Specialty Training for the New Era in Alzheimer’s Disease: Building Skills for Making an Early Diagnosis and Implementing Disease-Modifying Treatment
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May 23, 2024
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About This Presentation
Chair, Sharon Cohen, MD, FRCPC, discusses Alzheimer’s disease in this CME/MOC/AAPA activity titled “Specialty Training for the New Era in Alzheimer’s Disease: Building Skills for Making an Early Diagnosis and Implementing Disease-Modifying Treatment.” For the full presentation, downloadable ...
Slide Content
Specialty Training for the New Era
in Alzheimer’s Disease
Building Skills for Making an Early Diagnosis and
Implementing Disease-Modifying Treatment
Sharon Cohen, MD,FRCPC i; *
Neurologist and Medical Director
Toronto Memory Program
Toronto, Ontario, Canada
Copyright © 2000-2024, PeerView
in Alzheimer’s Disease
Building Skills for Making an Early Diagnosis and
Implementing Disease-Modifying Treatment
Sharon Cohen, MD,FRCPC i; *
Neurologist and Medical Director
Toronto Memory Program
Toronto, Ontario, Canada
Copyright © 2000-2024, PeerView
Our Goals for Today
Augment awareness of the rationale for identifying patients at risk
for AD early in the disease course
Enhance understanding of the relationships between specific AD
biomarkers, the underlying neuropathological changes that define
AD, and the clinical manifestations and severity of cognitive and
functional decline
Increase ability to employ validated biomarkers to make an
accurate neuropathological diagnosis of AD in patients who present
with cognitive complaints
Improve ability to apply new and emerging disease-modifying AD
therapies into customized treatment regimens for appropriate
patients with biological and clinical characteristics of early AD
Copyright © 2000-2024, Peerview
Augment awareness of the rationale for identifying patients at risk
for AD early in the disease course
Enhance understanding of the relationships between specific AD
biomarkers, the underlying neuropathological changes that define
AD, and the clinical manifestations and severity of cognitive and
functional decline
Increase ability to employ validated biomarkers to make an
accurate neuropathological diagnosis of AD in patients who present
with cognitive complaints
Improve ability to apply new and emerging disease-modifying AD
therapies into customized treatment regimens for appropriate
patients with biological and clinical characteristics of early AD
Copyright © 2000-2024, Peerview
Early Identification of
Patients at Risk for AD
Sharon Cohen, MD, FRCPC
Neurologist and Medical Director | 7
Toronto Memory Program re
Toronto, Ontario, Canada <
ry)
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Patients at Risk for AD
Sharon Cohen, MD, FRCPC
Neurologist and Medical Director | 7
Toronto Memory Program re
Toronto, Ontario, Canada <
ry)
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Early AD Detection and Diagnosis Rates in the Real World
+» The Alzheimer’s Association, CMS, and AAN all recommend early detection
and diagnosis of AD (eg, at MCI stage of illness)'*
— However, recent estimates from several studies indicate that only 8%-15%
of individuals with MCI receive a diagnosis of MCI*>
— 99% of primary care clinicians underdiagnose MCI®
1. Petersen RC et al. Neurology. 2018:90:126-135, 2. Cordel! CB et al. Alzheimers Dement. 20139:141-150. 3, Matte S et al. Alzheimers Res Ther. 2023:15:12.
4. White Let al. J Gen inter Med, 2021. 5. Sava GM et al. Age Ageing. 2015:44:642-647. 6. Lu Y etal. J Prov Alzheimers Dis. 2024:11:7-12. y
7. Rabinoviei GO et al. JAMA. 2010;321:1286-1294, PeerView.com
VQG827 Copyright © 2000-2024, PeerView
+» The Alzheimer’s Association, CMS, and AAN all recommend early detection
and diagnosis of AD (eg, at MCI stage of illness)'*
— However, recent estimates from several studies indicate that only 8%-15%
of individuals with MCI receive a diagnosis of MCI*>
— 99% of primary care clinicians underdiagnose MCI®
1. Petersen RC et al. Neurology. 2018:90:126-135, 2. Cordel! CB et al. Alzheimers Dement. 20139:141-150. 3, Matte S et al. Alzheimers Res Ther. 2023:15:12.
4. White Let al. J Gen inter Med, 2021. 5. Sava GM et al. Age Ageing. 2015:44:642-647. 6. Lu Y etal. J Prov Alzheimers Dis. 2024:11:7-12. y
7. Rabinoviei GO et al. JAMA. 2010;321:1286-1294, PeerView.com
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Barriers That Can Prevent a Timely Diagnosis of
MCI and Mild Dementia Due to AD
Patient and Community Barriers to
Early Detection/Diagnosis
Limited skill and lack of confi Cack of community/public awareness
and understanding of the disease’
ability to diagnose cognitive
impairment! Poor patient engagement in and
access to healthcare’?
Healthcare Provider Barriers to
Early Detection/Diagnosis
Physicians’ disbelief in the value of
early detection’ Inadequate linguistic and cultural
validation!
Wait lists are too |
a specialist! Patients hide symptoms and avoid
making appointments due to fear of
being diagnosed with AD and
perceived stigma surrounding
the diagnosis!2
Other system
(eg, time constrai lerical burden
reimbursement difficulties)"
1. Sideman AB et al. Front Neurol. 2022:13:760360, 2, Gautier S et al. Word Alzheimer Report 2021, Abridged version: Journey through the diagnosis of dementia si
London, England: Alzheimer's Disease Intematonai 3. Lu Y etal J Prev Alzheimers Dis, 2024:117-12. 4. Porstensson AP. J Prev Alzheimers Dis 2021;3371-288. Peer View.com
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MCI and Mild Dementia Due to AD
Patient and Community Barriers to
Early Detection/Diagnosis
Limited skill and lack of confi Cack of community/public awareness
and understanding of the disease’
ability to diagnose cognitive
impairment! Poor patient engagement in and
access to healthcare’?
Healthcare Provider Barriers to
Early Detection/Diagnosis
Physicians’ disbelief in the value of
early detection’ Inadequate linguistic and cultural
validation!
Wait lists are too |
a specialist! Patients hide symptoms and avoid
making appointments due to fear of
being diagnosed with AD and
perceived stigma surrounding
the diagnosis!2
Other system
(eg, time constrai lerical burden
reimbursement difficulties)"
1. Sideman AB et al. Front Neurol. 2022:13:760360, 2, Gautier S et al. Word Alzheimer Report 2021, Abridged version: Journey through the diagnosis of dementia si
London, England: Alzheimer's Disease Intematonai 3. Lu Y etal J Prev Alzheimers Dis, 2024:117-12. 4. Porstensson AP. J Prev Alzheimers Dis 2021;3371-288. Peer View.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Rationale for Early Detection of AD:
There ARE Things We Can Do!!-15
Why is it important for patients to receive an early and accurate diagnosis of AD?
It validates the patient's and family’s concerns and verifies the certainty of the diagnosis
It enables patients to participate in their own care planning while they are still capable
It empowers patients to make lifestyle changes that can slow progression of the disease
and manage comorbidities
It improves and facilitates access to education and personalized support services
Diagnosis of AD at early stages (MCI or mild dementia) is required for treatment with
recently approved ATTs
Clinical trials are available for individuals at early stages of AD, including at the
prevention stage
1. Sims J et al JAMA. 2023:390:512-527. 2. Van Dyck CH et al N Engl J Med 2023:388:921. 3, Omura JD etal. MMWR Morb Mor Why Rep. 2022.71: 880-685,
4 tps: aspe the govreporanatena plan 202rupdate, 5. iG et al CTAD 2029. P1456. Liss JL ea. Item Med. 2021290.310-324
Porteinsson AP et al J Prev Alzheimers Dis. 2021:3371-386. 8. Cordel CB et al Alzheimers Dement. 20139:141-150. 9. Johnson KA e al Alzheimers Dement
2013.5 suppl) 572-583. 10, MeCarten JR, Borson S. Am Fam Physician 2014/80:861-882. 11. Bousani M. J Am Garltr Soe. 2013:61:1205-1207.
12 MeCarten JR. Cin Gora Med. 201929.791-207. 13 ips www agreedementa.or. 14. Marasco RA. Am J Manag Caro, 202028:5167-5176 ”
15. ps www ai orgmeda Documents aizheimers-ear}-detecion-dagnoss-phs pal. PeerView.com
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There ARE Things We Can Do!!-15
Why is it important for patients to receive an early and accurate diagnosis of AD?
It validates the patient's and family’s concerns and verifies the certainty of the diagnosis
It enables patients to participate in their own care planning while they are still capable
It empowers patients to make lifestyle changes that can slow progression of the disease
and manage comorbidities
It improves and facilitates access to education and personalized support services
Diagnosis of AD at early stages (MCI or mild dementia) is required for treatment with
recently approved ATTs
Clinical trials are available for individuals at early stages of AD, including at the
prevention stage
1. Sims J et al JAMA. 2023:390:512-527. 2. Van Dyck CH et al N Engl J Med 2023:388:921. 3, Omura JD etal. MMWR Morb Mor Why Rep. 2022.71: 880-685,
4 tps: aspe the govreporanatena plan 202rupdate, 5. iG et al CTAD 2029. P1456. Liss JL ea. Item Med. 2021290.310-324
Porteinsson AP et al J Prev Alzheimers Dis. 2021:3371-386. 8. Cordel CB et al Alzheimers Dement. 20139:141-150. 9. Johnson KA e al Alzheimers Dement
2013.5 suppl) 572-583. 10, MeCarten JR, Borson S. Am Fam Physician 2014/80:861-882. 11. Bousani M. J Am Garltr Soe. 2013:61:1205-1207.
12 MeCarten JR. Cin Gora Med. 201929.791-207. 13 ips www agreedementa.or. 14. Marasco RA. Am J Manag Caro, 202028:5167-5176 ”
15. ps www ai orgmeda Documents aizheimers-ear}-detecion-dagnoss-phs pal. PeerView.com
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Strategies to Improve MCI Diagnosis Rates!
+ Implement cognitive screening at earlier ages A
— Age may depend on population O O
+ Increase biomarker testing
+ Improve referral systems between primary and specialist care O
+ Education of primary care and specialists
+ Increase availability and use of easy-to-implement digital cognitive assessment tools and
improve reimbursement for cognitive testing
+ Increase utilization of a multidisciplinary team approach to diagnosis and coordination
of interventions
+ Improve understanding and awareness in the community and on the national policy level
about AD and the importance of early diagnosis and prevention
+ Develop more “aging-in-place” strategies and support for families and caregivers to
decrease stigma and enhance independence
1. Galvin JE et al. Neurodegener Dis Manag. 2014:4:455-469.2, Sideman AB et al. Front Neurol 2022:13:768960. 3. Lu Y et al. Prev Alzheimers Di. 2024:11:7-12 Peer View.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
+ Implement cognitive screening at earlier ages A
— Age may depend on population O O
+ Increase biomarker testing
+ Improve referral systems between primary and specialist care O
+ Education of primary care and specialists
+ Increase availability and use of easy-to-implement digital cognitive assessment tools and
improve reimbursement for cognitive testing
+ Increase utilization of a multidisciplinary team approach to diagnosis and coordination
of interventions
+ Improve understanding and awareness in the community and on the national policy level
about AD and the importance of early diagnosis and prevention
+ Develop more “aging-in-place” strategies and support for families and caregivers to
decrease stigma and enhance independence
1. Galvin JE et al. Neurodegener Dis Manag. 2014:4:455-469.2, Sideman AB et al. Front Neurol 2022:13:768960. 3. Lu Y et al. Prev Alzheimers Di. 2024:11:7-12 Peer View.com
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The Relationship Between Biomarkers,
Neuropathological Changes, and
Clinical Manifestations in AD
Sharon Cohen, MD, FRCPC :; +
Neurologist and Medical Director
Toronto Memory Program an æ
Toronto, Ontario, Canada
rw)
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Neuropathological Changes, and
Clinical Manifestations in AD
Sharon Cohen, MD, FRCPC :; +
Neurologist and Medical Director
Toronto Memory Program an æ
Toronto, Ontario, Canada
rw)
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
2018 AT(N) Research Framework Biomarkers
and AD Classifications’
Validated AD Biomarkers AD Classifications
AT(N) AT(N)
ln CSF Imaging au Biomarker Category
A AB42; A Normal Alzheimer's disease biomarkers
‘Amyloid Apaz/ag4o Amyloid PET =
A#TAN)- Alzheimer’s
u Rei Tau PET pathologic change
u AHTHN)-
© Alzheimer's disease Alzheimer's
(ND/neuronal Total tau MRI; ASTH(N)+ continuum
: FDG PET
jury) Alzheimer's and concomitant
A+T4N)+ suspected non-Alzheimer's
pathologic change
A-THN)>
AT{N)+ Non-Alzheimer's pathologic change
ATHN)+
1. Jack ur CR et al, Alahoimers Dement. 2018:14:535:52. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
and AD Classifications’
Validated AD Biomarkers AD Classifications
AT(N) AT(N)
ln CSF Imaging au Biomarker Category
A AB42; A Normal Alzheimer's disease biomarkers
‘Amyloid Apaz/ag4o Amyloid PET =
A#TAN)- Alzheimer’s
u Rei Tau PET pathologic change
u AHTHN)-
© Alzheimer's disease Alzheimer's
(ND/neuronal Total tau MRI; ASTH(N)+ continuum
: FDG PET
jury) Alzheimer's and concomitant
A+T4N)+ suspected non-Alzheimer's
pathologic change
A-THN)>
AT{N)+ Non-Alzheimer's pathologic change
ATHN)+
1. Jack ur CR et al, Alahoimers Dement. 2018:14:535:52. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
Temporal Evolution of AD Biomarkers
and Cognitive Impairment’
+
— Af fluid
— Amyloid PET
— Phosphorylated tau fluid
— Tau PET
— MRI + FDG PET
— Cognitive impairment
Biomarker Abnormality
Detection
threshold
Preclinical AD MCI AD Dementia
1. Jack ur CR et al. Lancet Neurol. 2022;10:866-869,
PeerView.com
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and Cognitive Impairment’
+
— Af fluid
— Amyloid PET
— Phosphorylated tau fluid
— Tau PET
— MRI + FDG PET
— Cognitive impairment
Biomarker Abnormality
Detection
threshold
Preclinical AD MCI AD Dementia
1. Jack ur CR et al. Lancet Neurol. 2022;10:866-869,
PeerView.com
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Revised Criteria for Biomarker-Based Diagnosis
and Staging of AD!
Biomarker Category CSF Plasma Imaging
Core 1 Biomarkers
IAB proteinopathy) = = “Amyloid PET
T, (phosphorylated and
sécreted AD tau) = ANRT =
Men EDO, Pam = :
Core 2 Biomarkers
P1205, MTBR-243,
Ta (AD tau proteinopalhy) | nonphosphoriated pT205 Tau PET
tau fragments
Biomarkers of Nonspecific Processes Involved in AD Pathophysiology
N (nlury. dysfunction, or Fr Ni, ‘Anatomie MRI, FOG
degeneration of neuropil) PET
1 inflammation) astrocytic
ea GFAP GFAP z
Biomarkers of Non-AD Co Pathology
‘Anatomic infarction,
WMI, abundant
V (vascular brain injury) - - le
spaces
S (a-synuclein aSyn-SAA
7: Jock GR et a Revised cla Tr diego and staging of Aamara ease: Aetna’ S Assouaion Mongo, Wy progress.
AS
PeerView.com/VQG827
The new criteria are an update to
the 2018 research framework
based on recent developments
Disease-modifying therapies
for AD prompted shift from
research framework to
criteria for diagnosis and
staging to inform clinical care
Plasma-based biomarkers
have been incorporated into
updated criteria
Imaging and fluid biomarkers
within a category are not
interchangeable; this is
clarified in updated criteria
PeerView.com
Copyright © 2000-2024, PeerView
and Staging of AD!
Biomarker Category CSF Plasma Imaging
Core 1 Biomarkers
IAB proteinopathy) = = “Amyloid PET
T, (phosphorylated and
sécreted AD tau) = ANRT =
Men EDO, Pam = :
Core 2 Biomarkers
P1205, MTBR-243,
Ta (AD tau proteinopalhy) | nonphosphoriated pT205 Tau PET
tau fragments
Biomarkers of Nonspecific Processes Involved in AD Pathophysiology
N (nlury. dysfunction, or Fr Ni, ‘Anatomie MRI, FOG
degeneration of neuropil) PET
1 inflammation) astrocytic
ea GFAP GFAP z
Biomarkers of Non-AD Co Pathology
‘Anatomic infarction,
WMI, abundant
V (vascular brain injury) - - le
spaces
S (a-synuclein aSyn-SAA
7: Jock GR et a Revised cla Tr diego and staging of Aamara ease: Aetna’ S Assouaion Mongo, Wy progress.
AS
PeerView.com/VQG827
The new criteria are an update to
the 2018 research framework
based on recent developments
Disease-modifying therapies
for AD prompted shift from
research framework to
criteria for diagnosis and
staging to inform clinical care
Plasma-based biomarkers
have been incorporated into
updated criteria
Imaging and fluid biomarkers
within a category are not
interchangeable; this is
clarified in updated criteria
PeerView.com
Copyright © 2000-2024, PeerView
Diagnosing AD With Core 1 Biomarkers’
Core 1 Biomarkers With Sufficient Accuracy to Be Used as Standalone Diagnostic Tests
Biomarker Category CSF Plasma Imaging
A (AB proteinopathy) = = ‘Amyloid PET
T, (phosphorylated and
secreted AD tau) = Paiz? =
Ptaut81/AB42,
Hybrid ratios roads apazripao P-lau217InP-au217 =
+ Core 1 biomarkers define initial stage of AD that is detectable in
vivo
— AD can be diagnosed with any Core 1 biomarker
— Useful in identifying presence of AD in both symptomatic and
asymptomatic people
+ Tau biomarkers divided into two categories (T, and T,)
— T, biomarkers (P-tau181, 217, and 231) become abnormal
around the same time as amyloid PET and well before tau
PET, suggesting that they may represent a physiologic
reaction to B-amyloid plaques
1. Jack CR et al Revise tra for diagnosis and staping of Alzheimers disease: Alzheimer’ Associaton Workgroup. In progres. 7s
tps lac lz orp/tagnoste-citeria asp, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Core 1 Biomarkers With Sufficient Accuracy to Be Used as Standalone Diagnostic Tests
Biomarker Category CSF Plasma Imaging
A (AB proteinopathy) = = ‘Amyloid PET
T, (phosphorylated and
secreted AD tau) = Paiz? =
Ptaut81/AB42,
Hybrid ratios roads apazripao P-lau217InP-au217 =
+ Core 1 biomarkers define initial stage of AD that is detectable in
vivo
— AD can be diagnosed with any Core 1 biomarker
— Useful in identifying presence of AD in both symptomatic and
asymptomatic people
+ Tau biomarkers divided into two categories (T, and T,)
— T, biomarkers (P-tau181, 217, and 231) become abnormal
around the same time as amyloid PET and well before tau
PET, suggesting that they may represent a physiologic
reaction to B-amyloid plaques
1. Jack CR et al Revise tra for diagnosis and staping of Alzheimers disease: Alzheimer’ Associaton Workgroup. In progres. 7s
tps lac lz orp/tagnoste-citeria asp, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Amyloid PET1-5
e E 2 + Amyloid PET demonstrated 88%-98%
in O % sensitivity and 80%-95% specificity as a
reliable proxy for amyloid accumulation
based on PET-to-autopsy studies
‘Accumulation of amyloid plaques begins
10-20 years before onset of clinical
impairment
Amyloid PET can improve early diagnosis
and appropriate treatment of Alzheimer’s and
other dementias
— Inthe IDEAS Study, amyloid PET led to
changes in the management of 60.2% of
MCI and 63.5% of dementia patients
1. Clack OM eta. Lan
4. Spering RA Alzel
Neurol 2012:11:669:678. 2. Curt C etal. JAMA Neurol. 2015:72:287:294. 3, Sabr O et a, Alzho 1. 2015:11:964974, ar
‘Dement. 2011:7:280-292. 5. Rabinovei GD etal, JAMA. 2019:321:1286-1294 PeerView.com
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e E 2 + Amyloid PET demonstrated 88%-98%
in O % sensitivity and 80%-95% specificity as a
reliable proxy for amyloid accumulation
based on PET-to-autopsy studies
‘Accumulation of amyloid plaques begins
10-20 years before onset of clinical
impairment
Amyloid PET can improve early diagnosis
and appropriate treatment of Alzheimer’s and
other dementias
— Inthe IDEAS Study, amyloid PET led to
changes in the management of 60.2% of
MCI and 63.5% of dementia patients
1. Clack OM eta. Lan
4. Spering RA Alzel
Neurol 2012:11:669:678. 2. Curt C etal. JAMA Neurol. 2015:72:287:294. 3, Sabr O et a, Alzho 1. 2015:11:964974, ar
‘Dement. 2011:7:280-292. 5. Rabinovei GD etal, JAMA. 2019:321:1286-1294 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
FDA-Approved CSF In Vitro Diagnostic for AD:
Beta-Amyloid 1-42/401
m Ba 1.0 1(0.204.0.852)
08
= 2 2
3 2 06
5 04
10 ?
| | | | 02 ‘AUC: 0.873 (0.845-0.901)
IT
03 06 09 12 0 02 04 06 08 10
10 x B-Amyloid 1-42/1-40 1-Specificity
1. Gobom Jet al. Cin Chem Lab Med. 2022:60:207-219. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Beta-Amyloid 1-42/401
m Ba 1.0 1(0.204.0.852)
08
= 2 2
3 2 06
5 04
10 ?
| | | | 02 ‘AUC: 0.873 (0.845-0.901)
IT
03 06 09 12 0 02 04 06 08 10
10 x B-Amyloid 1-42/1-40 1-Specificity
1. Gobom Jet al. Cin Chem Lab Med. 2022:60:207-219. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
FDA-Approved In Vitro Diagnostics for AD:
CSF P-tau181/Aß42 and T-tau/AB4212
Individual Biomarkers Hybrid Ratio Biomarkers
10
E
075
Hybrid ratio
8
025
True Positive Rate (Sensitivity)
True Positive Rate (Sensitivity)
— AB42: AUC = 0.862
— T-tau: AUC = 0.814
— P-tau181: AUC = 0.844
— AB42/AB40: AUC = 0.936
— T-tau/AB42: AUC = 0.941
— P-tau181/AB42: AUC = 0.94
o
o 025 os 07 Yo 0 025 os 075 10
False Positive Rate (1-Specificity) False Positive Rate (1-Specificity)
1 Mts new abpulse comusinessinsighspolcy-and-regulatontda-learancelatce/15904098roche-nabstda-cearancefortwo-alheimers-daease-csassays a
2 Doecke JD et al. Alzheimers Res Ther. 2020.12: PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
CSF P-tau181/Aß42 and T-tau/AB4212
Individual Biomarkers Hybrid Ratio Biomarkers
10
E
075
Hybrid ratio
8
025
True Positive Rate (Sensitivity)
True Positive Rate (Sensitivity)
— AB42: AUC = 0.862
— T-tau: AUC = 0.814
— P-tau181: AUC = 0.844
— AB42/AB40: AUC = 0.936
— T-tau/AB42: AUC = 0.941
— P-tau181/AB42: AUC = 0.94
o
o 025 os 07 Yo 0 025 os 075 10
False Positive Rate (1-Specificity) False Positive Rate (1-Specificity)
1 Mts new abpulse comusinessinsighspolcy-and-regulatontda-learancelatce/15904098roche-nabstda-cearancefortwo-alheimers-daease-csassays a
2 Doecke JD et al. Alzheimers Res Ther. 2020.12: PeerView.com
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Plasma P-tau217 Performs Better Than
Plasma P-tau181 and 231!
ROC Curve Analysis for Differentiating MCI
Participants With Abnormal CSF Af42/40
From Those With Normal CSF AB42/40
A- MCI vs A+ MCI
100
80
=
¿e
=
ri
3° P-tauzatveer
unir Paten
20 -tau217408 u. P-tau18 14ST
tau 18140 » Ptau181#
taut Mes .... P-tau 1819
0 20 40 60 80 100
100-Specificity, %
1. Janetidze Set al Brain. 2022:146:1592-1601.
PeerView.com/VQG827
ROC Curve Analysis for Differentiating MCI
Patients Who Progressed to ADD During
Follow-Up From Those Who Did Not
Nonprogressors vs Progressors
100
80
Boo
2
2 40
3 —prau2i7en — prtauieiuy
—Prtau2t7y Pau2310007
20 —Ptau21720 + P-taut@1vcor
— Ptaut810r Ptaut8t"#
— Paute. P-tauig ts
0 20 40 60 80 100
100-Specificity, %
PeerView.com
Copyright © 2000-2024, Peerview
Plasma P-tau181 and 231!
ROC Curve Analysis for Differentiating MCI
Participants With Abnormal CSF Af42/40
From Those With Normal CSF AB42/40
A- MCI vs A+ MCI
100
80
=
¿e
=
ri
3° P-tauzatveer
unir Paten
20 -tau217408 u. P-tau18 14ST
tau 18140 » Ptau181#
taut Mes .... P-tau 1819
0 20 40 60 80 100
100-Specificity, %
1. Janetidze Set al Brain. 2022:146:1592-1601.
PeerView.com/VQG827
ROC Curve Analysis for Differentiating MCI
Patients Who Progressed to ADD During
Follow-Up From Those Who Did Not
Nonprogressors vs Progressors
100
80
Boo
2
2 40
3 —prau2i7en — prtauieiuy
—Prtau2t7y Pau2310007
20 —Ptau21720 + P-taut@1vcor
— Ptaut810r Ptaut8t"#
— Paute. P-tauig ts
0 20 40 60 80 100
100-Specificity, %
PeerView.com
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Biological Disease Staging With Core 2 Biomarkers’
Biomarker Category E Plasma Imaging
Core 1 Biomarkers
A (AB proteinopathy) E = “Amyloid PET
Ts {phosphore und = P-tau217, P-tau161, P-tau231 -
secreted AD tau)
P-tau181/AB42, T-tau/AB42, ares _
AB42/AG40
Core 2 Biomarkers
PT205, MTBR-243,
Hybrid ratios
T, (AD tau proteinopathy) nonphosphorylated tau
fragments
Biomarkers of nonspecific Processes Involved in AD Pathophysiology
DORE NE NL ‘Anatomic MRI, FDG PET
jegeneration of neuropil)
1 inflammation) astrocytic, rap rap L
activation
Biomarkers of non-AD Co-Pathology
‘Anatomic infarction, WMA,
V (vascular brain injury) - = abundant diluted perivascular
spaces
S (a-synuclein aSyn-SAA
1: Jck CR et Revised cri for diagnosis and staging of Ames disease: Alzheimer Associaton Workgroup. In progress. m
ps laaic az org/dagnoste <reria asp. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Biomarker Category E Plasma Imaging
Core 1 Biomarkers
A (AB proteinopathy) E = “Amyloid PET
Ts {phosphore und = P-tau217, P-tau161, P-tau231 -
secreted AD tau)
P-tau181/AB42, T-tau/AB42, ares _
AB42/AG40
Core 2 Biomarkers
PT205, MTBR-243,
Hybrid ratios
T, (AD tau proteinopathy) nonphosphorylated tau
fragments
Biomarkers of nonspecific Processes Involved in AD Pathophysiology
DORE NE NL ‘Anatomic MRI, FDG PET
jegeneration of neuropil)
1 inflammation) astrocytic, rap rap L
activation
Biomarkers of non-AD Co-Pathology
‘Anatomic infarction, WMA,
V (vascular brain injury) - = abundant diluted perivascular
spaces
S (a-synuclein aSyn-SAA
1: Jck CR et Revised cri for diagnosis and staging of Ames disease: Alzheimer Associaton Workgroup. In progress. m
ps laaic az org/dagnoste <reria asp. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Updated Criteria for Biological Staging’
+ Core 2 consists of T, biomarkers and includes tau PET, pT205, MTBR-423, and nonphosphorylated tau
+ T, biomarkers are considered an indication of pathologic tau aggregates in the brain which develop later than
T, markers 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 and
- Provide information on the likelihood that symptoms are associated with AD
- Inform the risk of progression in people without symptoms
- Inform the likely rate of progression in symptomatic individuals
+ Abiological staging scheme of A through D, using tau PET regional and quantitative information, is proposed
(A)
AmYORPET Tau PET medial Tau PET moderate Tau PET high
Core tieidtest [Emporalregion neocortical uptake _ neocorlical uptake
AXT- AtTyms At Tyooe AtTycne
RAR ADO NP a PR RENE Aunemers Atocton EE Innos PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
+ Core 2 consists of T, biomarkers and includes tau PET, pT205, MTBR-423, and nonphosphorylated tau
+ T, biomarkers are considered an indication of pathologic tau aggregates in the brain which develop later than
T, markers 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 and
- Provide information on the likelihood that symptoms are associated with AD
- Inform the risk of progression in people without symptoms
- Inform the likely rate of progression in symptomatic individuals
+ Abiological staging scheme of A through D, using tau PET regional and quantitative information, is proposed
(A)
AmYORPET Tau PET medial Tau PET moderate Tau PET high
Core tieidtest [Emporalregion neocortical uptake _ neocorlical uptake
AXT- AtTyms At Tyooe AtTycne
RAR ADO NP a PR RENE Aunemers Atocton EE Innos PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Positive Tau PET Predicts Faster Cognitive Decline
Than Amyloid Positivity Alone!
Progression to MCI Progression to All-Cause Dementia
10
z z
3 3075
3 3
E El
3 3
E & 05
3 cd
2 2
2 2 025
a i a
H ArTucor
o 0
0 2 24 3 4 6 72 0 12 a 8 4 6 72
Time, mo Time, mo
Cognitively unimpaired (A:
1. Osserkoppele R et al. Nat Mod. 2022:28:2381-2387,
PeerView.com
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Than Amyloid Positivity Alone!
Progression to MCI Progression to All-Cause Dementia
10
z z
3 3075
3 3
E El
3 3
E & 05
3 cd
2 2
2 2 025
a i a
H ArTucor
o 0
0 2 24 3 4 6 72 0 12 a 8 4 6 72
Time, mo Time, mo
Cognitively unimpaired (A:
1. Osserkoppele R et al. Nat Mod. 2022:28:2381-2387,
PeerView.com
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Biomarkers of Nonspecific Processes Associated With AD
and Biomarkers of Non-AD Co-Pathology!
Biomarl
y Category CSF Plasma Imaging
Core 1 Biomarkers
A (AB proteinopathy) = = “Amyloid PET
‘Telbhoepharyisted and = P-tau217, P-tau161, P-tau231 7
secreted AD tau)
Hybrid ratios ali meg
P-tau217/nP-tau217 -
Core 2 Biomarkers
1205, MTBR243,
7, (AD tau proteinopathy) nonphosphorylated tau pT205 Tau PET
fragments
Biomarkers of Nonspecific Processes Involved in AD Pathophysiology
DEEE NL NL ‘Anatomic MRI, FDG PET
jegeneration of neuropil)
1 inflammation) astrocytic. cap rap
activation
Biomarkers of Non-AD Co-Pathology
‘Anatomic infarction, WMH,
V (vascular brain injury) - abundant diluted perivascular
spaces
1. Jack GR et al Revised extra for diagnosis and staging of Aheimers disease: Alzheimer Associaton Workgroup. In progress im
Intips:faacalzorg/siagnostic-ritera.asp. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
and Biomarkers of Non-AD Co-Pathology!
Biomarl
y Category CSF Plasma Imaging
Core 1 Biomarkers
A (AB proteinopathy) = = “Amyloid PET
‘Telbhoepharyisted and = P-tau217, P-tau161, P-tau231 7
secreted AD tau)
Hybrid ratios ali meg
P-tau217/nP-tau217 -
Core 2 Biomarkers
1205, MTBR243,
7, (AD tau proteinopathy) nonphosphorylated tau pT205 Tau PET
fragments
Biomarkers of Nonspecific Processes Involved in AD Pathophysiology
DEEE NL NL ‘Anatomic MRI, FDG PET
jegeneration of neuropil)
1 inflammation) astrocytic. cap rap
activation
Biomarkers of Non-AD Co-Pathology
‘Anatomic infarction, WMH,
V (vascular brain injury) - abundant diluted perivascular
spaces
1. Jack GR et al Revised extra for diagnosis and staging of Aheimers disease: Alzheimer Associaton Workgroup. In progress im
Intips:faacalzorg/siagnostic-ritera.asp. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Role of MRI in the Workup of MCI and AD‘?
+ MRI rules out other non-AD causes of cognitive impairment, including
— Cerebrovascular disease: microangiopathic changes and micro/lacunar infarcts
— Mass lesions: tumors, cysts, abscesses
— Traumatic brain injury: gliosis, hemorrhagic contusions, subdural hematomas
+ MRI identifies changes that are suggestive of AD
— Focal atrophy (eg, hippocampal atrophy, medial temporal lobe atrophy)
— Microbleeds that are suggestive of CAA
IRI needed to evaluate patient eligibility for ATTs
1. Mpslraologyassistant nüneuroradology dementiarle-cmn. D.
2 Dickerson 8, An A. Dementia: Comprehensive Principles and Practices. Oxford, UK: Oxford University Press; 2014 PeerView.com
PeerView.com/VQG827 Copyrigh 0-2024, PeerView
+ MRI rules out other non-AD causes of cognitive impairment, including
— Cerebrovascular disease: microangiopathic changes and micro/lacunar infarcts
— Mass lesions: tumors, cysts, abscesses
— Traumatic brain injury: gliosis, hemorrhagic contusions, subdural hematomas
+ MRI identifies changes that are suggestive of AD
— Focal atrophy (eg, hippocampal atrophy, medial temporal lobe atrophy)
— Microbleeds that are suggestive of CAA
IRI needed to evaluate patient eligibility for ATTs
1. Mpslraologyassistant nüneuroradology dementiarle-cmn. D.
2 Dickerson 8, An A. Dementia: Comprehensive Principles and Practices. Oxford, UK: Oxford University Press; 2014 PeerView.com
PeerView.com/VQG827 Copyrigh 0-2024, PeerView
(N) Biomarker: 18F-FDG PET in Dementia’
Hypometabolism measures neurodegeneration
+ Changes are multifactorial: atrophy, metabolic rate,
synaptic activity/blood flow
Differential diagnosis: pattern may discriminate between
neurodegenerative conditions
+ Changes are comparable with atrophy on MRI, but usually
easier to see visually
1. Nasrai IM, Wok DA. J Ne! Med. 2014:55:2009-2011.2. Images courtesy of Dr, Nasratan. PeerView.com
Copyright © 2000-2024, PeerView
Hypometabolism measures neurodegeneration
+ Changes are multifactorial: atrophy, metabolic rate,
synaptic activity/blood flow
Differential diagnosis: pattern may discriminate between
neurodegenerative conditions
+ Changes are comparable with atrophy on MRI, but usually
easier to see visually
1. Nasrai IM, Wok DA. J Ne! Med. 2014:55:2009-2011.2. Images courtesy of Dr, Nasratan. PeerView.com
Copyright © 2000-2024, PeerView
King's College London Cohort
(N) (Neurodegeneration) Biomarker: Plasma NfL'
Diagnostic Accuracy in Distinguishing
Sena Seeman coe Neurodegenerative Disorders From Depression
E ER, +
Lu tb:
Ea !
q j
is :
SPAS EEES, ° PERTE 5 Fo nou ©
CLARA EE ES of ana.
Ga Yen mann" par" Omar
1. Ashton NJ et al, Nat Commun, 2021:12:9400.
PeerView.com/VQG827
Nu
plasma is a sensitive but nonspecific biomarker of neurodegeneration
PeerView.com
Copyright © 2000-2024, PeerView
(N) (Neurodegeneration) Biomarker: Plasma NfL'
Diagnostic Accuracy in Distinguishing
Sena Seeman coe Neurodegenerative Disorders From Depression
E ER, +
Lu tb:
Ea !
q j
is :
SPAS EEES, ° PERTE 5 Fo nou ©
CLARA EE ES of ana.
Ga Yen mann" par" Omar
1. Ashton NJ et al, Nat Commun, 2021:12:9400.
PeerView.com/VQG827
Nu
plasma is a sensitive but nonspecific biomarker of neurodegeneration
PeerView.com
Copyright © 2000-2024, PeerView
(I) Inflammatory Biomarker: Plasma GFAP1?2
+ Plasma GFAP increases in individuals with AD
- Differentiates by amyloid PET status and increases with increasing amyloid burden
‘Group Comparisons in TRIAD Cohort Group Comparisons in Paris Cohort Group Comparisons in ALFA+ Cohort
200 — KA 1000 pco Pr
Paar + phew wo 2,
pom.
$
Plasma GFAP, pg/ml.
38
4 ‘
=:
He
Plasma GFAP,
8
+
= 5
mu
ty
i
100
ga 8
hi
E.
=
i
at
1. Benedet AL eta. JAMA Neurol 2021:78:1471-1485. 2. Teunissen CE et al. Lancet Neuro, 2022:21:86-77. oe
3. Sheherbinin § et al. JAMA Neurol. 2022:78:1015-1024. 4. van Dyck © et al. N Engl J Med. 2023;388:0-21, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
+ Plasma GFAP increases in individuals with AD
- Differentiates by amyloid PET status and increases with increasing amyloid burden
‘Group Comparisons in TRIAD Cohort Group Comparisons in Paris Cohort Group Comparisons in ALFA+ Cohort
200 — KA 1000 pco Pr
Paar + phew wo 2,
pom.
$
Plasma GFAP, pg/ml.
38
4 ‘
=:
He
Plasma GFAP,
8
+
= 5
mu
ty
i
100
ga 8
hi
E.
=
i
at
1. Benedet AL eta. JAMA Neurol 2021:78:1471-1485. 2. Teunissen CE et al. Lancet Neuro, 2022:21:86-77. oe
3. Sheherbinin § et al. JAMA Neurol. 2022:78:1015-1024. 4. van Dyck © et al. N Engl J Med. 2023;388:0-21, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
(S) a-Synuclein Biomarker: aSyn-SAA
Potential Co-Pathology in Patients With AD!*
« aSyn-SAA in CSF has gained attention in PD and DLB
+ Although no aSyn-SAA assay has received regulatory approval, one has received
Breakthrough Device Designation from the FDA and is commercially available
+ aSyn-SAA are sensitive and specific for antemortem identification of limbic/neocortical
a-synuclein pathologic change in patients with limbic/neocortical a-synuclein as a primary
or as a co-pathology
+ Assays are less sensitive to a-synuclein inclusions in multi-system atrophy where cellular
location and conformation of inclusions differ from DLB and PD
ive, or inconclusiv
utput that is |
1. Faifoul G et a. Ann Cin Trans! Neuro, 2016:3:812:818. 2. Shahnavaz M et al JAMA Neu, 2017.74:163-172. 3, Amok MR et al Am Neural 202292650462. Deer View.com
4, Rossi M et al. Acta Neuropathol. 2020;140:49-82. 5. Bargar C et al. Mol Neurodegener. 2021:16:82. 6. Poggioini | et al. Brain. 2022;145 584-595. re co
Copyright © 2000-2024, PeerView
Potential Co-Pathology in Patients With AD!*
« aSyn-SAA in CSF has gained attention in PD and DLB
+ Although no aSyn-SAA assay has received regulatory approval, one has received
Breakthrough Device Designation from the FDA and is commercially available
+ aSyn-SAA are sensitive and specific for antemortem identification of limbic/neocortical
a-synuclein pathologic change in patients with limbic/neocortical a-synuclein as a primary
or as a co-pathology
+ Assays are less sensitive to a-synuclein inclusions in multi-system atrophy where cellular
location and conformation of inclusions differ from DLB and PD
ive, or inconclusiv
utput that is |
1. Faifoul G et a. Ann Cin Trans! Neuro, 2016:3:812:818. 2. Shahnavaz M et al JAMA Neu, 2017.74:163-172. 3, Amok MR et al Am Neural 202292650462. Deer View.com
4, Rossi M et al. Acta Neuropathol. 2020;140:49-82. 5. Bargar C et al. Mol Neurodegener. 2021:16:82. 6. Poggioini | et al. Brain. 2022;145 584-595. re co
Copyright © 2000-2024, PeerView
Employing Biomarkers and Clinical
Assessment Tools to Make an
Early and Accurate Diagnosis
Sharon Cohen, MD, FRCPC 52
Neurologist and Medical Director y
Toronto Memory Program [a 1
Toronto, Ontario, Canada
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Assessment Tools to Make an
Early and Accurate Diagnosis
Sharon Cohen, MD, FRCPC 52
Neurologist and Medical Director y
Toronto Memory Program [a 1
Toronto, Ontario, Canada
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Appropriate Use of AD Biomarkers by Modality
‘Appropriate Use
Appropriate Use Appropriate Use
for CSF Test?
Clinical Scenarios
for Amyloid PET!
Patients with SCD (cognitively unimpaired based on objective testing) who are
at increased risk for AD (eg, due to APOE4 positivity) de jo Yea
Patients with MCI younger than 65 years and in whom AD pathology is va vs ve
suspected
Patients with MCI or dementia which is consistent with AD pathology vn =
(amnestic presentation) with onset at 65 years or older
Patients with MCI or dementia that could be consistent with AD pathology but Va = =
has atypical features
Patients with MCI or dementia with equivocal or inconclusive results on recent
CSF biomarkers vee be ne
To inform the prognosis of patients presenting with MCI due to clinically
suspected AD pathology Yes Yes te
To inform the prognosis of patients presenting with dementia due to clinically = es ne
suspected AD pathology
To determine eligibility for treatment with an approved amyloidtargeting ven YES es
therapy
To monitor response among patients that have received an approved = = _
amyloidtargeting therapy
if patient has contraindication to lumbar puncture Yes No No
1. Rabinovi GD et al. Updated Appropriate Use Crta for Amyloid and Tau PET in Alzheimer Disease. In Progress. his ww az orgmedia/Documens/AUC- 1) 7;
Amyloké-Tau-PET-Azheimers_ Manuscriptpdl 2. Shaw LM et al Alzheimers Dement. 2018; 14:1505-1521 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
‘Appropriate Use
Appropriate Use Appropriate Use
for CSF Test?
Clinical Scenarios
for Amyloid PET!
Patients with SCD (cognitively unimpaired based on objective testing) who are
at increased risk for AD (eg, due to APOE4 positivity) de jo Yea
Patients with MCI younger than 65 years and in whom AD pathology is va vs ve
suspected
Patients with MCI or dementia which is consistent with AD pathology vn =
(amnestic presentation) with onset at 65 years or older
Patients with MCI or dementia that could be consistent with AD pathology but Va = =
has atypical features
Patients with MCI or dementia with equivocal or inconclusive results on recent
CSF biomarkers vee be ne
To inform the prognosis of patients presenting with MCI due to clinically
suspected AD pathology Yes Yes te
To inform the prognosis of patients presenting with dementia due to clinically = es ne
suspected AD pathology
To determine eligibility for treatment with an approved amyloidtargeting ven YES es
therapy
To monitor response among patients that have received an approved = = _
amyloidtargeting therapy
if patient has contraindication to lumbar puncture Yes No No
1. Rabinovi GD et al. Updated Appropriate Use Crta for Amyloid and Tau PET in Alzheimer Disease. In Progress. his ww az orgmedia/Documens/AUC- 1) 7;
Amyloké-Tau-PET-Azheimers_ Manuscriptpdl 2. Shaw LM et al Alzheimers Dement. 2018; 14:1505-1521 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
Inappropriate Uses of AD Biomarkers'?
+ Patients who are cognitively unimpaired (outside of a preventative
clinical trial)
+ Patients with SCD who are not considered to be at increased risk
for AD (outside of a clinical trial)
Biomarker testing is + Non-medical usage (eg, legal, insurance coverage, or
rarely if ever employment screening)
In lieu of genotyping for suspected autosomal-dominant
mutation carriers
Any biomarker quantified in an unregulated, noncertified,
nonaccredited laboratory
appropriate in the
following situations:
In lieu of cognitive testing
In any facility in the absence of trained physicians
1. Rabinoviel GD etal. Updated Appropriate Use Criteria for Amyloid and Tau PET in Alzheimer’s Disease. In Progress. ps Jin alzorgimedia/Documents/AUC-
Amyoid-Tau-PET-Alzheimers_ Manuscript pa. er
2. Shaw UM eta. Alzheimers Dement. 2018:14:1505-1521 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
+ Patients who are cognitively unimpaired (outside of a preventative
clinical trial)
+ Patients with SCD who are not considered to be at increased risk
for AD (outside of a clinical trial)
Biomarker testing is + Non-medical usage (eg, legal, insurance coverage, or
rarely if ever employment screening)
In lieu of genotyping for suspected autosomal-dominant
mutation carriers
Any biomarker quantified in an unregulated, noncertified,
nonaccredited laboratory
appropriate in the
following situations:
In lieu of cognitive testing
In any facility in the absence of trained physicians
1. Rabinoviel GD etal. Updated Appropriate Use Criteria for Amyloid and Tau PET in Alzheimer’s Disease. In Progress. ps Jin alzorgimedia/Documents/AUC-
Amyoid-Tau-PET-Alzheimers_ Manuscript pa. er
2. Shaw UM eta. Alzheimers Dement. 2018:14:1505-1521 PeerView.com
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Advantages and Limitations of Three
Modalities of AD Biomarkers
Mod: Advantages
+ Associated with changes in management of patients
N with MCI and dementia + Costly without coverage
+ Long history of use and standardized interpretation + Limited capacity and availabilty
Aine CET ER PET: + Multiple FDA-approved tracers + Invasive (radiation)
+ Reflects spatial distribution and amount of pathology
+ Widely available
+ Test characteristics vary by method (sampling and
ees + Reimbursed by CMS for certain diagnoses a =>
en + Long history of use and standardized interpretation Invasive lumbar puncture)
pe > + Multiple FDA-approved tests. p
-tau181/Ap42 pe en Contraindications
+ Can be performed by a radiologist, neurologist, or | Post LP compli
advanced practice provider ost Le complications
¡CUR cdi + Not reimbursed by CMS
Plasma?" + Minimally invasive E baa FDA approved
A = Widely accosalblo * Test parormance varies by essay and messurement
nP-tau217 + Can be ordered by any provider
+ Relatively new; lacking validation in a general
Analytically validated rs
1. Wong OF et al. Jue! Med. 2010.51:913-920. 2. Rabinovil GD et al. JAMA. 2019;321:1286-1204. 3. sie CVM et al. Pharmaceuticals. 2021:14:110.
4. Chavez-Fumagall MA et al. J Alzheimers Dis Rep, 2021'5:15-30. 5. Duts FH et al Alzheimers Dement. 2016;12: 184-1636. Biter T et al. Alzheimers
‘Dement. 2016:12'517-526, 7, Janekéze § et al Ann Cin Trans! Neurol, 2016::154-165. 8. Caneveli Metal. Front Aging Neurosci. 2019:11:282. 9, Qu Y eta
"Nourse! Biobehav Rev. 2021;128:470-486, 10. LY et al. Neurology. 2022.98:0688-e609. 11 Jack CR et al Revised ortrl for diagnosis and staging of PeerView.
‘Alzheimer’s disease: Alzheimers Associaton Workgroup. In progress. htpsi/aaic air orp/iagnoste-criteria asp, ¡ew.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Modalities of AD Biomarkers
Mod: Advantages
+ Associated with changes in management of patients
N with MCI and dementia + Costly without coverage
+ Long history of use and standardized interpretation + Limited capacity and availabilty
Aine CET ER PET: + Multiple FDA-approved tracers + Invasive (radiation)
+ Reflects spatial distribution and amount of pathology
+ Widely available
+ Test characteristics vary by method (sampling and
ees + Reimbursed by CMS for certain diagnoses a =>
en + Long history of use and standardized interpretation Invasive lumbar puncture)
pe > + Multiple FDA-approved tests. p
-tau181/Ap42 pe en Contraindications
+ Can be performed by a radiologist, neurologist, or | Post LP compli
advanced practice provider ost Le complications
¡CUR cdi + Not reimbursed by CMS
Plasma?" + Minimally invasive E baa FDA approved
A = Widely accosalblo * Test parormance varies by essay and messurement
nP-tau217 + Can be ordered by any provider
+ Relatively new; lacking validation in a general
Analytically validated rs
1. Wong OF et al. Jue! Med. 2010.51:913-920. 2. Rabinovil GD et al. JAMA. 2019;321:1286-1204. 3. sie CVM et al. Pharmaceuticals. 2021:14:110.
4. Chavez-Fumagall MA et al. J Alzheimers Dis Rep, 2021'5:15-30. 5. Duts FH et al Alzheimers Dement. 2016;12: 184-1636. Biter T et al. Alzheimers
‘Dement. 2016:12'517-526, 7, Janekéze § et al Ann Cin Trans! Neurol, 2016::154-165. 8. Caneveli Metal. Front Aging Neurosci. 2019:11:282. 9, Qu Y eta
"Nourse! Biobehav Rev. 2021;128:470-486, 10. LY et al. Neurology. 2022.98:0688-e609. 11 Jack CR et al Revised ortrl for diagnosis and staging of PeerView.
‘Alzheimer’s disease: Alzheimers Associaton Workgroup. In progress. htpsi/aaic air orp/iagnoste-criteria asp, ¡ew.com
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Potential Confounders and Mitigation
for AD Blood-Based Biomarkers’
Possible Confounder Mitigation
Demographic characteristics Establish adjustment factor or prospective cut-point validation by
(eg, age, sex, race, ethnicity) enrolling a diverse population into clinical trials
Biotin and supplements Stop all supplements 72 hours before blood draw
CKD Establish adjustment factor or prospective cut-point validation for renal function
Genetic disorders Establish adjustment factor or prospective cut-point validation for genetic
(eg, tuberous sclerosis) subpopulations and compare with confirmatory CSF findings prospectively
Intraindividual and Perform serial sampling at regular intervals in fasted and fed state in clinic
test-retest variation to assess validity of testing before broader implementation
Screen for OSA and other respiratory illness causing hypoxemia;
if positive, consider 6-month treatment before biomarker testing in
patients with SCI/SCD/MCI
OSA, obstructive
sleep-disordered breathing
1. Pleen J eta. Practica Neurology, 2024,2327-42 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
for AD Blood-Based Biomarkers’
Possible Confounder Mitigation
Demographic characteristics Establish adjustment factor or prospective cut-point validation by
(eg, age, sex, race, ethnicity) enrolling a diverse population into clinical trials
Biotin and supplements Stop all supplements 72 hours before blood draw
CKD Establish adjustment factor or prospective cut-point validation for renal function
Genetic disorders Establish adjustment factor or prospective cut-point validation for genetic
(eg, tuberous sclerosis) subpopulations and compare with confirmatory CSF findings prospectively
Intraindividual and Perform serial sampling at regular intervals in fasted and fed state in clinic
test-retest variation to assess validity of testing before broader implementation
Screen for OSA and other respiratory illness causing hypoxemia;
if positive, consider 6-month treatment before biomarker testing in
patients with SCI/SCD/MCI
OSA, obstructive
sleep-disordered breathing
1. Pleen J eta. Practica Neurology, 2024,2327-42 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
Commercially Available Biomarkers for AD?
FDA-Approved/CLIA-
Test Name (Developer) Biomarker Modality Biomarkers Assay Platform _ Certified/Breakthrough
Device Status
Florbetapi (Lily) ‘Amyloid PET “Amyloid plaques: NA FDA-approved
Florbetaben (Life Molecular Imaging) Amyloid PET Amyloid plaques: NA FDA approved
Flutemetamol (GE Healthcare) ‘Amyloid PET ‘Amyloid plaques NA FDA-approved
Flortaucipir (Lill) Tau PET Tau aggregates NA FDA-approved
Eleosys AD (Roche) CSF Petaut8t/Ap42, T-tawAß42 Eleosys FDA-approved
Lumipuise G (Fujirebio) csr AQAZIAO Lumipuise FDA-approved
‘AD-Detect (Quest Diagnostics) Plasma 64240 IPLC-MSMS CLA-certiied
‘Amyloid Plasma Panel (Roche, Lily) Plasma u Breakthrough device
ATN Profle (Labcorp) Plasma AG42/A40, P.tau181, NIL Simoa CLA-certfied
Lucent-AD (Lucent Diagnostics) Plasma P-tau217 Simoa cuiAcertiied
PreciviyAD (C2N) Plasma ‘AB42I40, APOE4 status, age IP-LC-MSMS CLiAbreakthrough
PreciviyAD2 (C2N) Plasma haran dl IP-LO-MSIMS CLiAcertiied
1 Pleen Jet al Practical Neurology, 2024282742, 2. Hampel etal Neon. 2021112701270. Peel VieW.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
FDA-Approved/CLIA-
Test Name (Developer) Biomarker Modality Biomarkers Assay Platform _ Certified/Breakthrough
Device Status
Florbetapi (Lily) ‘Amyloid PET “Amyloid plaques: NA FDA-approved
Florbetaben (Life Molecular Imaging) Amyloid PET Amyloid plaques: NA FDA approved
Flutemetamol (GE Healthcare) ‘Amyloid PET ‘Amyloid plaques NA FDA-approved
Flortaucipir (Lill) Tau PET Tau aggregates NA FDA-approved
Eleosys AD (Roche) CSF Petaut8t/Ap42, T-tawAß42 Eleosys FDA-approved
Lumipuise G (Fujirebio) csr AQAZIAO Lumipuise FDA-approved
‘AD-Detect (Quest Diagnostics) Plasma 64240 IPLC-MSMS CLA-certiied
‘Amyloid Plasma Panel (Roche, Lily) Plasma u Breakthrough device
ATN Profle (Labcorp) Plasma AG42/A40, P.tau181, NIL Simoa CLA-certfied
Lucent-AD (Lucent Diagnostics) Plasma P-tau217 Simoa cuiAcertiied
PreciviyAD (C2N) Plasma ‘AB42I40, APOE4 status, age IP-LC-MSMS CLiAbreakthrough
PreciviyAD2 (C2N) Plasma haran dl IP-LO-MSIMS CLiAcertiied
1 Pleen Jet al Practical Neurology, 2024282742, 2. Hampel etal Neon. 2021112701270. Peel VieW.com
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Patient: Kevin
Initial Presentation and Medical History
+ 56-year-old gentleman presented to primary care with trouble coming up with words. He sometimes
substitutes wrong words and does not complete sentences; spelling has also declined
+ He endorses mild change in memory and multitasking but communication is his main concern
+ He has withdrawn from social interactions due to his trouble communicating and has mild anxiety and
depressive symptoms due to his communication difficulties
Medical and Social History
+ Diagnosed with hypertension 7 years ago + Lab work (CBC, glucose, HbA‘cTSH, B12,
+ Concussion from MVA 5 years ago; full recovery hepatic and renal function, lipids) all normal
©. Current medication: Lisinopril + Family history negative for dementia
+ Exercises 3x/week and has a healthy diet — Mother living and cognitively well
+ 2-3 drinks, 2 nights per week - Father died at age 72 from a stroke
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Initial Presentation and Medical History
+ 56-year-old gentleman presented to primary care with trouble coming up with words. He sometimes
substitutes wrong words and does not complete sentences; spelling has also declined
+ He endorses mild change in memory and multitasking but communication is his main concern
+ He has withdrawn from social interactions due to his trouble communicating and has mild anxiety and
depressive symptoms due to his communication difficulties
Medical and Social History
+ Diagnosed with hypertension 7 years ago + Lab work (CBC, glucose, HbA‘cTSH, B12,
+ Concussion from MVA 5 years ago; full recovery hepatic and renal function, lipids) all normal
©. Current medication: Lisinopril + Family history negative for dementia
+ Exercises 3x/week and has a healthy diet — Mother living and cognitively well
+ 2-3 drinks, 2 nights per week - Father died at age 72 from a stroke
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Patient: Kevin (Cont’d)
Neuropsychological Assessment Structural Imaging
MMSE 25/30; CDR global 0.5, sum of boxes 2.5 + Structural MRI showed mild cerebral white matter
Impaired working memory T2/FLAIR hyperintensities consistent with
Impaired phonemic fluency microvascular disease
Impaired semantic fluency
Picture naming impaired (BNT 10/15)
Verbal memory impaired for encoding and retrieval
Visuospatial function impaired
Mild depression symptoms
FAQ: 3/30 (difficulty with taxes but still does them
on his own; still plays games of skill and strategy)
Clinical diagnosis: MCI
Etiology: AD? Versus FTD? What would you do next?
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Neuropsychological Assessment Structural Imaging
MMSE 25/30; CDR global 0.5, sum of boxes 2.5 + Structural MRI showed mild cerebral white matter
Impaired working memory T2/FLAIR hyperintensities consistent with
Impaired phonemic fluency microvascular disease
Impaired semantic fluency
Picture naming impaired (BNT 10/15)
Verbal memory impaired for encoding and retrieval
Visuospatial function impaired
Mild depression symptoms
FAQ: 3/30 (difficulty with taxes but still does them
on his own; still plays games of skill and strategy)
Clinical diagnosis: MCI
Etiology: AD? Versus FTD? What would you do next?
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Patient: Kevin (Cont’d)
9 performed: P-taut81/A842 = 0.054 pg/mLf
+ This is a positive test result (>0.023 pg/mL is abnormal)
+ Since Kevin is young and reports predominantly language symptoms, his clinical differential diagnosis lies between
language variant AD and FTD; his CSF Core 1 biomarker is, however, consistent with AD
+ Atau-PET scan was then ordered to further stage his disease and showed moderate uptake in the neocortex
(left frontal and bitemporal neocortical regions)
Initial-Stage Early-Stage |Intermediate-Stage Advanced-Stage
Biomarkers Biomarkers Biomarkers Biomarkers
What is his AD A) (6) © ©)
Tau PET medial | TauPET moderate | Tau PET high
temporal region | neocortical uptake | neocortical uptake
Atom Ar Too AT
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9 performed: P-taut81/A842 = 0.054 pg/mLf
+ This is a positive test result (>0.023 pg/mL is abnormal)
+ Since Kevin is young and reports predominantly language symptoms, his clinical differential diagnosis lies between
language variant AD and FTD; his CSF Core 1 biomarker is, however, consistent with AD
+ Atau-PET scan was then ordered to further stage his disease and showed moderate uptake in the neocortex
(left frontal and bitemporal neocortical regions)
Initial-Stage Early-Stage |Intermediate-Stage Advanced-Stage
Biomarkers Biomarkers Biomarkers Biomarkers
What is his AD A) (6) © ©)
Tau PET medial | TauPET moderate | Tau PET high
temporal region | neocortical uptake | neocortical uptake
Atom Ar Too AT
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Revised Clinical Staging for Individuals on
the Alzheimer’s Disease Continuum!
Stage 0: Asymptomatic, deterministic gene or Trisomy 21
Stage 1: Asymptomatic, biomarker evidence only
Stage 2: Transitional decline: Mild detectable change, but
Amyloid-targeting function
therapies are early functional impact (MCI)
approved for
patients in Stage 4: Dementia with mild functional impairment
stages 3 and4
Stage 5: Dementia with moderate functional impairment
Stage 6: Dementia with severe functional impairment
1. Jack CR et al Revise teria for diagnosis and staging of Alzheimers disease: Alzheimer Association Werkgroup. In progress. m
tps lac aiz orp/tagnoste-criteria asp. PeerView.com
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the Alzheimer’s Disease Continuum!
Stage 0: Asymptomatic, deterministic gene or Trisomy 21
Stage 1: Asymptomatic, biomarker evidence only
Stage 2: Transitional decline: Mild detectable change, but
Amyloid-targeting function
therapies are early functional impact (MCI)
approved for
patients in Stage 4: Dementia with mild functional impairment
stages 3 and4
Stage 5: Dementia with moderate functional impairment
Stage 6: Dementia with severe functional impairment
1. Jack CR et al Revise teria for diagnosis and staging of Alzheimers disease: Alzheimer Association Werkgroup. In progress. m
tps lac aiz orp/tagnoste-criteria asp. PeerView.com
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Integrated Biological and Clinical Staging’
2024 Integrated Biological and Clinical Staging
jological Stage Stage Clinical Clinical Clinical Clinical Clinical Clinical
of AD 0 Stage1 Stage2 Stage3 Stage4 Stage5 Stage6
What is Kevin's
A Initial st x 1A 2A 3A aA 5A 6A
integrated biological "ae
and clinical staging Early stage x 1B 28 38 48 58 68
score, based on the re
? termediat
update? 3C pau x 1c 2c [+] 4c 5c 6c
Advancedstage X 1D 2D 3D 4D 5D 6D
Display format is intended to convey that biological AD stage and clinical severity are related,
but do not travel in lockstep
Typical relationship between biology and symptoms moves along an upper left to lower right diagonal (gray cells)
Those in cells above diagonal (ie, worse clinical stage than expected for biological stage; blue cells) are expected to have
greater comorbid pathologic change
Those in cells below diagonal (ie, better clinical stage than expected for biological stage; green cells) may have exceptional
resilience or cognitive reserve
1. Jack CR et al. Revised cera for diagnosis and staging of Alzheimers disease: Alzheimer's Associaton Workgroup. In progress.
ps asi air org/dagnoste mena asp. PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
2024 Integrated Biological and Clinical Staging
jological Stage Stage Clinical Clinical Clinical Clinical Clinical Clinical
of AD 0 Stage1 Stage2 Stage3 Stage4 Stage5 Stage6
What is Kevin's
A Initial st x 1A 2A 3A aA 5A 6A
integrated biological "ae
and clinical staging Early stage x 1B 28 38 48 58 68
score, based on the re
? termediat
update? 3C pau x 1c 2c [+] 4c 5c 6c
Advancedstage X 1D 2D 3D 4D 5D 6D
Display format is intended to convey that biological AD stage and clinical severity are related,
but do not travel in lockstep
Typical relationship between biology and symptoms moves along an upper left to lower right diagonal (gray cells)
Those in cells above diagonal (ie, worse clinical stage than expected for biological stage; blue cells) are expected to have
greater comorbid pathologic change
Those in cells below diagonal (ie, better clinical stage than expected for biological stage; green cells) may have exceptional
resilience or cognitive reserve
1. Jack CR et al. Revised cera for diagnosis and staging of Alzheimers disease: Alzheimer's Associaton Workgroup. In progress.
ps asi air org/dagnoste mena asp. PeerView.com
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Incorporating New and
Emerging DMTs Into
Customized Treatment Plans
Sharon Cohen, MD, FRCPC
Neurologist and Medical Director
Toronto Memory Program
Toronto, Ontario, Canada
A
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Emerging DMTs Into
Customized Treatment Plans
Sharon Cohen, MD, FRCPC
Neurologist and Medical Director
Toronto Memory Program
Toronto, Ontario, Canada
A
Go online to access full CME/MOC/AAPA information, including faculty disclosures.
Copyright © 2000-2024, PeerView
Anti-AB Monoclonal Antibodies for Alzheimer’s Disease‘
2024
FDA advisory committee
July 2023 meeting to be held to
Lecanemab received full discuss donanemab
traditional FDA approval for
the treatment of early AD
June 2021
Aducanumab received FDA
accelerated approval for the
treatment of early AD January 2024
Manufacturer announced
di ti ti f
January 2023 ta.
Lecanemab received FDA
accelerated approval for the
treatment of early AD
1. ps: fda govinews-events/press-announcements/tda-grants-accelerated-approvalalzheimers-drug
2 hits wiv da govinews-evens/press-announcementstéa-convers-novelalzhemmers-isease-teatmenttraditonah approval
3 tps sr ightocus orpalzneme'sinewsialoheme'srug-adchelm-be-ascortnves i
4. tos ww euters.com/business/nealtncare-pharmaceuticals/us-{da-delays ily alzheimers-drug-decision-cals-advisory pane 2024-03-08, PeerView.com
Peerview.com/VQG827 Copyright © 2000-2024, PeerView
2024
FDA advisory committee
July 2023 meeting to be held to
Lecanemab received full discuss donanemab
traditional FDA approval for
the treatment of early AD
June 2021
Aducanumab received FDA
accelerated approval for the
treatment of early AD January 2024
Manufacturer announced
di ti ti f
January 2023 ta.
Lecanemab received FDA
accelerated approval for the
treatment of early AD
1. ps: fda govinews-events/press-announcements/tda-grants-accelerated-approvalalzheimers-drug
2 hits wiv da govinews-evens/press-announcementstéa-convers-novelalzhemmers-isease-teatmenttraditonah approval
3 tps sr ightocus orpalzneme'sinewsialoheme'srug-adchelm-be-ascortnves i
4. tos ww euters.com/business/nealtncare-pharmaceuticals/us-{da-delays ily alzheimers-drug-decision-cals-advisory pane 2024-03-08, PeerView.com
Peerview.com/VQG827 Copyright © 2000-2024, PeerView
Lecanemab Met Its Primary and
Secondary Clinical Endpoints’
Tecanemab MEN Slowed Den Progression on COR SB TS NN
. Zo
iy A BES
+ 04 Locanemab at 18mo.-0451 LE
> 27% slowir ES
ES o BES -
ae 5
oa oe
eg &
Ea ig:
e 3 y
Bu E,
3
38 2]
o 3
7 2 5 1
vial wo o 3 5 5 Rn 0‘
Lecanemab Significantly Slowed Disease Progression on ADCS MCI-ADL
o
(2 SE) in ADCOMS
‘Adjusted Mean Change From
Visit, mo"? a o 3 y
5
1. van Dyek Get al N Engl J Med. 2023:368:9-21 PeerView.com
“peo Pope y
P< 01. P<.0001.¢P<.001. Va
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Secondary Clinical Endpoints’
Tecanemab MEN Slowed Den Progression on COR SB TS NN
. Zo
iy A BES
+ 04 Locanemab at 18mo.-0451 LE
> 27% slowir ES
ES o BES -
ae 5
oa oe
eg &
Ea ig:
e 3 y
Bu E,
3
38 2]
o 3
7 2 5 1
vial wo o 3 5 5 Rn 0‘
Lecanemab Significantly Slowed Disease Progression on ADCS MCI-ADL
o
(2 SE) in ADCOMS
‘Adjusted Mean Change From
Visit, mo"? a o 3 y
5
1. van Dyek Get al N Engl J Med. 2023:368:9-21 PeerView.com
“peo Pope y
P< 01. P<.0001.¢P<.001. Va
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Lecanemab Improved Amyloid Biomarkers’
e CSF ABA2/AB40
238°] easaine 0040047
Sue e a
SBE 0m a
Lecanemab Significantly Reduced Fibrillar Amyloid Burden # Lecanemab,
ES 0m
por &
A ID 333 0
BS 0 36 o
Êz
Pepe ER
ER Em
BES 2 Mean <30 o = Te
bee Cents tr Vist, mo
Pr: emos at
as” tomo
222404 saseine 750779 seer Plasma AB42/AB40
323 comets, 2 3 0.01) Baseline 0.088-0.088 ‘5
E fog i e.
=a HE
23 oom
33: 0002
868 o.
3° ° 8
pe. Visit, mo
PeerView.com
1. van Dyck Get al. N Engl J Med. 2023:388:9-21
Peerview.com/VQG827 Copyright © 2000-2024, PeerView
e CSF ABA2/AB40
238°] easaine 0040047
Sue e a
SBE 0m a
Lecanemab Significantly Reduced Fibrillar Amyloid Burden # Lecanemab,
ES 0m
por &
A ID 333 0
BS 0 36 o
Êz
Pepe ER
ER Em
BES 2 Mean <30 o = Te
bee Cents tr Vist, mo
Pr: emos at
as” tomo
222404 saseine 750779 seer Plasma AB42/AB40
323 comets, 2 3 0.01) Baseline 0.088-0.088 ‘5
E fog i e.
=a HE
23 oom
33: 0002
868 o.
3° ° 8
pe. Visit, mo
PeerView.com
1. van Dyck Get al. N Engl J Med. 2023:388:9-21
Peerview.com/VQG827 Copyright © 2000-2024, PeerView
Lecanemab Improved Tau and
Neurodegeneration Biomarkers?
CSF P-Tau181 Plasma P-Tau181
Placebo
PEZ 22 ] Bsseine 02092402
15 Piecovo
522 10
FEE 5
EA
2: 5
SES +10
228 as
20
o y 3 7
Visi mo
CSF Neurogranin
50 y Baseline 519.1-500.1
‘Adjusted Mean Change
From Baseline (£ SE) in
(CSF Neurogranin, pgm.
as Visit, mo
2p< 001
1. van Dyck G et a. M Eng! J Med. 2025386 9-21 A
2 Legembi(lecanemab) Preserbing Information. htps./uwaccessdata1da govidrugsatida,_ docsñabel/2023/7612690191500 1 pat PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Neurodegeneration Biomarkers?
CSF P-Tau181 Plasma P-Tau181
Placebo
PEZ 22 ] Bsseine 02092402
15 Piecovo
522 10
FEE 5
EA
2: 5
SES +10
228 as
20
o y 3 7
Visi mo
CSF Neurogranin
50 y Baseline 519.1-500.1
‘Adjusted Mean Change
From Baseline (£ SE) in
(CSF Neurogranin, pgm.
as Visit, mo
2p< 001
1. van Dyck G et a. M Eng! J Med. 2025386 9-21 A
2 Legembi(lecanemab) Preserbing Information. htps./uwaccessdata1da govidrugsatida,_ docsñabel/2023/7612690191500 1 pat PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Donanemab Met Its Primary
and Secondary Clinical Endpoints!
TAORS! Low Medium Tou Population THORS! Combined Tau Population
la Doramas ES do
Ka $ 88
Er Fr I» M
Bao Bao
3 L
du de
Timo, wh Time wt
COR 82: Low edu Tau Population COR.SB: Combined Tau Population
8 8
po A
Bao leg ‘
35 38 4
FFM HE que
7
À 20 I ls
A ta
a sr Timm k Timo, wk PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
and Secondary Clinical Endpoints!
TAORS! Low Medium Tou Population THORS! Combined Tau Population
la Doramas ES do
Ka $ 88
Er Fr I» M
Bao Bao
3 L
du de
Timo, wh Time wt
COR 82: Low edu Tau Population COR.SB: Combined Tau Population
8 8
po A
Bao leg ‘
35 38 4
FFM HE que
7
À 20 I ls
A ta
a sr Timm k Timo, wk PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Donanemab Improved Amyloid Biomarkers
Adjusted Mean Change (95% Cl) in Participants With Amyloid Clearance
Amyloid PET (<24.1 Centiloids)
100 y Lowmedlum tau
o
E So
32 Low/medium tau = Combined
2 A Donanemab 3
E Ariane S 60 | mmOnaneneo
Se Combined E [ee
E e Donanemab g
a 60 Placebo 2 4
3 $
2 Él
z= § 2»
<
400 o
0 Rn a 2 o 76 2 52 76
Time After Baseline, wk Time After Baseline, wk
Sim Reta sun 2029990 1257 PeerView.com
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Adjusted Mean Change (95% Cl) in Participants With Amyloid Clearance
Amyloid PET (<24.1 Centiloids)
100 y Lowmedlum tau
o
E So
32 Low/medium tau = Combined
2 A Donanemab 3
E Ariane S 60 | mmOnaneneo
Se Combined E [ee
E e Donanemab g
a 60 Placebo 2 4
3 $
2 Él
z= § 2»
<
400 o
0 Rn a 2 o 76 2 52 76
Time After Baseline, wk Time After Baseline, wk
Sim Reta sun 2029990 1257 PeerView.com
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Donanemab Improved Tau Biomarkers’
Low-Medium Tau Population Combined Population
39% decrease by donanemab at 76 wk 35% decrease by donanemab at 76 wk
00
|
} 29% merase
- ge
ms too
ge el. ook: toma Boge eee
ues SE m
ag 0 22
FPT me fin iene
io iy oon
7 +2 ¿ 2 on
pe ss
ung
PeerView.com
1. Sims JR et a. JAMA, 2023:300:512:527,
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Low-Medium Tau Population Combined Population
39% decrease by donanemab at 76 wk 35% decrease by donanemab at 76 wk
00
|
} 29% merase
- ge
ms too
ge el. ook: toma Boge eee
ues SE m
ag 0 22
FPT me fin iene
io iy oon
7 +2 ¿ 2 on
pe ss
ung
PeerView.com
1. Sims JR et a. JAMA, 2023:300:512:527,
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Selecting Patients to Treat With Anti-AB
Monoclonal Antibodies!?
FDA Prescribing Info and Appropriate Use Recommendations for Lecanemab
R for lecanemab more restrictive than the FDA prescribing information
Inclusions Exclusions
1. Clinical diagnosis of MCI or mild dementia 1. Contraindication to MRI procedure
due to AD 2. MRI with >4 microhemorrhages, >1 area of
2. Confirmed amyloid positivity superficial siderosis or significant cerebrovascular
(PET or CSF) disease, severe white matter changes,
macrohemorrhage, >2 lacunar infarcts, or a single
3. MMSE = 22-30 or other cognitive screening infarct tien
instrument with a score compatible with
early AD (eg, MOCA 218) 3. Anticoagulant use (AUR restriction)
4. Unstable medical/psychiatric conditions
APOE £4 genotype testing is recommended for all patients considering treatment
with anti-AB monoclonal antibodies to inform discussion with patients and
care partners about risks/benefits of treatment
cummings Je a. Prov Alzheimer Ds, 2023:10262:97.2. van Dyck Cet al. N Engl J Mad. 2028388921 air:
egembi (ecanemab) Preserbing Information. ttps:hvww.accessdata fda gov drugsatida_ docs/abel2023/76126901415001IbIpat PeerView.com
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Monoclonal Antibodies!?
FDA Prescribing Info and Appropriate Use Recommendations for Lecanemab
R for lecanemab more restrictive than the FDA prescribing information
Inclusions Exclusions
1. Clinical diagnosis of MCI or mild dementia 1. Contraindication to MRI procedure
due to AD 2. MRI with >4 microhemorrhages, >1 area of
2. Confirmed amyloid positivity superficial siderosis or significant cerebrovascular
(PET or CSF) disease, severe white matter changes,
macrohemorrhage, >2 lacunar infarcts, or a single
3. MMSE = 22-30 or other cognitive screening infarct tien
instrument with a score compatible with
early AD (eg, MOCA 218) 3. Anticoagulant use (AUR restriction)
4. Unstable medical/psychiatric conditions
APOE £4 genotype testing is recommended for all patients considering treatment
with anti-AB monoclonal antibodies to inform discussion with patients and
care partners about risks/benefits of treatment
cummings Je a. Prov Alzheimer Ds, 2023:10262:97.2. van Dyck Cet al. N Engl J Mad. 2028388921 air:
egembi (ecanemab) Preserbing Information. ttps:hvww.accessdata fda gov drugsatida_ docs/abel2023/76126901415001IbIpat PeerView.com
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Step-by-Step Guidance From Diagnosis to Treatment With
Anti-AB Monoclonal Antibody Infusions‘
Step 1: Assess cognition; confirm clinical diagnosis of MCI or mild dementia presumed
to be due to AD based on history, physical, and cognitive testing
Step 2: Structural imaging (eg, MRI) and lab tests to rule out non-AD etiologies and
contributors (tip: you can evaluate potential MRI eligibility for monoclonal ATT using the
same MRI as long as appropriate MRI sequences are obtained)
Step 3: Confirm AD diagnosis with a Core 1 biomarker of AB pathology
Step 4: MRI to rule out exclusionary findings for monoclonal ATT if not done in step 2;
consider ordering APOE genotyping to inform risk/benefit discussion
Step chedule follow-up MRIs to monitor for ARI, ed to order unscheduled
MRIs in the event of symptoms suggestive of ARIA
1. ips ww legembinep.com-mediaFiles/Legembiep/Diagnosis-Brochure pd?hash=48 1b2689-a662-4d1a-9te-2oc boe7dba7, PeerView.com
m/VQG827 Copyright © 2000-2024, PeerView
Anti-AB Monoclonal Antibody Infusions‘
Step 1: Assess cognition; confirm clinical diagnosis of MCI or mild dementia presumed
to be due to AD based on history, physical, and cognitive testing
Step 2: Structural imaging (eg, MRI) and lab tests to rule out non-AD etiologies and
contributors (tip: you can evaluate potential MRI eligibility for monoclonal ATT using the
same MRI as long as appropriate MRI sequences are obtained)
Step 3: Confirm AD diagnosis with a Core 1 biomarker of AB pathology
Step 4: MRI to rule out exclusionary findings for monoclonal ATT if not done in step 2;
consider ordering APOE genotyping to inform risk/benefit discussion
Step chedule follow-up MRIs to monitor for ARI, ed to order unscheduled
MRIs in the event of symptoms suggestive of ARIA
1. ips ww legembinep.com-mediaFiles/Legembiep/Diagnosis-Brochure pd?hash=48 1b2689-a662-4d1a-9te-2oc boe7dba7, PeerView.com
m/VQG827 Copyright © 2000-2024, PeerView
Practical Tips for Implementing Anti-AB Therapy
in Clinical Practice
Develop site-specific protocol that takes into account all local stakeholders
If external infusion center, GO VISIT it and meet with staff and medical director
Develop local inclusion/exclusion criteria and consider a consensus process to
review cases for infusion depending on HCP expertise
Ensure radiology and nuclear medicine have capacity for scans and expertise
in reading them
Meet with the emergency department to review signs and symptoms of ARIA
Discuss with any covering physicians the signs, symptoms, and management
of ARIA
Consider asking patients to get a medical alert bracelet signifying they are on
an anti-AB therapy or to carry a wallet card
PeerView.com
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in Clinical Practice
Develop site-specific protocol that takes into account all local stakeholders
If external infusion center, GO VISIT it and meet with staff and medical director
Develop local inclusion/exclusion criteria and consider a consensus process to
review cases for infusion depending on HCP expertise
Ensure radiology and nuclear medicine have capacity for scans and expertise
in reading them
Meet with the emergency department to review signs and symptoms of ARIA
Discuss with any covering physicians the signs, symptoms, and management
of ARIA
Consider asking patients to get a medical alert bracelet signifying they are on
an anti-AB therapy or to carry a wallet card
PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
What Are Amyloid-Related Imaging Abnormalities ?12
ARIA results from amyloid in cerebral vessels (CAA) and can occur spontaneously in AD
Treatment- + Risk of ARIA increases with antibodies that clear aggregated amyloid
related changes + Two types of ARIA
noted on brain swelling (vasogenic edema)
RENE microhemorrhage, superficial siderosis, macro-hemorrhage
ARIA-E and + ARIAis typically asymptomatic and resolves spontaneously
ARIA-H + When symptoms occur, they are usually mild-moderate (eg, headache, dizziness)
+ However, although rare, serious and life-threatening events can occur
ARIA-E ARIA-H
A L
1. Spering Ret al Alzheimers Demont.2011.7:367-385, 2. Cogswell P et al. AINR Am J Neuroradil 202243:£19:£35, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
ARIA results from amyloid in cerebral vessels (CAA) and can occur spontaneously in AD
Treatment- + Risk of ARIA increases with antibodies that clear aggregated amyloid
related changes + Two types of ARIA
noted on brain swelling (vasogenic edema)
RENE microhemorrhage, superficial siderosis, macro-hemorrhage
ARIA-E and + ARIAis typically asymptomatic and resolves spontaneously
ARIA-H + When symptoms occur, they are usually mild-moderate (eg, headache, dizziness)
+ However, although rare, serious and life-threatening events can occur
ARIA-E ARIA-H
A L
1. Spering Ret al Alzheimers Demont.2011.7:367-385, 2. Cogswell P et al. AINR Am J Neuroradil 202243:£19:£35, PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, Peerview
ARIA Risk Factors and Monitoring!
ARIA risk factors
APOE e4 copy number
Dose of anti-AB monoclonal antibody
Presence and severity of underlying cerebral amyloid angiopathy
Presence of extensive ischemic cerebrovascular disease
Anti-AB antibodies require MRI assessment and monitoring before and
during treatment
+ At baseline (up to 1 year prior to treatment initiation)
» At recommended intervals (early in treatment and during titration period if any)
+ In response to symptoms suggesting possible ARIA
+ Important to obtain consistent serial imaging by using a standardized imaging protocol
with the same field strength for every MRI assessment
4. Spering R et al. Alzheimers Dement. 2011:7.387-385, 2. Cogswell P et al. AUNR Am J Neuroradiol. 2022:43:E19-E35,
3. Cummings Jet al. J Prov Alzheimers Dis. 2023:10:362.377.
PeerView.com
PeerView.com/VQG827
Copyright © 2000-2024, PeerView
ARIA risk factors
APOE e4 copy number
Dose of anti-AB monoclonal antibody
Presence and severity of underlying cerebral amyloid angiopathy
Presence of extensive ischemic cerebrovascular disease
Anti-AB antibodies require MRI assessment and monitoring before and
during treatment
+ At baseline (up to 1 year prior to treatment initiation)
» At recommended intervals (early in treatment and during titration period if any)
+ In response to symptoms suggesting possible ARIA
+ Important to obtain consistent serial imaging by using a standardized imaging protocol
with the same field strength for every MRI assessment
4. Spering R et al. Alzheimers Dement. 2011:7.387-385, 2. Cogswell P et al. AUNR Am J Neuroradiol. 2022:43:E19-E35,
3. Cummings Jet al. J Prov Alzheimers Dis. 2023:10:362.377.
PeerView.com
PeerView.com/VQG827
Copyright © 2000-2024, PeerView
Symptoms/Signs Consistent With ARIA That Should Trigger
Out-of-Sequence MRI for Patients Receiving an ATT'$
Acute or Subacute Onset of New Symptom Severity
Neurological Signs or Symptoms + Mild Symptoms: Discomfort noted;
Headache no disruption of daily activity
Confusion/altered mental + Moderate Symptoms: Discomfort
status/delirium/disorientation sufficient to reduce or affect normal
Dizziness/vertigo daily activity
Nausea + Severe Symptoms: Incapacitating,
Vomiting with inability to work or to perform
+ Fatigue normal daily activity
Vision disturbance/impairment
Gait disturbance
Seizures
1. Cummings J etal. Prev Alzheimers Dis, 2023:10:362-377. 2. Cummings J etal. J Prev Alzheimers Dis. 20222221-230, x
3. Cummings Jet al. J Prev Alzheimers Dis, 2021:4:398-410, PeerView.com
PeerView.com/VQG827 Copyrigh
Out-of-Sequence MRI for Patients Receiving an ATT'$
Acute or Subacute Onset of New Symptom Severity
Neurological Signs or Symptoms + Mild Symptoms: Discomfort noted;
Headache no disruption of daily activity
Confusion/altered mental + Moderate Symptoms: Discomfort
status/delirium/disorientation sufficient to reduce or affect normal
Dizziness/vertigo daily activity
Nausea + Severe Symptoms: Incapacitating,
Vomiting with inability to work or to perform
+ Fatigue normal daily activity
Vision disturbance/impairment
Gait disturbance
Seizures
1. Cummings J etal. Prev Alzheimers Dis, 2023:10:362-377. 2. Cummings J etal. J Prev Alzheimers Dis. 20222221-230, x
3. Cummings Jet al. J Prev Alzheimers Dis, 2021:4:398-410, PeerView.com
PeerView.com/VQG827 Copyrigh
PeerView.com/VQG827
Characterizing ARIA Radiographic Severity1-8
ARIA MRI Classification Criteria
Radiographic Severity
ARIA Type
Moderate
FLAIR hyperintensity
measure >10 cm, often with
FLAIR hyperiniensiy confined FLAIR hyperintensity 5-10 cm, or significant subcortical white
ARIA-E o matter more than 1 ste o involvement, | matter and/or sulcal
‘each measure <10 cm involvement; 1 or more
in 1 location <5 om separate sites of
involvement might be noted
<4 new incident 5-9 new incident 210 new incident
ARIA-H microhemorthi
R ee microhemorrhages microhemorrhages microhemorrhages
ARIAH superficial siderosis. 1 focal area of superficial 2 focal areas of superficial 2 focal areas of superficial
siderosis siderosi siderosis
1. Cummings J eta. J Prev Alzheimers Dis. 2028;10:262-377. 2. Cummings Jet al. Prev Alzheimers Dis. 20222:221-230.
3. Cummings J etal. J Prev Alzheimers Dis. 2021:4:398-410. 4 van Dyck CH et a. N Eng! J Med, 2023:3809-21
5. Aduhelm (aducanumab) Preserbing Information. ps www accessdata fa govldrugaitda_docs/abe1 2023761178501 1 pt.
6. Legembi (lecanemab) Preserbing infomation. ips www accessdata da govldrugstida_docs/abel/2023/7612690rg1s0011 ét. peers
7. Spering R et a. Alzheimers Dement. 2011.7:367-385. 8. Cogswell P etal, AUNR Am J Neuroradiol, 2022:43:£19-E35. PeerView.com
Copyright © 2000-2024, PeerView
Characterizing ARIA Radiographic Severity1-8
ARIA MRI Classification Criteria
Radiographic Severity
ARIA Type
Moderate
FLAIR hyperintensity
measure >10 cm, often with
FLAIR hyperiniensiy confined FLAIR hyperintensity 5-10 cm, or significant subcortical white
ARIA-E o matter more than 1 ste o involvement, | matter and/or sulcal
‘each measure <10 cm involvement; 1 or more
in 1 location <5 om separate sites of
involvement might be noted
<4 new incident 5-9 new incident 210 new incident
ARIA-H microhemorthi
R ee microhemorrhages microhemorrhages microhemorrhages
ARIAH superficial siderosis. 1 focal area of superficial 2 focal areas of superficial 2 focal areas of superficial
siderosis siderosi siderosis
1. Cummings J eta. J Prev Alzheimers Dis. 2028;10:262-377. 2. Cummings Jet al. Prev Alzheimers Dis. 20222:221-230.
3. Cummings J etal. J Prev Alzheimers Dis. 2021:4:398-410. 4 van Dyck CH et a. N Eng! J Med, 2023:3809-21
5. Aduhelm (aducanumab) Preserbing Information. ps www accessdata fa govldrugaitda_docs/abe1 2023761178501 1 pt.
6. Legembi (lecanemab) Preserbing infomation. ips www accessdata da govldrugstida_docs/abel/2023/7612690rg1s0011 ét. peers
7. Spering R et a. Alzheimers Dement. 2011.7:367-385. 8. Cogswell P etal, AUNR Am J Neuroradiol, 2022:43:£19-E35. PeerView.com
Copyright © 2000-2024, PeerView
ARIA Management Summary‘?
ARIA Type/Severity Response
Asymptomatic: dosing continued?
pedos aba TIARA Symptomatic: dosing suspended>
Moderate/severe ARIA-E or Dosing suspended until resolution
moderate ARIA-H of ARIA-E or stabilization of ARIA-Hb
Severe ARIA-H or brain
hemorrhage >1 cm in diameter Dosing permanently discontinued
Continue treatment and monitor wth monthly MR; discontinue monthly MRI # ARIA-E resoWes/ARIAH stabilzes.
® Suspend treatment and monitor with monthly MR: resume treatment i ARIA-E resolves/ARIA-H stablzes Peer.
1. Cummings J eta. J Prev Alzheimers Ds. 2023;10'262-377. 2, Saloway S etal. JAMA Neurol, 2022.78 12-21 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
ARIA Type/Severity Response
Asymptomatic: dosing continued?
pedos aba TIARA Symptomatic: dosing suspended>
Moderate/severe ARIA-E or Dosing suspended until resolution
moderate ARIA-H of ARIA-E or stabilization of ARIA-Hb
Severe ARIA-H or brain
hemorrhage >1 cm in diameter Dosing permanently discontinued
Continue treatment and monitor wth monthly MR; discontinue monthly MRI # ARIA-E resoWes/ARIAH stabilzes.
® Suspend treatment and monitor with monthly MR: resume treatment i ARIA-E resolves/ARIA-H stablzes Peer.
1. Cummings J eta. J Prev Alzheimers Ds. 2023;10'262-377. 2, Saloway S etal. JAMA Neurol, 2022.78 12-21 PeerView.com
PeerView.com/VQG827 Copyright © 2000-2024, PeerView
Educating Your Patients and Their
Families/Care Partners About ARIA
Key discussion points prior to starting treatment with an anti-AB monoclonal antibody
+ ARIA is a common side event of these treatments
+ ARIA can present as brain swelling (ARIA-E) or small spots of bleeding in the brain (ARIA-H); an MRI
is needed to determine safety of treatment prior to treatment and to monitor for ARIA during treatment
+ Having one or two copies of the APOE £4 gene is a risk factor for ARIA
+ In most cases, ARIA is asymptomatic. However, sometimes ARIA presents with these symptoms
Less frequent Uncommon
Confusion Neuropsychiatric Visual disturbance!
and dizziness symptoms disturbance blurred vision
PeerView.com/VQG827 Copyrigh
Families/Care Partners About ARIA
Key discussion points prior to starting treatment with an anti-AB monoclonal antibody
+ ARIA is a common side event of these treatments
+ ARIA can present as brain swelling (ARIA-E) or small spots of bleeding in the brain (ARIA-H); an MRI
is needed to determine safety of treatment prior to treatment and to monitor for ARIA during treatment
+ Having one or two copies of the APOE £4 gene is a risk factor for ARIA
+ In most cases, ARIA is asymptomatic. However, sometimes ARIA presents with these symptoms
Less frequent Uncommon
Confusion Neuropsychiatric Visual disturbance!
and dizziness symptoms disturbance blurred vision
PeerView.com/VQG827 Copyrigh
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