Visualizing the Role of Neuroinflammation in the Pathophysiology and Management of Alzheimer’s Disease

Chair, Erik Musiek, MD, PhD, prepared useful Practice Aids pertaining to Alzheimer’s disease for this CME activity titled “Visualizing the Role of Neuroinflammation in the Pathophysiology and Management of Alzheimer’s Disease.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/408KAzl. CME credit will be available until March 9, 2026.

1. Understanding the Links Between Neuroinflammation
and Alzheimer?s Disease
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 Microglial activation
Neurotoxic trigger
Aβ plaque and NFT formation
Proinflammatory response
TLR
DAMPs
TNFɑ
IL-1β
IL-4
IL-10
IL-6
IL-18
Damaged neuron
DAMPs bind to TLRs on microglia
and shift their phenotype to an
activated state, initiating microgliosis
Proinflammatory cytokines
damage neurons and promote
formation of Aβ plaques and NFTs
Aβ and NFTs induce
neuron death and
activate local microglia
Neuron death triggers
release of DAMPs
Activated microglia release
proinflammatory cytokines
Chronic Microglial Activation and Neuroinflammation Can Cause a Positive Feedback Loop
That Facilitates the Onset and Progression of AD
1-3

2. Understanding the Links Between Neuroinflammation
and Alzheimer?s Disease
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 •DAM may play a protective role early in the disease course
•Chronic inflammatory response may become more harmful in later stages of disease
•Underscores complex role of microglia in onset and progression of AD
DAM: a subset of CNS
microglia that are found at
sites of neurodegeneration
and express certain genes
TREM2: a receptor expressed
almost exclusively on
macrophages and microglia
DAM express CLEC7A,
CST7, SPP1, and APOE
proteins, among others
Genes that are upregulated
in DAM include:
TREM2
APOE
TYROBP
CLEC7A
CST7
SPP1
AXL
LPL
Aβ plaque
DAM
Damaged
neuron
Homeostatic
microglia
Neuron
TREM2
signaling
Disease-Associated Microglial Phenotype in AD
4
Homeostatic Microglia DAM Microglia

3. Understanding the Links Between Neuroinflammation
and Alzheimer?s Disease
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 1. Hickey JP et al. Curr Issues Mol Biol. 2024;46:4379-4402. 2. Kinney JW et al. Alzheimers Dement: Transl Res Clinl Interv. 2018;4:575-590. 3. Kiraly M et al. J Prev Alzheimers Dis. 2023;10:686-698.4. Deczkowska A et al. Cell. 2018;173:1073-1081. 5. Leng F, Edison P. Nat Rev Neurol.
2021;17:157-172 . 6. Heneka MT et al. Nature. 2012;493:674-678. 7. Ising C et al. Nature. 2019;575:669-673.
NLRP3 Inflammasome Response
5-7
Deletion of the NLRP3 gene
prevents amyloid plaque
formation and reduces tau
pathology in mice
Microglia degrade Aβ and activate the
NF-kB pathway, which leads to
•The expression of proinflammatory cytokines
•NLRP3 inflammasome activation
Inflammasomes can lead to
•Further glial activation
•Neuronal dysfunction and death
•Production of Aβ
Aβ Positive Feedback Loop
More Aβ is
produced
Aβ causes
inflammation
Inflammasome is
upregulated
Aβ plaque
DAMP-sensing
receptor
Inflammatory
cytokines
NF-κB
Activated caspase 1
NLRP3
inflammasome
Exocytosis of
ASC specks
NLRP3
DAM microglia
ASC
Increase local
inflammatory response
Damage local neurons
Stimulate production
of Aβ through
upregulation of BACE

4. Optimizing the Diagnosis of AD
With Current and Emerging Tools
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 CDR Assessment Protocol
1,2
Memory
Home and
hobbies
Community
affairs
Judgment/
problem solving
Orientation
Personal
care
None (0) Questionable (0.5) Mild (1) Moderate (2) Severe (3)
Consistent slight forgetfulness;
partial recollection of events;
“benign” forgetfulness
Moderate memory loss;
more marked for recent
events; defect interferes
with everyday activities
Severe memory loss;
only highly learned material
retained; new material
rapidly lost
Severe memory loss;
only fragments remain
No memory loss or slight
inconsistent forgetfulness
Fully oriented except for
slight difficulty with time
relationships
Moderate difficulty with time
relationships; usually oriented
for place at examination;
may have geographic
disorientation elsewhere
Severe difficulty with
time relationships;
usually disoriented to
time and often to place
Oriented to person onlyFully oriented
Slight impairment in solving
problems, similarities, and
differences
Moderate difficulty in handling
problems, similarities, and
differences; social judgment
usually maintained
Severely impaired in handling
problems, similarities, and
differences; social judgment
usually impaired
Unable to make judgments
or solve problems
Solves everyday problems
and handles business
and financial affairs well;
judgment good in relation
to past performance
Life at home, hobbies,
and intellectual interests
slightly impaired
Mild but definite impairment
of function at home; more
difficult tasks abandoned;
more complicated hobbies
and interests abandoned
Only simple tasks preserved;
very restricted interests;
poorly maintained
No significant ability to do
things in home
Life at home, hobbies,
and intellectual interests
well maintained
Slight impairment in
these activities
Unable to function independently
at these activities, although
may still be engaged in some;
appears normal at first glance
Appears well enough to be
taken to functions outside
a family home
Appears too ill to be taken
to functions outside
a family home
Independent function at usual
level in job, shopping, and
volunteer and social groups
No possibility of independent function outside home
Needs prompting
Requires assistance
in dressing, hygiene,
and keeping of personal
belongings
Requires much help
with personal care;
frequent incontinence
Fully capable of self-care

5. Optimizing the Diagnosis of AD
With Current and Emerging Tools
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 1. https://knightadrc.wustl.edu/wp-content/uploads/2021/06/CDR-Table.pdf. 2. https://otm.wustl.edu/washu-innovations/tools/cdr-licensing/. 3. https://championsforhealth.org/wp-content/uploads/2021/09/Alzheimers-Project-Booklet-v11-082221-Web.pdf.
4. https://mocacognition.com. 5. Borson S et al. J Am Geriatr Soc. 2003;51:1451-1454. 6. https://www.dementiacareaware.org/wp-content/uploads/2023/04/UCSF_ADL_IADL_JobAid.pdf. 7. https://aric.cscc.unc.edu/aric9/sites/default/files/public/visitdocuments/v6/NPI.pdf. 
8. https://www.apa.org/depression-guideline/patient-health-questionnaire.pdf.
Screening Tools
Cognitive
3-5
•Montreal Cognitive Assessment
(MoCA): orientation, short-term
memory, language, abstraction,
clock-drawing test
•Mini-Mental State Examination
(MMSE): orientation, immediate
memory, short-term memory,
language
•Mini-Cog: word registration,
clock-drawing test, 3-word recall
Behavioral
3,7,8
•Neuropsychiatric Inventory–
Questionnaire (NPI-Q):
neuropsychiatric and behavioral
symptoms
•Patient Health Questionnaire-9
(PHQ-9): depression symptoms
Functional
3,6
•Activities of Daily Living and
Instrumental Activities of Daily
Living (ADLs/IADLs): administer
to patient or care partner

6. Neuroinflammation and Other
Targets in Alzheimer?s Disease
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 2
I
n
t
e
r
l
e
u
k
i
n
s
Caspase 1
T
L
R
s
T
R
E
M
2
ASC polymerization
Complement receptor
c
G
A
S
- S
T
IN
G
N
L
R
P
3
M
i
c
r
o
g
l
i
a

m
o
d
u
la
t
io
n
C
o
m
p
l
e
m
e
n
t
c
a
s
c
a
d
es
C200
Fractalkin
IL-10
CSF1R
Pro–IL-1β
cGAMP
ROS
cGAS
C1q
secretion
CR1
C8G
C5aR
C3R
Synapse
elimination
CR3
C1q
C4
C3
C3a
C3b
iC3b
C2
STING
IL-1β
Inflammatory
targets against
Alzheimer’s
disease
Microglia
Receptors
and
pathways
Complement system
Inflammasomes
These targets highlight key
molecular pathways and molecules
implicated in neuroinflammation
and immune dysregulation
1
Treatment will vary depending on
disease stage
• Inflammatory response in
preclinical phase: may prevent
amyloid plaque formation
• Inflammatory response after
formation of amyloid plaques:
will cause more damage

7. Neuroinflammation and Other
Targets in Alzheimer?s Disease
Full abbreviations, accreditation, and disclosure information available at PeerView.com/AFJ40 1. Serradas ML et al. Cells. 2024;13:1426. 2. Monney M et al. Diabetes and Metabolism. 2023;49:101470.
GLP-1 Agents May Have an Effect on Alzheimer’s Disease
2
•Increase BBB integrity
•Increase synapse viability
•Neurite growth
•Cell repair and replacement
•↑ cell metabolism
•↓ apoptosis
Growth factor
•↑ mitochondrial biogenes
Mitochondrial dysfunction
•↓ amyloid β deposition
•↓ tau protein hyperphosphorylation
Amyloid β deposition and
tau hyperphosphorylation
•↓ ɑ-synuclein deposition
Impaired nigrostrial dopamine function
and nigrostrial dopamine depletion
•↑ insulin release
•Amplify insulin signaling: ↑ insulin sensitivity
•↑ IR and IGF-1R expression
Hyperinsulinemia and
brain insulin resistance
•↓ neuroinflammation (↓ TNF-ɑ and IL-1β
released by microglia and astrocytes)
•↓ endoplasmic reticulum stress
•Protect neurons from advanced glycation
end products
•↓ oxidative stress
Inflammation
GLP-1