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NIH Research Programs

and Multiple Potential


Pathways to Address
Alzheimer’s Disease and
Alzheimer’s Disease-
Related Dementias

April 30, 2019

Roderick Corriveau, PhD


Program Director &
NINDS AD/ADRD Program Lead
1980s: Pathway to Dementia

Alzheimer’s Disease
Emerging Evidence That There are Multiple
Potential Pathways to Dementia
 Alzheimer’s disease pathology is the most common brain
pathology observed postmortem
 Alzheimer’s disease pathology typically does not occur alone

Clinical Diagnosis (During Life):


“Probable Alzheimer’s” ~ Dementia
AD (3%)
Pathological Diagnoses (Postmortem):
AD = beta-amyloid plaques + tau tangles
Vascular = infarcts/vessel disease (macro, micro;
athero, arteriolosclerosis, and CAA)
Other Pathological Diagnosis (> 1):
Lewy Body (neocortical)
TDP-43 (beyond amygdala)
AD + OD + V
Hippocampal sclerosis
0 = no pathology found

Kapasi A, et al. Acta Neuropathol. 2017


Aug;134(2):171-186
N = 447 (ROS/MAP)
NIH is Responsive to the
National Alzheimer’s Project Act (NAPA)
• Became law in 2011 - unanimously approved bipartisan legislation
• Includes Alzheimer’s Disease (AD) & AD-Related Dementias (ADRD)
• Mandates national plan to address escalating dementia burden
National Plan to Address Alzheimer’s Disease
• First National Plan issued by DHHS in 2012, with annual revisions
National Plan has five overarching goals:
1. Prevent and effectively treat AD/ADRD by 2025
2. Enhance care quality and efficiency
3. Expand supports for people with AD/ADRD and their families
4. Enhance public awareness and engagement
5. Improve data to track progress
Alzheimer’s Disease-Related Dementias (ADRD)
NIH Leadership in AD/ADRD Research

The NIA and NINDS Collaborate on AD/ADRD Research


o NIA is the NIH lead for AD research and responding to the National Plan
o NINDS is the NIH lead for ADRD research, including ADRD Summit planning

NAPA Goal 1: Prevent and Effectively Treat AD/ADRD by 2025

Triennial Scientific
ADRD Research Milestones Advances
Recommendations
Summits Toward Goal 1
Triennial NAPA-Responsive Summits

2020

Triennial Scientific
ADRD Research Milestones Advances
Recommendations
Summits Toward Goal 1
AD/ADRD Research Funding Increases at NIH
FY19 $2.47 B
($425 M increase)

Regular NIH Appropriations ($M) Added Funds ($M)


Multiple Potential Pathways to Dementia
Lifestyle Factors *Misfolded Proteins
physical activity amyloid
diet tau
drug/alcohol abuse alpha synuclein
Environmental Factors TDP-43
education *Vascular Disorders
head trauma stroke
toxins/other blood vessel diseases
Psychosocial Factors *Other Neuropathology Cognitive Impairment
depression/anxiety Including Dementia
Aging
Genetic Factors *BRAIN Alzheimer’s Dementia
Lewy Body Dementias
Sex F>M
Other Medical Risks CHANGES Vascular Dementias
hypertension Frontotemporal Dementias
obesity Limbic Predominant TDP
stroke Mixed Dementias
heart disease Other Cognitive Impairment
diabetes Other Dementias
metabolic
inflammation
certain infectious diseases
certain medications Concept by:
Health Disparities Julie A. Schneider, MD, MS, Rush University &
Roderick A. Corriveau, PhD, NINDS
Multiple Potential Pathways to Dementia
Lifestyle Factors *Misfolded Proteins Which Pathways Should be Treated?
physical activity amyloid What People are Should be Treated?
diet tau
drug/alcohol abuse alpha synuclein
Environmental Factors TDP-43
education *Vascular Disorders
head trauma stroke
toxins/other blood vessel diseases
Psychosocial Factors *Other Neuropathology Cognitive Impairment
depression/anxiety Including Dementia
Aging
Genetic Factors *BRAIN Alzheimer’s Dementia
Lewy Body Dementias
Sex F>M
Other Medical Risks CHANGES Vascular Dementias
hypertension Frontotemporal Dementias
obesity Limbic Predominant TDP
stroke Mixed Dementias
heart disease Other Cognitive Impairment
diabetes Other Dementias
metabolic
inflammation
certain infectious diseases
certain medications Concept by:
Health Disparities Julie A. Schneider, MD, MS, Rush University &
Roderick A. Corriveau, PhD, NINDS
ALZHEIMER’S DISEASE- Target Discovery and Preclinical Validation Project

Which Pathways Should be Treated?

AMP-AD: A Systems Biology Approach to Discovery of Novel Therapeutic Targets

Develop a data portal to enable rapid and broad


sharing of data and analytical results
Predictive
Modeling •AMP-AD Knowledge Portal
Molecular Experimental Generate multi-omic human data from well-
Profiling Validation phenotyped postmortem brain and blood plasma
•gene expression
•proteomic
AMP-AD Knowledge
Portal •metabolomic
Carry out early target validation in cell-based and
Rapid and Broad Sharing of Data animal models
6 Academic Teams/NIA RFA AG13-013
5 private partners (pharma and non-profit )
Emory University
Build network models of targets/pathways
UCLA
 >100 novel candidate targets identified and made
available via the AGORA platform
Understanding Multiple Pathways to Dementia
Which Pathways Should be Treated?

Trauma, chemicals radiation, radicals,


GENETICS and Environment stress, metabolic, viruses

Aging Proteonopathy DNA damage


Proteostasis
Mitochondria Abeta
Inflammation Tau
Endosomes Synuclein
Growth Factors TDP43 Transposable elements
Epigenetics Others
DNA damage
Senescent cells
Immune surveillance senescence/immune surveillance
Synapse damage T cells
Mac’s
NK’s

Neurodegeneration
Multiple Pathways: Diagnosis & Biomarkers for AD/ADRD

Which People Should be Treated?

Goal – Determine if Cognitive Impairment Present


• Detect cognitive impairment, including dementia in primary care
and other everyday care settings, including in health disparities
populations, and provide guidance for appropriate follow-up

Biomarkers for AD/ADRD – Goals:


• Identify patients to treat – e.g. DetectCID
• Identify the correct pathway(s) to treat in a given patient - biomarkers
• Treat when positive outcomes are possible (early enough) - biomarkers

Examples of NINDS ADRD biomarker programs:

The Lewy Body Dementias


Biomarkers Initiative
October 2018 V75 Number 10

Potential Biomarker for Synapses – In Living People!!


Cognitively Normal (Age 74 y)

Mild Cognitive Impairment (PIB+)(Age 77 y)

Funded in part via NIA PAR-18-596: In Vivo Synaptic Function in AD/ADRD


NIA AD “Bench to Bedside” Programs
NINDS ADRD “Bench to Bedside” Programs

MarkVCID
TAU CWOW M2OVE
LBD Biomarkers
VCID Mechanisms FTD Consortium
DetectingCID

Discovery & Validation Stages Development Stage

Establish Test Safety Human Human Human Human


Basic Identify Identify and Select and Select Clinical Clinical Clinical Clinical
Research Target Compounds Validate Candidates Clinical Trial Phase Trial Phase Trial Phase Trial Phase
Activity Canadine I II III IV

-------------Investigator Initiated--------------
---------------Blueprint Neurotherapeutics ----------------
------------------CREATE Bio----------------------
---------IGNITE--------- ----------Exploratory Trial---------
-------------NeuroNEXT-------------
-Phase 3 Clinical Trial-
Examples of Trans-NIH AD/ADRD Collaborations

NINDS & NIA fund ARTFL and LEFFTDS, with NCATS support:
• ARTFL: study of individuals with a clinical diagnosis of FTD to help
determine clinical, genetic and biomarker profiles
• LEFFTDS: study of families that have one of the three most common gene
variants associated with FTD to learn more about the natural history

• 5 active awards funded by NIA and NINDS


• M2OVE-AD aims to gain a deeper understanding
of risk phenotypes and mechanisms of VCID

• VCID Research in NIH-Supported National and International Cohorts


• VCID Workshops
• Neuropathological Impact of Sleep Deficiency & Sleep Disorders AD
• Viewed as a Neurovascular Inflammatory Disorder
Stroke, VCID and Healthy Brain Aging

“High blood pressure, the primary driver of stroke, is thought to impart physiological
damage on blood vessels in the brain. The damage can lead to ischemic and hemorrhagic
stroke and even “silent strokes” – small infarcts that go relatively unnoticed, but which affect
nearly 30 percent of elderly individuals. In addition to the well-known burden of illness due
to clinical stroke, decades of research has also shown a causative link between stroke and
cognitive impairment and dementia late in life.” “Higher blood pressure levels over time
have been linked to more extensive areas of white matter damage, which itself has been
linked to diminished performance on tests of cognitive function.”

Preventing Cognitive Decline and Dementia: A Way Forward (2017)


National Academy of Sciences.Engineering.Medicine
Consensus Study Report
“… some degree of support for the benefit of three classes of intervention:
cognitive training, blood pressure management in people with hypertension,
and increased physical activity.”

2015
www.mindyourrisks.nih.gov