Update on clinical research in

Alzheimer’s disease
R. Scott Turner, MD, PhD
Director, Memory Disorders Program
Professor, Department of Neurology
Georgetown University

7344170994
rst36@georgetown.edu
 Protein aggregates in AD:
silver stained brain sections
Neurofibrillary Tangles Amyloid Plaques
Braak and Braak stages of AD, Kretzschmar 2009
Future treatments for Alzheimer disease are exploring four major targets. (1) the cleavage of APP into plaque-prone
amyloid by inhibition of the beta-or (2) gamma- secretases (b and y symbol). (3) Interference of plaque formation using
inhibitors of Ab. (4) Enhancing the clearance of Ab using immunotherapy.
 Causes APP turnover
Aging Biomarkers
ApoE4 > 3 > 2 Ab accumulation low Ab, high tau in
Downs syndrome Ab oligomers, fibrils cerebrospinal fluid
Familial AD mutations amyloid plaques
positive amyloid-
neurotoxicity PET
neurofibrillary tangles

mild cognitive impairment (MCI)

Drug treatments
microgliosis and astrocytosis focal
donepezil
inflammation hypometabolism on
rivastigmine
focal encephalopathy FDG-PET
galantamine
neuronal morbidity
memantine
synaptic and neurotransmitter loss

neuronal mortality atrophy, white

brain atrophy matter changes on
white matter rarefaction MRI
Dementia (AD)
death

Turner, in Alzheimer’s Disease, 2012

Amyloid Precursor Protein (APP) catabolism

NH2 Ab COOH

b-secretase (BACE-1)
a-secretase

g-secretase (presenilin) g-secretase

p3 Ab
Figure 11 The dynamic relationship between plaques and oligomers with differential effects on brain physiology
and pathophysiology. Oligomers may affect signaling functions of neurons, while plaques either act as storage
sites orFrom Diseases
directly of the
attract andNervous System.
activate Copyright
microglia, © 2015an
eliciting Elsevier Inc. All rights
inflammatory reserved.
response.
7
 A mutation in APP (A673T)
protects against AD and age-
related cognitive decline
APP A673T reduces BACE-1 cleavage of APP

1/OR Odds p value

Ratio
AD - - -
AD vs. population 4.24 0.23 4.2 x 10-5
controls
AD vs. population 5.29 0.19 4.8 x 10-7
controls > 85
AD vs. cognitively 7.52 0.13 6.9 x 10-6
intact controls > 85

Assigned paper: Jonsson et al, Nature 2012

Decreased plasma
amyloid in AD
A673T APP
carriers

Martiskainen et al.,
Neurology 2017
 Risk factors for Alzheimer’s disease
• Aging
• Family history/genetics
– ApoE4 polymorphism, other genetic variants
– Minority (African-American, Hispanic)
– Down syndrome
• Diabetes, midlife obesity, metabolic syndrome
• Traumatic brain injury with loss of consciousness
• Smoking
• Stroke
• Low education, occupational level
• Female
 How to preserve brain health with aging
(modifiable risk factors)
• Exercise and physical activity
• Maintain ideal body weight
• Mediterranean diet (fruits, vegetables, nuts, beans, olive oil, fish)
• Greater quantity and quality of education
• Limit alcohol consumption (1-2 drinks/day)
• Mental activities, social connections and activities
• Avoid traumatic brain injury (seat belts, helmets, fall prevention…)
• Adequate sleep
• No smoking
• Minimize stress
• Use glasses and hearing aids if needed
• Treat hypertension, diabetes, high cholesterol, sleep apnea, and depression with
your care provider
• If memory problems develop, rule out thyroid disorder, vitamin B12
deficiency, and perhaps syphilis, HIV with your care provider
 ApoE4
increases
risk of AD
with aging

Strittmatter et al, Science, 1993.

 APOE4 causes an earlier onset of
amyloid - by about 15 years

Jansen et al, JAMA, 2015

 Age, ApoE4+ and AD diagnosis increase
amyloid PET positivity

Healthy older (> 50)

control subjects
% florbetapir positive

AGE

Fleisher AS et al. Neurobiol Aging. 2013;34:1-12.

 Genetics of Sporadic AD (top 10)
Gene Ethnicity Odds Genes are involved in:
Ratio
• Cholesterol/lipid transport
ApoE 2/3/4 All 3.7
• Immune system/inflammation
BIN1 All 1.2 • Protein trafficking/metabolism
CLU Caucasian 0.9 • Synaptic function/plasticity
ABCA7 All 1.2 • Protein turnover/degradation
CR1 Caucasian 1.2
PICALM Caucasian 0.9
MS4A6A All 0.9
CD33 All 0.9
MS4A4E All 1.1
CD2AP All 1.1
Alzheimer Research Group. Alzforum.org.
Bettens K et al, Lancet Neurol, 2013.
Inheritance of 1 APOE4: 3X
Inheritance of 2 APOE4: 12X

Triggering receptor expressed

on myeloid cells 2
The Continuum of Alzheimer’s Disease

Sperling RA, et al, Alzheimers Dement. 2011;7:280-292.

Hypothetical Course of AD and Biomarker Changes

Jack CR Jr, et al. Lancet Neurol. 2010;9: 119-28.

DIAN (Dominantly Inherited Alzheimer Network) Study

Biomarkers of AD change decades before

symptom onset
(from study of individuals with known familial
AD mutations)

Jack CR Jr, et al. Lancet Neurol. 2013;9: 119-28.

Jacobs HIL, Buckley RF, Where do white matter alterations dovetail with the cascade model of
Alzheimer’s disease? Brain. 2018;141(10):2830-2833
Sperling RA et al, Alzheimers Dement. 2011;7:280-292.
Sperling RA, et al, Alzheimers Dement. 2011;7:280-292.
 Diagnostic Criteria of Dementia

Dementia
• Interferes with ability to function at work or at usual
activities
• A decline from a previous level of functioning
• Not delirium or psychiatric disorder
• Diagnosed by history, examination
• Involves at least 2 cognitive domains:
• Memory
• Reasoning and judgment
• Visuospatial
• Language
• Personality, behavior, comportment
McKhann GM et al, Alzheimers Dement. 2011;7:263-69.
 Diagnostic Criteria of AD

Probable AD [based on clinical criteria]

• Dementia
• Insidious onset
• Worsening of cognition over time
• Amnestic vs. non-amnestic presentation
• Not due to another dementia diagnosis

Probable AD with evidence of AD pathophysiology

• Ab (CSF or amyloid PET)
• Neuronal injury (CSF tau, FDG-PET, structural MRI)

McKhann GM et al. Alzheimers Dement. 2011;7:263-69.

 Biomarkers
Biomarkers of Ab amyloid deposition
• CSF Ab42
• PET amyloid imaging

Biomarkers of neuronal injury

• CSF tau/phosphorylated tau
• Hippocampal volume or medial temporal atrophy
• Rate of brain atrophy
• FDG-PET imaging
• SPECT perfusion imaging
• Less well validated biomarkers: fMRI activation studies, resting BOLD
functional connectivity, MRI perfusion, MRI spectroscopy, diffusion tensor
imaging, voxel-based and multivariate measures

Associated biochemical change

• Inflammatory biomarkers (cytokines)
• Oxidative stress (isoprostanes)
• Other markers of synaptic damage and neurodegeneration

Albert MS et al. Alzheimers Dement. 2011;7:270-79.

AD brains reveal
atrophy --
particularly in regions
mediating higher
cognitive functions
 MRI Atrophy in
MCI & AD

McDonaldCR, et al. Neurology. 2009;73:457-65.

Tau

CSF
AD
Biomarkers
Normal

Ab42
Shaw LM, et al. Ann Neurol. 2009;65:403–413.
 FDG-PET:
AD

MCI

Langbaum JB, et al. Neuroimage, 2009.

 PET Amyloid and Tau Imaging

Amyloid-b
(PiB)

Tau
(T807)
Clinically Clinically Alzheimer’s
Normal Normal Dementia
Tau PET correlates with cognition

Okamura N et al., Brain 2014.

 NIA-AA Research Framework
A/T/N classification
• A: Aggregated b-amyloid or associated pathologic state
– CSF Ab42, or 42/40 ratio
– Amyoid PET
• T: Aggregated tau (neurofibrillary tangles) or associated tau
pathology
– CSF p-tau
– Tau PET
• N: Neurodegeneration or neuronal injury
– Anatomic MRI
– FDG-PET
– CSF total tau Jack et al., Neurology 2016
 FDA-Approved Drugs for AD
Year
Drug Approved Mechanism of Action FDA-Approved Indications

Donepezil
1996 Cholinesterase inhibitor Mild-to-severe AD
Aricept
Mild-to-severe AD
Rivastigmine
2000 Cholinesterase inhibitor Mild-to-moderate Parkinson’s
Exelon
dementia

Galantamine
2001 Cholinesterase inhibitor Mild-to-moderate AD
Razadyne

Memantine
2003 NMDA antagonist Moderate-to-severe AD
Namenda

Fixed-dose combination:
Memantine +
NMDA antagonist
donepezil 2014 Moderate-to-severe AD
plus cholinesterase
Namzaric
inhibitor
Amyloid plaque reduction with aducanumab

Sevigny et al., Nature 2016

Aducanumab effect (change from baseline)
on CDR-SB and MMSE

Sevigny et al., Nature, 2016

 Phase 3 trial of semagacestat for AD
gamma-secretase inhibitor - worsened cognition

Doody et al., NEJM 2013

 BACE-1 inhibitor for
individuals with mild to
moderate AD

Mean Change from Baseline

in the ADAS-cog and
ADCS-ADL Scores
over 78 Weeks

Egan et al. N Engl J Med 2018;378:1691-1703.

 BACE-1 inhibitor
for individuals with
prodromal AD

Mean Change from

Baseline in the CDR-SB,
CCS-3D, and ADCS-ADLMCI
Scores over 104 Weeks

Egan et al. N Engl J Med 2019;380:1408-1420.

 Trends in clinical AD research
• Biomarkers for diagnosis, prognosis, drug efficacy...
– PET imaging – Abeta/amyloid, tau/tangles
– Spinal fluid proteins – Abeta, tau, sTREM2…
– Blood biomarkers? Exosomes, -omics…
• Shift to earliest disease states – to MCI or prodromal AD
– MCI trials
– Prevention trials of normal at-risk individuals
– Web-based screening and recruitment
• Increased NIH research funding
• Precision medicine
– Prevention and treatment tailored to individual genotype
 National Registries (websites)

•Alzheimer’s Prevention Registry (18+ years old)

– endalznow.org
– Information on AD prevention
• GeneMatch (55-75 years old)
– endalznow.org/genematch
– Genetic testing (ApoE) and possible referral to local
research studies
•Brain Health Registry (18+ years old)
– Brainhealthregistry.org
– Study of brain health, information on research opportunities
 National Registries (websites)

•Alzheimer Prevention Trials Webstudy (50+ years old)

– aptwebstudy.org
– Tracks cognitive performance (every 3 months), information
on AD prevention, possible referral to local research studies
•Brain Health (18+ years old)
– Healthybrains.org
– Brain health index score and report, memory testing,
information on AD prevention
 Sites of Action of
Failed Therapeutic
Approaches to
Alzheimer’s Disease

Knopman. N Engl J Med 2019;380:1476-1478.

 A framework for selecting the right time for the right drug

Golde et al. Science 2018;362:1250-1251

Published by AAAS
Update on clinical research in
Alzheimer’s disease
R. Scott Turner, MD, PhD
Director, Memory Disorders Program
Professor, Department of Neurology
Georgetown University

7344170994
rst36@georgetown.edu
 Memory Disorders Program Studies
• Biomarker discovery and validation (normal, MCI,
AD)
– NIA: ADNI
– DOD: DOD-ADNI (veterans with PTSD, TBI or both)
– NIA: LEARN (amyloid PET negative)
– BrightFocus Foundation: fMRI of MCI
– DC CFAR: fMRI of HIV associated neurocognitive
decline (HAND)
– NIA/Marymount: Language changes with MCI/AD
– DCLSA – DC Longitudinal Study on Aging
Memory Disorders Program Studies
• Therapeutic trials (MCI, prodromal AD, AD)
– NIA: Nicotine patch (MIND)
– ADDF: Nilotinib (tyrosine kinase inhibitor)
– Roche: Anti-tau antibody
– Roche: Gantenerumab (anti-amyloid antibody)
(GRADUATE)
– Eisai: BAN2401 (anti-amyloid antibody)
 Memory Disorders Program Studies
• Prevention studies (normal older individuals at risk)
– NIA/Lilly: Solanezumab (A4) (anti-amyloid antibody)
– Novartis: Alzheimer Prevention Initiative for
ApoE4/4 individuals, BACE-I or active vaccine
(GENERATION 1)
– Novartis: Alzheimer Prevention Initiative for
ApoE4/x individuals, BACE-I (GENERATION 2)