Chair, Tammie L.S. Benzinger, MD, PhD, Jerome A. Barakos, MD, and Gregory S. Day, MD, MSc, MSCI, FAAN, prepared useful Practice Aids pertaining to Alzheimer's disease for this CME activity titled “The Expanding Role of Neuroimaging in Alzheimer’s Disease Diagnosis and Management: Is Radiology Prepared for New Challenges?” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/2YzMICB. CME credit will be available until February 14, 2023.

1. Molecular and Imaging Biomarkers in AD1-7
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• (A) A plaques or associated pathophysiology specific to AD
– Biomarkers = CSF Aβ42 (low), CSF Aβ42/40 ratio (low), Aβ PET
• (T) Aggregated tau or associated pathophysiology specific to AD
– Biomarkers = CSF phosphorylated tau (high), tau PET
• (N) Neuronal injury and neurodegeneration that is nonspecific
– Biomarkers = CSF total tau (high), structural MRI, FDG PET
Three-Class Categorization of AD: ATN Biomarker Grouping
A/T/N
Category
Biomarker Findings in AD
A
Plaques
or
Associated
Pathophysiology
CSF A 42
• Reduced Aβ42 is characteristic of AD dementia and prodromal AD (mean change: 50% of levels
in cognitively unimpaired elderly)
• Reduction in CSF Aβ42 in AD reflects brain amyloidosis and shows high concordance with Aβ PET
CSF A 42/
A 40 Ratio
• Reduced Aβ42/Aβ40 ratio is characteristic of AD dementia and prodromal AD (mean change: 50%
of levels in cognitively unimpaired elderly)
• Aβ42/Aβ40 ratio is believed to control for between‐individual variations in total Aβ production and
variations in CSF dynamics and/or correct for preanalytical confounders
A PET
• An Aβ PET scan can help to differentiate AD from other causes of dementia: a negative scan
decreases the likelihood of AD, and a positive scan in a symptomatic patient with dementia
indicates that the person has AD pathology
• A positive finding does not rule out a coexisting pathology
Aggregated
Tau
or
Associated
Pathophysiology
CSF pTau
• High pTau is characteristic of AD dementia and prodromal AD, and it is specific to AD
• Mean change: ~250% of levels in cognitively unimpaired elderly
Tau PET
• Medial temporal tau tracer uptake, but not whole-brain tracer uptake, correlated with medial
temporal lobe atrophy and memory scores in AD
• Tau PET may predict location and extent of brain atrophy a year in advance in patients with AD
Neuronal
Injury
and
Neurodegeneration
CSF tTau
• Increased CSF tTau is characteristic of AD dementia and prodromal AD and probably reflects the
intensity of neurodegeneration (mean change: 250% of levels in cognitively unimpaired elderly)
• CSF tTau is not specific to AD, and it is elevated in CJD and acute brain disorders (eg, stroke)
with levels depending on the severity of the lesion
FDG PET
• Distinct regions of hypometabolism in hippocampus, precuneus (mesial parietal lobes), and lateral
parietal and posterior temporal cortex observed in AD
• May be most useful in distinguishing AD from FTLD in patients with atypical presentations and in
discriminating from non-neurodegenerative conditions (eg, depression)
Structural
MRI
• Reduced hippocampal volume, medial temporal lobe atrophy, and white matter lesions are
characteristic of AD
• Findings can provide incremental support for an AD diagnosis in a patient with a typical
clinical presentation

2. Molecular and Imaging Biomarkers in AD1-7
Full abbreviations, accreditation, and disclosure information available at
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Structural and Functional Neuroimaging Techniques
for Studying Brain Changes Associated With AD
SPECT
Chemical and
cellular changes
FDG PET
Glucose
metabolism
ASL
CBF
DTI
Nonrandom
movement water,
white matter
MRS
NAA, ml
fMRI
Oxygen concentration
Tau PET
NFTs with [18F]AV1451, T-807,
[18F]PI-2620, [18F]MK-6240,
[18F]THK523, [18F]THK5117,
[18F]THK5105, [18F]THK5351,
[18F]AV1451(T807), [11C]PBB3
Ophthalmic
imaging
Retina,
cornea, AH,
crystalline lens
TSPO PET
Translocator
protein TSPO
CT
Structural
changes
MRI
Hippocampal
volumetry and
other structural
changes
Amyloid PET
A with PiB,
florbetapir,
florbetaben,
flutemetamol
Epigenetic PET
HDACs with
[11C]Martinostat,
[18]MGS3
PET targeting SV2A
Synaptic vesicles with
[11C]UCB-J, [11C]UCB-A,
[18F]UCB-H
Chemical and cellular changes
Metabolism
Tau pathology
Ophthalmic signs
Inflammation
Structure
A pathology
Epigenetics
Synapsis
Alternative techniques/interchangeable

3. Molecular and Imaging Biomarkers in AD1-7
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/KZA40
1. Jack CR Jr et al. Neurology. 2016;87:539-547. 2. Luwczuk P et al. Pharm Rep. 2020;72:528-542. 3. Blennow K et al. JIM. 2018;284:643-663. 4. Balasa AF et al. Biomedicines. 2020;8:421.
5. Nguyen TT et al. Diagnostics. 2020;10:326. 6. Marquez F et al. Mol Neurodegener. 2019;14:21. 7. Villa C et al. J Pers Med. 2020;10:61.
Biomarker Measuring
Mechanism of
AD Pathology
Monitoring
Fatty acid
binding protein 3
CSF Neuronal damage Diagnostic
VILIP-1 CSF Neuronal damage Pharmacodynamic/response
BACE1 CSF
Synaptic dysfunction
and/or loss
Diagnostic,
susceptibility/risk
Neurogranin CSF
Synaptic dysfunction
and/or loss
Diagnostic,
susceptibility/risk
Neuronal pentraxin 2 CSF Inflammation Diagnostic
-synuclein CSF Neurodegeneration Diagnostic
Neuronal pentraxin 1 Blood/plasma Neuronal damage Diagnostic
ApoE-4 Blood/plasma Genetic variation/DNA Susceptibility/risk
A 42 Blood/plasma Amyloid Diagnostic
A 42/A 40 Blood/plasma Amyloid
Pharmacodynamic/response,
susceptibility/risk, safety
mtDNA damage Blood/plasma Genetic variation/DNA Diagnostic, monitoring
Ceramides Blood/plasma Inflammation Diagnostic
Clusterin Blood/plasma Apoptosis Susceptibility/risk
Neurofilament light (NfL) Blood/plasma Neuronal damage Diagnostic, monitoring
pTau 181 Blood/plasma Tau pathology Diagnostic, monitoring
pTau 217 Blood/plasma Tau pathology Diagnostic, monitoring
TNF- Blood/plasma Inflammation Diagnostic
tTau Blood/plasma Tau pathology Diagnostic, monitoring
Vascular cell
adhesion molecule 1
Blood/plasma Neuronal damage
Diagnostic, monitoring,
prognostic
Investigational Fluid Biomarkers for Diagnosing
and Monitoring Treatment Response in Patients With AD

4. Select Ongoing Clinical Trials Investigating Anti-Aβ
Monoclonal Antibodies in AD1
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1. https://clinicaltrials.gov.
Agent
Aducanuemab
A Study to Evaluate Safety and Tolerability of Aducanumab
in Participants With AD Who Had Previously Participated
in the Aducanumab Studies 221AD103, 221AD301,
221AD302 and 221AD205
NCT04241068
Phase 3
Not recruiting
Donanemab
A Phase 3, Open-Label, Parallel-Group, 2-Arm Study
to Investigate Amyloid Plaque Clearance With Donanemab
Compared With Aducanumab-avwa in Participants
With Early Symptomatic Alzheimer's Disease
NCT05108922
Phase 3
Recruiting
Aducanumab comparator
Early symptomatic AD
Donanemab
A Study of Donanemab (LY3002813) in Participants With
Early AD (TRAILBLAZER-ALZ 2)
NCT04437511
Phase 3
Not recruiting
Donanemab
A Donanemab (LY3002813) Prevention Study
in Participants With AD (TRAILBLAZER-ALZ 3)
NCT05026866
Phase 3
Recruiting
Intact cognitive functioning, presence
of amyloid and early tau pathology
Donanemab
A Follow-On Study of Donanemab (LY3002813) With Video
Assessments in Participants With AD (TRAILBLAZER-EXT)
NCT04640077
Phase 2
Recruiting among participants
in pervious TRAILBLAZER trials
Gantenerumab
A Study to Evaluate the Safety, Tolerability, and Efficacy
of Long-term Gantenerumab Administration
in Participants With AD
NCT04374253
Phase 3
Open-label extension trial
Recruiting among participants
in parent studies WN29922 or
WN3965
Solanezumab
Clinical Trial of Solanezumab for Older Individuals
Who May be at Risk for Memory Loss (A4)
NCT02008357
Phase 3
Not recruiting
Gantenerumab,
Solanezumab
A Phase II/III Randomized, Double-Blind,
Placebo-Controlled, Cognitive Endpoint, Multi-Center Study
of Potential Disease Modifying Therapies in Individuals
at Risk for and With Dominantly Inherited AD
NCT01760005
Phase 2/3
PBO-controlled
Cognitively normal, MCI,
or mild dementia
with a dominantly inherited AD
mutation in self or family
Trial Status