From Early Detection to Disease Modification: Personalized Approaches to Biomarker Testing and Therapeutic Management of Alzheimer’s Disease

Chair, Marwan Noel Sabbagh, MD, FAAN, FANA, prepared useful Practice Aids pertaining to Alzheimer’s disease for this CME activity titled “From Early Detection to Disease Modification: Personalized Approaches to Biomarker Testing and Therapeutic 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/3yeq3NG. CME credit will be available until September 16, 2025.

1. Revised Criteria for Biomarker-Based Diagnosis
and Staging of AD
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 Core 1 Biomarkers Core 2 Biomarkers Biomarkers of Nonspecific Processes Involved in AD Pathophysiology Biomarkers of Non-AD Co-Pathology Categorization of Fluid and Imaging Biomarkersβ Biomarker Category CSF Plasma Imaging
A (Aβ proteinopathy)
Hybrid ratios
T2 (AD tau proteinopathy)
N (injury, dysfunction, or degeneration
of neuropil)
I (inflammation) astrocytic activation
V (vascular brain injury)
S (α-synuclein)
–
–
– Amyloid PET
–
P-tau217/nP-tau217
pT205 Tau PET
P-tau181/Aβ42,
T-tau/Aβ42, Aβ42/Aβ40
pT205, MTBR-243,
nonphosphorylated
tau fragments
NfL NfL Anatomic MRI, FDG PET
Anatomic infarction,
WMH, abundant diluted
perivascular spaces
––
GFAP GFAP –
––αSyn-SAA
–
T
1
(phosphorylated and secreted AD tau)
• Core 1 biomarkers define
the initial stage of AD that
is detectable in vivo
• AD can be diagnosed with
any Core 1 biomarker
• Core 2 biomarkers
develop later than
Core 1 biomarkers, and
are closely tied to onset
of neurodegeneration and
clinical symptoms
• Core 2 biomarkers
can be combined with
Core 1 biomarkers
to stage biological
disease severity
P-tau217

2. Revised Criteria for Biomarker-Based Diagnosis
and Staging of AD
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 Core 2 biomarkers can be combined with Core 1 biomarkers to stage biological disease severity and
• Provide information on the likelihood that clinical symptoms are associated with AD
• Inform the risk of clinical progression in people without symptoms
• Inform the likely rate of clinical progression in symptomatic individuals
Amyloid PET
Tau PET Medial
Temporal
Region
Tau PET
Moderate
Neocortical
Uptake
Tau PET High
Neocortical
Uptake
AT Notation
Stage A
(Initial)
+ - - - A+T-
+ + - - A+T
MTL
+
+ + + - A+T
MOD
+
+ + + + A+T
HIGH
+
Stage B
(Early)
Stage C
(Intermediate)
Stage D
(Advanced)Biological Staging of AD Using Amyloid PET and Tau PET
1. Jack CR et al. Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. In progress. https://aaic.alz.org/diagnostic-criteria.asp.

3. Selecting Patients for Treatment With
Amyloid-Targeting Therapies (ATTs)
Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 Lecane mab Inclusion and Exclus ion Crite ria From CLARITY AD
1
Inclusion Criteria
Clinical diagnosi s of MCI or mild AD dement ia 
Positive biomarker f or brain amyloid pathology 
50-90 years of age
MMSE score 22-30 at screening and baseline
Have a care partner or family member(s) who can ensure that the patient has the support needed to be treated with lecanemab 
Exclusion Criteria
Any medical, neurologic, or psychiatric condition that may be contributing to the cognitive impairment or any non-AD MCI
or dementia 
>4 microhemorrhages (defned as ≤10 mm at the greatest diameter); a single macrohemorrhage >10 mm at greatest diameter;
an area of superfcial siderosis; evidence of vasogenic edema; multiple lacunar infarcts or strokes involving a major vascular
territory; severe small-vessel disease; or other major intracranial pathology
Any immunological disease that is not adequately controlled or which requires treatment with immunoglobulins, systemic
monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during
the study 
Participants with a bleeding disorder that is not adequately controlled (including a platelet count 1.5 for participants 
who are not on anticoagulant treatment [eg, warfarin]) 
Participants who are on anticoagulant therapy should have their anticoagulant status optimized and be on a stable dose for
4 weeks before screening
Have any contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic)
implants/cardiac pacemaker

4. Selecting Patients for Treatment With
Amyloid-Targeting Therapies (ATTs)
Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 Donanemab Inclusion and Exclusion Criteria From TRAILBLAZER-ALZ2
2
Inclusion Criteria
Clinical diagnosi s of MCI or mild AD dement ia 
Positive biomarker f or brain amyloid pathology 
60-85 years of age
MMSE score 20-28 at screening and baseline
Have a care partner or family member(s) who can ensure that the patient has the support needed to be treated with
donanemab
Exclusion Criteria
Any medical, neurologic, or psychiatric condition that may be contributing to the cognitive impairment or any non-AD
MCI or dementia
Amyloid-related imaging abnormalities of edema/efusion, >4 cerebral microhemorrhages (defned as ≤10 mm at the 
greatest diameter), >1 area of superfcial siderosis, and any intracerebral hemorrhage >1 cm or severe white-matter 
disease on MRI
Current treatment with  IVIG therapy
Have any contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic) 
implants/cardiac pacemaker

5. Selecting Patients for Treatment With
Amyloid-Targeting Therapies (ATTs)
Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 1. van Dyck C et al. N Engl J Med. 2023;388:9-21. 2. Sims J et al. JAMA. 2023;330:512-527. 3. Leqembi (lecanemab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269Orig1s001lbl.pdf. 4. Kisunla (donanemab) Prescribing Information.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf.
WARNING: AMYLOID-RELATED IMAGING ABNORMALITIES
3,4
Monoclonal antibodies directed against aggregated forms of beta amyloid can cause
amyloid-related imaging abnormalities (ARIA), as ARIA with edema (ARIA-E) and ARIA with
hemosiderin deposition (ARIA-H). ARIA is usually asymptomatic, although serious and
life-threatening events can rarely occur. Serious intracerebral hemorrhages >1cm have
occurred in patients treated with this class of medications. ARIA-E can cause focal
neurologic defcits that can mimic ischemic stroke.
APOEε4 Homozygotes
Patients treated with this class of medications who are APOEε4 homozygotes have a higher
incidence of ARIA, including symptomatic and serious ARIA, compared to heterozygotes
and noncarriers. Testing for APOEε4 status should be performed prior to initiation of
treatment to inform the risk of developing ARIA. Prior to testing, prescribers should
discuss with patients the risk of ARIA across genotypes and the implications of genetic
testing results.
Consider the beneft for the treatment of Alzheimer's disease and risk of ARIA when
deciding to treat with this class of medications.

6. Topics to Include in a Shared Decision-Making Discussion 
With Patients and Care Partners Regarding ATTs
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/NMQ40 •Potential slowing of cognitive and functional decline, but counsel that symptoms are not expected to improve
•How will efectiveness be measured in individual patients?
Expected beneft
of treatment
•Risks of ARIA and symptoms to watch out for, such as headache, confusion, dizziness, and visual changes
•What are the possible complications of ARIA?
•What is the patient's individualized risk profle, based on their APOE genotype, baseline MRI brain scan, 
comorbid medical conditions, and current medications?
Risks of
amyloid-targeting
therapies
•Signifcant commitment of time/efort/burden to undergo biomarker testing to confrm elevated amyloid, 
to receive infusions (once or twice a month, depending on the agent), and to receive follow-up MRIs 
(minimum of four in the frst year of treatment) to monitor for ARIA
Commitment/
burden
•How much will treatment cost?
•What additional costs are associated with treatment (eg, pretreatment evaluations, follow-up visits, MRIs)?
•Will the patient's insurance cover the cost of the medication and the additional costs associated with 
the treatment?
Cost
•Would a clinician consider patients younger or older than the age range selected in the pivotal trials?
•What is the duration of treatment, and when should a patient stop? (This may vary depending on the type of
amyloid-targeting therapy)
•Would concomitant symptomatic therapy be benefcial in addition to the disease-modifying therapy?
•Would participating in an Alzheimer's disease research trial for another type of emerging treatment be more appealing?
Questions
remaining
1. Day GS et al. Neurology. 2022;98:619 - 631.