would have repeated, more frequent 
activation of the sympathetic system, leading to 
downstream changes that lead to higher IL-6 levels. 
However, caregivers with higher self-efficacy would 
experience less dysregulation of the sympathetic 
nervous system, and hence lower IL-6 levels.  
 These results suggest that future 
psychoeducational interventions for caregivers may 
have benefits in aiming to increase coping self-
efficacy. However, future research is needed before 
deciding to invest further into increasing coping self-
efficacy among caregivers. More studies need to be 
conducted to see how IL-6 levels change from pre- 
to post-coping self-efficacy psychoeducational 
intervention. Additionally, lower IL-6 levels reduce 
the physiological risks of caregiving. Hence, future 
research should also focus on exploring how coping 
self-efficacy interventions may help reduce caregiver 
cardiovascular and cerebrovascular incidents.  
22..22  PPlleeaassaanntt  EEvveennttss  PPrrooggrraamm  ((PPEEPP))  ttoo  RReedduuccee  IILL--
66  LLeevveellss  

    Moore et al. (2013) explored the efficacy of the 
Pleasant Events Program (PEP), a behavioral 
activation intervention, in reducing IL-6 levels in 
caregivers of dementia patients.24 The intervention 
lasted six weeks. Caregivers engaged in sessions to 
learn how to improve their participation in leisure 
activities.24 A control was also used in the study, 
where some participants were randomly assigned to 
a time-equivalent Information-Support (IS) control 
group, which included discussions on general topics 
that are usually explored in caregiver support groups. 
The PEP intervention group mainly focused on 
leisure-related support, whereas the IS group 

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focused on general skills, such as communication 
skills.24 

 IL-6 levels were measured pre- and post-
intervention and one year following the intervention. 
Results suggested that there was a significant 
difference observed post-intervention between the 
PEP and IS group with respect to the change in IL-
6 levels. 20.0% of PEP participants noticed a 50% 
reduction in IL-6 levels compared to only 6.5% of IS 
participants.24 However, this change in IL-6 levels 
from baseline was not significant between the PEP 
and IS groups at the 1-year follow-up. Also, based 
on the Reliable Change Index (RCI) cutoffs, 8.6% 
of PEP participants noticed clinically significant 
change compared to 0% of the IS participants.25   
  The study also observed the physiological 
outcomes of the improved IL-6 levels by measuring 
depression levels in caregivers using the Center for 
Epidemiological Studies Depression (CESD) scale. 
Similar to IL-6, the study showed there was a 
significant difference observed post-intervention 
between the PEP and IS groups with respect to 
change in the CESD score. 32.7% of the PEP 
participants showed a 50% reduction in depression 
levels compared to only 11.8% of IS participants.24 
Based on the RCI cutoff, 27.9% of PEP participants 
demonstrated a clinically significant decrease in 
depression levels compared to only 9.3% of IS 
participants.24 However, this change in depression 
levels was not significantly different between the 
PEP and IS groups at the 1-year follow-up. A 
significant difference in negative affect levels was 
also measured between the groups at the post-
intervention measurement, but not at the 1-year 
follow-up.  
 The significant reduction in IL-6 levels from 
pre- to post-intervention suggests that the Pleasant 
Events Program (PEP) intervention was more 
successful compared to the active Information-
Support (IS) control. The PEP delivers significant 
physiological changes as seen with the reductions in 
depression and negative affect levels. Although more 
research is needed, this study suggests that PEP may 

help reduce frequent activation of the sympathetic 
nervous system, which leads to higher IL-6 levels 
and other physiological symptoms.  
 PEP also appears more useful compared to other 
interventions due to its ease in implementation and 
distribution among dementia caregivers. However, 
more studies need to be conducted with adaptations 
to improve PEP efficacy over the long-term before 
it can be disseminated to caregivers. Future research 
needs to test PEP interventions that have longer 
lasting effects and have booster sessions after the 
intervention is completed. Nevertheless, these 
preliminary PEP results bring hope of a more 
convenient way to reduce IL-6 levels and improve 
physiology of caregivers for patients with dementia.  
22..33  AA  LLoonnggeerr  PPlleeaassaanntt  EEvveennttss  PPrrooggrraamm  ((PPEEPP))    
 The previous study prompted alterations to the 
Pleasant Events Program (PEP) intervention by 
extending the time period to 12 weeks compared to 
the previous 6-week program. von Kanel et al. 
(2020) explored the efficacy of the 12-week PEP 
program in reducing IL-6 levels in caregivers of 
dementia patients.26 This study also used the active 
Information and Support (IS) intervention as the 
control with the caregiving stress levels measured 
pre-treatment and IL-6 levels measured pre- and 
post-treatment.26 No IL-6 levels were taken at 1-
year following the intervention, which were taken in 
the 6-week program.26  
 Contrary to the previous 6-week study’s results, 
this study did not show any significant time-by-
treatment interaction.26 This suggests that the PEP 
intervention did not significantly decrease IL-6 
levels compared to the IS active control. Additional 
analysis also suggested that there were no significant 
time effects, which means that there was no 
significant reduction in IL-6 levels from pre- to 
post-intervention for all the participants combined 
regardless of the treatments.26 The treatment effect 
was also not significant, which means that the pre- 
and post-treatment IL-6 levels in the PEP and IS 
treatment groups separately were not significantly 
different.26  

14



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 Although the study did not show PEP to 
significantly reduce IL-6 levels, indicators of 
caregiving stress did show significant interactions. 
There was a higher chance of caregivers showing a 
significant reduction in IL-6 when they had a higher 
level of personal mastery, which is having a greater 
skill set to tackle situations,. With a one-unit 
increase in personal mastery pre-treatment, there 
was a 19.6% chance of a decrease in IL-6 levels from 
pre- to post-treatment.26 Also, with a one-unit 
increase in the distress due to caring for a patient’s 
behavioral symptoms, there was a 2.4-fold greater 
chance of reduction in IL-6 levels.26 These results 
align with our understanding since higher personal 
mastery would allow one to deal with stressful 
caregiving situations more effectively, and the PEP 
study would help lower IL-6 levels further. 
Additionally, those caregivers who care for dementia 
patients with more frequent and severe behavioral 
symptoms would have a higher level of stress and 
would benefit more from the PEP intervention.  
 As mentioned above, these results are 
contradictory to those from the 6-week program, 
which showed a significant reduction in IL-6 levels 
in the PEP group compared to the IS group. This 
can be attributed to several differences between the 
6-week and 12-week study. One difference is the 
treatment duration: the results suggest that the 
shorter intervention is more effective. This may be 
because longer interventions are more burdensome 
on the participants.27 The longer intervention may 
also lead to a decrease in overall interest and morale 
of the participants, which may have some 
physiological effects. Additionally, the results 
suggest that PEP may be helpful for caregivers with 
higher personal mastery levels and those caring for 
dementia patients with higher severity and frequency 
of behavioral symptoms.  
22..44  SSuummmmaarryy  
 Higher IL-6 levels have been linked to increased 
severity of illnesses, like pneumonia, and higher 
mortality rates due to its association with increased 
risk of cardiovascular and cerebrovascular 

incidents.28 Dementia caregivers tend to have a 
significantly higher IL-6 level compared to non-
caregivers, exposing them to these higher risks. 
Therefore, it is crucial to establish a 
psychoeducational intervention that helps caregivers 
of dementia patients to reduce their IL-6 levels.  
 The studies reviewed above provide promising 
results. Mausbach et al. (2011) suggested that IL-6 
levels were significantly associated with stress when 
coping self-efficacy (CSE) levels of dementia 
caregivers were low.22 However, IL-6 was not 
associated with stress when CSE levels were high, 
which means that coping self-efficacy practices allow 
caregivers to have lower IL-6 levels despite the 
caregiving stress. Future studies are still needed to 
explore whether coping self-efficacy (CSE) 
interventions reduce IL-6 levels from pre- to post-
intervention.  
 The Pleasant Events Program (PEP) studies 
discussed above also show promising results. PEP 
aims to help caregivers for dementia patients 
increase their ability to participate in leisure activities 
and pursue their interests despite their caregiving 
responsibilities. The 6-week study showed that PEP 
was successful with significant reductions in IL-6 
levels from pre- to post-intervention. The shorter 
PEP also showed positive physiological results as it 
showed significant reductions in depression and 
negative affect. However, the 12-week PEP study 
did not show significant reductions in IL-6 levels 
from pre- to post-intervention, which may suggest 
that longer interventions may have reduced 
effectiveness.  

Psychoeducational interventions may help 
caregivers for dementia patients by reducing the 
frequency of activation of their sympathetic nervous 
system caused by stress, thereby reducing IL-6 
levels. However, more research, with different types 
of intervention delivery methods and structures, 
needs to be performed before marketing these 
interventions to caregivers for dementia patients. 
For example, more frequent intervention sessions in 

15



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�

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a shorter period may potentially yield better results 
for caregivers.  
CCoonncclluussiioonn    
 The research studies discussed over the course of 
this paper have provided key highlights on the 
association between IL-6 levels and caregiving 
activities for people living with dementia. Caregivers 
are known to face a higher level of daily stress and 
burden due to their increased responsibilities and 
costs. The 6-year longitudinal study discussed earlier 
showed that IL-6 levels in caregivers were predicted 
to increase at a rate approximately 4 times faster than 
in non-caregivers.17 Kiecolt-Glaser et al. (2003) also 
showed that there were no significant differences in 
IL-6 levels between current and former caregivers, 
which suggests that the physiological effects of the 
caregiving and increased stress may be more long-
term in nature.17  

This association between IL-6 levels and 
caregiving can be explained by the idea that the stress 
from caregiving overstimulates the proinflammatory 
response and leads to higher IL-6 levels. 
Additionally, these effects are more long-term 
potentially due to the stress having a more 
permanent effect by prolonging the 
proinflammatory response and keeping the IL-6 
production levels elevated.  
 Higher IL-6 levels over an extended period of 
time can have several physiological consequences. 
For example, it can affect the anticoagulant and 
profibrinolytic capabilities of endothelial cells. This 
leads to a higher risk of blood clots and hence cardio-
cerebrovascular diseases, such as heart failure, 
myocardial infarction, ischemic stroke, and 
atherosclerosis.5 Due to these risk factors, it is crucial 
that the caregivers for PLWD receive an 
intervention to reduce their IL-6 levels.  
 Moving forward, more research is needed to help 
develop interventions to reduce IL-6 levels in 
caregivers. Psychoeducation interventions with 
different delivery methods, such as virtual training, 
online modules, and in-person sessions, along with 

different time frames, such as a 1-month versus 6-
month training, need to be tested to create the most 
effective intervention. Additionally, mindfulness 
and meditation interventions, and physical activity 
interventions, such as yoga, need to be studied as 
potential methods to reduce IL-6 levels in 
caregivers.  
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