Alzheimer’s Disease:

Amyloid Cascades,
Inflammation and Oxidative
Stress Creating Age-Related
Neuroplasticity Failure?
Douglas F. Watt, Ph.D.

Cambridge City Hospital

Harvard Medical School
 Dylan Thomas on Aging & Death
Do not go gentle into that good
night,
Old age should burn and rave at
close of day;
Rage, rage against the dying of the
light.
Though wise men at their end know
dark is right,
Because their words had forked no
lightning they
Do not go gentle into that good
night.
Good men, the last wave by, crying
how bright
Their frail deeds might have danced
in a green bay,
Rage, rage against the dying of the
light.
Wild men who caught and sang
the sun in flight,
And learn, too late, they grieved it
on its way,
Do not go gentle into that good
night.
Grave men, near death, who see
with blinding sight
Blind eyes could blaze like meteors
and be gay,
Rage, rage against the dying of the
light.
And you, my father, there on the
sad height,
Curse, bless me now with your
fierce tears, I pray.
Do not go gentle into that good
night.
Rage, rage against the dying of the
light.
 Aging is . . . . vastly over-rated!
„ Bible states that aging is ‘wages of sin’? Colorful but . .
„ Appears to be more the wages of metabolism and
defense (damage to multiple systems from inflammation,
oxidative stress, other products of energy generation).
„ Damage to basic cellular components (DNA, nuclear &
mitochondrial), glycation of proteins (sugar-protein
bonds) → advanced glycation end products (‘AGE’)
(e.g deterioration of collagen), ↑ junk proteins (amyloid).
„ Major role for inflammation (and INFLAM ↑ OS) . . . we
are slowly eaten from within by own immune systems.
„ INFLAM may increase with age (↑ pro-INFLAM cytokines)
„ Evidence that defenses against OS & regulation of
INFLAM decline with age → losing tug of war between
forces of cellular protection vs cellular degradation.
„ Aging process may even accelerate?
 “Youth is wonderful, and it is a
shame to waste it on the young!”
„ Most lifestyle choices that decrease CAD and CA also
decrease AD (fruits/veggies, ω-3, exercise, good quality
sleep, ↓ chronic stress), suggesting convergent
mechanisms across the diseases of aging (DOA).
„ Sleep, exercise and ω-3/ω-6 ratio all decrease tonic
INFLAM. Exercise upregulates antioxidant defenses.
„ Calorie restriction (↓~30%) is gold standard for reducing
both DOA & aging itself, but . . . .
„ CR a painfully difficult lifestyle modification (<1%).
„ Suggests key area is finding CR mimetics (e.g.
resveratrol,) and importance of finding even more
effective CR mimetics.
„ CR mimetics could in theory prevent or delay all DOA,
including AD (one exception - ALS accelerated by CR).
The Big Picture (Diseases of Aging/AD)
„ Aging population, (large demographic group of baby
boomers), heading into decades of greatest risk.
„ Prevention effort re: all ‘DOA’ (CA, CAD/MI/CVA, Diabetes,
AD, arthritis) virtually nonexistent (2-4% of health care
dollar spent on prevention, 75-90% on established DOA).
„ Old adage: ounce of prevention is worth a pound of cure,
but is real ratio > 1 oz to 500 lbs? No cure in sight for DOA
„ AD shows no sign of decreasing its penetration (doubles
incidence every five years starting with 60-65).
„ AD may even increase (explosion of DM & obesity), as CV
disease risk increases AD risk. Comorbidities of INFLAM?
„ No major “disease-modifying” treatment yet available, esp.
if one considers treatment to start only once patient is
demented (several new drugs may be such a treatment?).
„ No definitive laboratory measure, although several
available good biomarkers.
 Popular Conceptions Re: AD
„ If someone is becoming forgetful in their old age,
that is more likely aging rather than AD.
„ AD has little to nothing to do w/ diet or lifestyle.
„ Exercise has no impact on either the generation
or treatment of AD.
„ Genes account for most of AD.
„ AD is caused by exotic cellular derangements and
is not related to basic aging processes.
„ AD is largely untreatable. Not much point in
cholinesterase inhibitors. No other treatments.
„ AD is an aggressive disease and often causes a
fairly rapid decline.
„ EACH OF THESE IS MORE WRONG THAN RIGHT!
 SOME BASICS ABOUT AD
„ Most common brain disease in US (& possibly globally)
„ A neuropsychiatric epidemic, in context of “graying of
America.” Frequently quoted statistics (~ 4/5 mil) are
serious underestimation.
„ Late Dx contributes to serious underestimation, along
with overreliance on MMSE, and overestimation of VD.
„ Incidence doubles every five years after age of 60 to 65.
„ Suggests etiology of AD is intrinsically linked to brain's
aging, and/or responses to aging.
„ By middle 80’s, 35-45% chance of some stage of
Alzheimer's disease, all other factors being equal.
„ Including earliest prodromal stages (MCI amnestic
subtype), incidence may be significantly greater.
 Hebert LE, Scherr PA, Bienias JL, Bennett DA, & Evans DA
(2003). Alzheimer disease in the US population. Prevalence
estimates using the 2000 census. Arch Neurol, 60:1119-1122.
 Hebert LE, Scherr PA, Bienias JL, Bennett DA, & Evans DA
(2003). Alzheimer disease in the US population. Prevalence
estimates using the 2000 census. Arch Neurol 60:1119-1122.
 Hebert LE, Scherr PA, Bienias JL, Bennett DA, & Evans DA.
(2003). Alzheimer disease in the US population. Prevalence
estimates using the 2000 census. Arch Neurol, 60:1119-1122.

In 2000, ~ 4.5 million persons with AD in the US population. By 2050, this

number will increase by 3-fold, to 13.2 million. (These numbers may be
underestimations, given late diagnosis and other issues)
 Clinical Presentation of AD.
„ Insidious, virtually invisible, onset of progressively
amnestic cognitive decline. Includes classically,
but not invariably:
¾ Declining short-term memory (retrieval failures initially,
then deepening storage failure);
¾ Mild attentional and working memory declines,
disruption of cognitive executive functions;
¾ Dysnomia, verbal fluency & semantic process. declines;
¾ Declining spatial cognition/spatial relations esp. analytic,
although this tends to appear later in the disease;
¾ Affective and behavioral comportment declines, with
personality – affective changes, late onset psychiatric
disorders, frequently misdiagnosed as ‘idiopathic’.
„ Other clinical phenotypes besides this. Variability in presentation esp.
in context of co-morbid conditions (depression, CV disease, metabolic
compromise, other neurologic & medical diseases).
 The Problem of Early
Diagnosis: A Search for
Better Biomarkers
Biomarkers Critical to The Effort to Dx and Treat
Dx is often way too late (mild to mod dementia)
MMSE is totally inadequate as dementia screen
Need for simple clinical tests prior to decline
Disease staging and prediction
Critical to evaluation of early stage Rx
Cost effective approaches
 Early Diagnosis Problem
Preventative Treatment Clinical Treatment

Age
BRAIN HEALTH

Pre-Clinical
MCI
NOT here
(where current
Rx often starts)
AD
From Mony de Leon,
2008 (Alz Forum)
TIME
 Need for Early Diagnosis
„ Recent candidates: HC atrophy, CSF protein alterations,
changes in rate of ventricular enlargement in aging,
regional cortical thinning, SPECT/PET patterns.
„ Current CSF markers: ↑ total tau, ↑ phosphorylated tau,
amyloid β42 (↓ instead of ↑!). Spinal taps unpleasant.
„ Most desirable would be serum assays (no spinal tap).
„ Five protein biomarker molecular signature recently
showed 96% total accuracy predicting clinical AD: IL-1α,
IL-3, EGF (epidermal growth factor), TNF-α & G-CSF
(granulocyte colony-stimulating factor - ↑ white cells).
„ All these are cytokines! Cytokine elevation marks
transition from MCI to mild dementia (suggests AD
brought on by INFLAM, or AD leads to INFLAM, or both).
„ But this is too late!!! We need biomarkers that define
beginning of clinical decline!
 Early Biomarker Aβ Ligand PET vs.
Structural Atrophy Biomarker on MRI
 Progression of Biomarkers in AD
Aβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and
dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by
use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.
Variables Might Shift Biomarkers
Current Ability To Assay Biomarkers
Is Missing Critical Components!!
„ No reliable chemical biomarkers of toxic oligomeric forms
of soluble Aβ or other soluble Aβ or diffuse plaques.
„ Absence of PET ligands for density of NFTs is a serious
gap in both our research and clinical tool set.
„ Absence of accepted biomarker for microglial activation
(imaging CNS inflammation).
„ Absence of biomarker for synaptic function/loss
(appearing to be the most critical biological issue in AD).
„ Doubtful that virtually any imaging or other biomarker is
likely to be as revealing as postmortem brain biopsy.
„ However, better biomarkers would offer huge gains to
early diagnosis, early treatment, & gauging effective Rx.
 Cognitive Screening Issues
„ Identification of early amnestic issues is critical, and
cannot be done reliably through clinical interviewing.
„ Most commonly applied screening instrument (MMSE)
„ Underestimates cognitive deficit seriously (not normed properly).
„ Poor screen for short-term memory issues (critical!)
„ Poor screen for executive issues (important).
„ Poor screen for naming and fluency issues (important).
„ Montréal Cognitive Assessment (MoCA): much better
„ Decent assessment of short-term memory (? delay interval?)
„ Assessment of verbal fluency.
„ Some assessment of at least a subset of executive functions.
„ Not in widespread use (but improving).
„ Requires more time than MMSE but returns much better data.
„ Requires minimal training (but more than MMSE).
 Functional Imaging Biomarker
EC Glucose Metabolism
4-year advance MCI prediction

Prediction of future MCI

Accuracy
84%
de Leon et al, PNAS, 2001
Hippocampus metabolism: automated sampling

7-years advance prediction of symptoms

Prediction of future MCI

Accuracy 84%
Mosconi et al Neurobiol. Aging, 2007
 AD NL

PIB

FDG
Li , Rinne, de Leon in press EJNM 2008
 Atrophy and Metabolism
10-Year decline from NL to AD (de Leon, 2008)

NL MCI AD
1993 1997 2003

E E E

NYU 2008
 Accuracy for FDG and PIB
PIB
AD vs NL MCI vs NL
FDG

PIB -Frontal 96 75
L. SS 94 SP 100 SS 62 SP 100

FDG -HIPPO 92 85
SS 88 SP 100 SS 85 SP 86

Li , Rinne, de Leon in press EJNM 2008

P-tau231 Diagnostic Specificity for AD

Buerger et al Arch Neuro 2002

2-Year Longitudinal Performance Of CSF Biomarkers
Accuracy: MCI to AD prediction (plus progression?)
P-tau231 T-tau

83% 83%

Aβ42/40 Isoprostane

69% 74%

Baseline – White bars

Longitudinal
Brys et al Neurobiol. Aging 2007
Follow-up – Dark bars
 CSF Biomarkers:
Which Predict Declines (CDR>0)?

Fagan et al Arch Neurol 2007

Pathological Markers for
Alzheimer’s Disease:

“Plaques and Tangles”

Beta
Amyloid:
Inter-cellular ‘junk’
proteins (found more in
structures that receive
heavy inputs from
cortex). In form of
large oligomers & fibrils
(Aβ ‘sticky’ & tends to
aggregate). Exists as
oligomers inside of cells
also. Research has
tended to focus on
large extracellular
plaques (fibrils) rather
than small oligomers,
but evidence suggests
that oligomers are more
destructive (↓synapses)
Imaging Plaques in AD w/
PIB
Klunk et al. used PET radio-
ligand Pittsburgh Compound-B
(PIB), which selectively binds
to amyloid plaques. Greatest
PIB binding in frontal lobes, w/
greatest metabolic defects in
temporal-parietal lobes.
Suggests poor correlation of
plaque burden w/ symptoms
and that other issues (tangle
density) must be considered.
 Amyloid Processing in AD
Turned on by neuroplasticity challenge, esp. injury, but
APP proteolysis. The amyloid-
amyloid-β (Aβ)
peptide derived via proteolysis from also from cholinergic and other amine deafferentation.
larger precursor molecule (amyloid
precursor protein (APP 695–
695–770 amino
acids). APP can undergo proteolytic
processing by 1 of 2 pathways. Mostly
processed via a nonamyloidogenic
pathway, precluding Aβ. First cleavage
mediated by α-secretase, (disintegrin
(disintegrin//
metalloproteases - ADAM), within Aβ
domain, preventing creation of Aβ
peptide. Two fragments released, one
larger (sAPP
(sAPPα α), smaller carboxy-
carboxy-
terminal fragment (C83). APP not
cleaved by non-
non-amyloidogenic pathway
becomes substrate for β-secretase (β (β-
site APP cleaving enzyme 1; BACE1),
releasing sAPPβ
sAPPβ, retaining last 99 amino
acids of APP (C99) within membrane.
The first amino acid of C99 is the first
amino acid of Aβ. C99 is subsequently
cleaved 38–
38–43 amino acids from the
amino terminus to release Aβ, by γ-
secretase complex, (presenilin 1/2,
nicastrin,
nicastrin, anterior pharynx defective, &
presenilin enhancer 2). This γ cleavage
produces AβAβ1–40, & amyloidogenic
Aβ1–42 at ratio of 10:1. AICD, APP
intracellular domain; APH-
APH-1, anterior
pharynx defective; PEN2, presenilin
enhancer 2.

AICD recently implicated

Basic Cellular Compartments
Organelles:
(1) nucleolus
(2) nucleus
(3) ribosomes (little
dots)
(4) vesicle
(5) rough endo-
endo-
plasmic reticulum
(6) Golgi apparatus
(7) Cytoskeleton
(8) smooth endo-
endo-
plasmic reticulum
(9) mitochondria
(10) vacuole
(11) cytoplasm
(12) lysosome
(13) centrioles within
centrosome
Beta Amyloid intracellular,
not just extra-cellular.
Relationship between intra-
cellular & extracellular Aβ
pools is poorly understood.
Found in many cellular
compartments, and gains
entry to cell via several
receptors: RAGE, lipid,
NMDA, and nicotinic.
APOE 4 facilitates intake of
Aβ more than other alleles.
Binding to RAGE increases
inflammation. ERAB
(endoplasmic-reticulum
associated binding protein)
combines w/ beta amyloid,
attracting beta amyloid into
cells. Assembly state of Aβ LeFerla et al, NRN, 2007
inside cells critical to
pathogenic effects, w/ large
oligomers of Aβ destructive
re: many cellular functions.
 Synaptic loss correlates best w/ cognitive decline in AD.
FROM QUERFORTH & LAFERLA: Normal
synapse shown at top. At bottom, an
“Alzheimer’s disease synapse” showing
pleiotropic effects of β-amyloid peptide
(Aβ). Rings represent synaptic vesicles.
Application/expression of Aβ, especially
oligomers, impair synaptic plasticity by
altering balances between long-term
potentiation (LTP) & long-term
depression (LTD) and reducing numbers
of dendritic spines. At high
concentrations, oligomers suppress
synaptic transmission. Aβ facilitates
endocytosis of MNDA and AMPA
receptors. Aβ binds to receptors of p75
neurotrophin (p75NTr) and BDNF
(receptor is tyrosine kinase B receptor
[trkBr]), exacerbating already low levels
of BDNF and nerve growth factor
(NGF). Aβ impairs nicotinic acetylcholine
(ACh) receptor (nAChr) signaling and
release from presynaptic terminal.
Numbers of hippocampal synapses
decrease in MCI while remaining
synaptic profiles show compensatory
increases in size.
(APP = amyloid precursor protein, pCaMKII
phosphorylated calcium–
calcium–calmodulin–
calmodulin–dependent
protein kinase 2, pCREB phosphorylated cyclic AMP
response-
response-element-
element-binding protein, trkAr tyrosine
kinase A receptor, and VGCC voltage-
voltage-gated calcium
channel.)
Molecular Pathways (MAP-K) Mediating
Response to Cellular Stress (yikes!)
Underlines non-linear regulatory envelopes
operating at deep cellular levels involved
in response to
biological
stressors!
Data supporting primacy of Aß in AD.
„ Deposition of Aß in neuropil is sin qua non for Dx of AD.
„ Mutations of AßPP gene (or secretase) cause early onset
form of AD (familial AD).
„ Mutation alone enough to generate both plaques & tangles.
„ Triplication of AßPP in Down’s syndrome leads to invariable
AD in Down’s at age > middle to late 30’s.
„ Mutations of PS1, PS2 and AßPP (familial AD) all have in
common production of “longer” forms (Aß-42.)
„ ApoE4 allele promotes aggregation & internalization of Aß.
„ At least in vitro (? in vivo), long forms of Aß neurotoxic,
promotes apoptosis, phosphorylation of tau (→ NFT).
„ Transgenic mice over-expressing mutations of AßPP show
cognitive decline and plaque (but no NFT).
„ Synaptic effects of Aß mediated by small oligomers of Aß40
more than Aß42, correlates much better w/ cog dysfxn.
Neurofibrillary Tangles
Tends to be found early more in
structures that send many projections
to cortex (reticular activating system,
basal forebrain, thalamic intralaminar
nuclei, hippocampus). Highly correlated
with atrophic change & regional brain
failure. Extensive tangling of neocortex
only in middle-late stages.
Distribution of neurofibrillary tangles
Mesulam,
2000
Imaging Both Plaques and Tangles
From Shoghi-Jadid et al.
PET radioligand (18-
FDDNP), which binds to
both amyloid plaques and
neurofibrillary tangles.
Greatest 18FDDNP
binding in medial temporal
area (amygdala, entorhinal
cortex & hippocampus
proper). Greater metabolic
defects, with FDG PET, in
lateral temporal lobe. Note
brainstem tagging in AD,
suggesting significant
plaque and/or tangle
burden.
(Holmes, C. et al. (2008) β amyloid vaccine
does not slow progression of AD dementia –
too little too late . . . or wrong idea all together?
 Plaques vs. tangles – Linkage of
these markers still not elucidated.
„ Genetics of AD favor process related to Aß.
„ Neuropsychology of AD favors process related to NFT, as
tangling density predicts regional decline/atrophy.
„ Beta amyloid pathway, when genetically mutated (FAM AD)
yields same progressive tangling as sporadic AD but
„ No accepted explanation links spatial & temporal distribution
of NFT to distribution of Aß. If Aß → NFT, why do regions
w/ highest Aß not have highest NFT?
„ Recent suggestions: intra-cellular Aß and small oligomers
may drive pathway into NFT. NFT: marker for oxidative
stress associated with upregulated stress kinases?
„ Deposition of Aß is upstream of tangling & regional failure.
„ Likely multiple cell pathways interpolated between Aß &
NFT. Would stopping progression of NFT stop decline?
„ Markers for oxidative stress in CNS appear before either
plaques or tangles. Plaques appear before tangles.
Mesulam’s theory linking known risk
factors to neuroplasticity issues.

Recent work underlines additional risk factors: hyper-

lipidemia, obesity, serious ischemic change, diabetes,
low education, recurrent depression, ? PTSD.
 Oxidative Stress & Inflammation:
Relationship to Plaques & Tangles?
„ Roughly 1-2% of absorbed O2 forms free radicals → 1011 per
cell/day – mostly MITO (mitochondrial).
„ In animal models, OS markers (lipid OS) appear BEFORE Aβ/NFT.
„ Reduced MITO enzymes in AD expose other parts of cell (lacking
protective mechanisms in MITO) to ↑ OS (H2O2 and ONOO).
„ Antioxidant defenses ↑ (esp. heme oxygenase) promote tau
phosphorylation via GSK3 → PHF & neurofibrillary tangling.
„ Aβ accumulates, creating OS extra-cellularly (via lipid membranes)
and intra-cellularly (via many organelles).
„ Aβ plaques irritate (and even attract) glial cells → ↑ INFLAM and OS
from this, particularly upregulation of pro-inflammatory cytokines.
„ Aβ plaques contain Fe++ (disturbed iron homeostasis) ↑ OS (H2O2)
„ PHF often glycated, promoting INFLAM, and increasing APP/Aβ. OS
upregulates APP and Aβ via stress kinase pathways (JNK and p38).
„ Conclusions: OS precedes Aβ/NFT, but Aβ increases INFLAM &
OS → vicious circle of OS/INFLAM/NFT driving synaptic loss.
Oxidative Stress, Inflammation, Intra/Extra
Cellular Amyloid, Phosphorylation of Tau,
Synaptic Loss and Eventual Apoptosis

INFLAM and more OXIDATIVE STRESS

TANGLING &
FENTON
APOPTOSIS
CHEMISTRY
 Peroxynitrite as mediator between
plaques and tangles?
„ Aβ deposits stimulate production of NO/superoxide
through activating microglia and astrocytes.
„ Peroxynitrite (from NO + superoxide) upstream effector
for tau phosphorylation.
„ In recent study, research group (Zhang et al.) injected
SIN-1 (peroxynitrite generator) bilaterally into rat HC.
„ Levels of nitrated and hyperphosphorylated tau markedly
increased immediately after drug administration (~ hrs).
„ GSK-3β involved in peroxynitrite-induced tau hyper-
phosphorylation. Phosphorylated tau degraded efficiently
by proteasomes, but nitrated tau more resistant.
„ However, did not cause cell death, and tau alterations
were reversed within 48 hrs.
„ More long-term studies will be necessary (OS long term
issue).
 Intracellular β-
Amyloid driving a
destructive cascade?
Promotes tangles, synaptic &
Ca++ channel dysfunction,
inhibits proteasomes,
increases oxidative stress,
decreases mitochondrial
energy generation. APOE 4
allele → ↑ production &
uptake of βA.

How to reduce this? In

animal models: ↑ DHA, ↓
CHOL, NMDA blockade,
multiple polyphenols (esp.
turmeric, resveratrol &
EGCG), and ↓ homocystine.

LeFerla et al, NRN, 2007

 Inflammation and
Neuroplasticity: Two
Sides of the AD Equation?
Cytokines Regulate Neuroplasticity, Sleep and Other CNS Functions
Pro-Inflammatory Cytokines Show U-Shaped Functional Curve in Cognition
Depression of Neuroplasticity is Primary Consequence of Inflammation
Current Treatments Have Focused Solely on Neuroplasticity Side
Prediction: Future Treatments Will Address Inflammation
 Inflammation in CNS: Decreased
Plasticity/Neurogenesis & ↑ Apoptosis
„ Activated microglia actually consume Aβ in an antibody-dependent
fashion and organize inflammatory responses. May be mixed bag –
yields major ↑ in pro-INFLAM cytokines.
„ Markers for CNS inflammation (glial activation) correlate w/ amyloid
deposition but precede atrophy/tangling by many years.
„ Aβ is potent activator of release of IL-1β, IL-6, TNF-α, NO and NOS
by glial cells. IL-1β also promotes amyloid precursor protein.
„ Interferon-α promotes above process: suggests basic for
comorbidity of depression/AD as comorbidities of INFLAM.
„ ↑ TNF-α promotes GLU toxicity and Ca++ channel overload,
depresses neuroplasticity. Both TNF-α and IL-1β decrease LTP.
„ Pro-INFLAM cytokines depress neurogenesis/stem cells and cause
over-selection of apoptosis → ↑ neuroplasticity challenge & failure.
„ Serum levels of IL-6 & CRP: modestly predictive re: AD.
„ Why long time lag between plaque, INFLAM markers and cognitive
decline/tangling? Suggests unknown intermediate variables.
 Treatments for tangling in Alzheimer’s
disease – the neglected biomarker?
„ Two processes of tau phosphorylation & synaptic loss in parallel.
What about aiming at tangling instead of Aβ?
„ Peroxynitrites contribute to high GSK3 activity, increasing
phosphorylation of tau (↓ PK B/C, inhibitory of GSK3).
„ Peroxynitrites decrease PKC-mediated uptake of choline and ACh
acetyltransferase activity, thus ↓ cholinergic activity in BF.
„ Methylene blue ↓ peroxynitrites (limiting superoxides (produces ↓
peroxynitrites), in turn producing ↓ phosphorylation of tau .
„ GSK3 promotes phosphorylation of kinesin (vesicle ‘cargo’
protein), inhibiting axonal transport, promoting synaptic loss.
„ Most interesting new treatment might be AD-108, based on
fragment of ADNP (‘activity dependent neuroprotective protein’ –
huge peptide affecting ~ 400 genes).
„ This fragment (NAP or AL-108) is anti-tangle agent and also
appears to be very promoting of neuroplasticity and synaptic
function (and thus is anti-AD).
NAP (fragment of larger neuro-
protective/trophic peptide)
Cholinergic Issues in
Alzheimer’s Disease:

Therapy Opportunities,
Links to Neuroplasticity Challenge
 Where is ACh decline in AD:
Possible Interactions?
„ ACh promotes α (alpha) secretase (sAPP) which blocks Aβ.
„ BF ACh tangling is excellent marker for severity of AD.
„ ACh deprivation (from BF tangling) leads to cortical
dysfunction and likely neuroplasticity challenge/decrement.
„ Aβ blocks ACh synthesis and ACh neurotransmission in BF.
„ ACh deprivation promotes Aβ pathway (positive feedback)?
„ In PD, exposure to anti-ACh drugs predicts AD/Aβ & tangles.
„ M1 receptors preserved in cortex, nicotine receptors and M2
more affected/pruned out. Muscarinic agonists?
„ ACh modulates effects of central cytokines, reducing potential
for delirium in peripheral infection.
„ ACh deprivation is not primary correlate of STM troubles but
may be very relevant to vulnerability to confusional states.
„ Increased ACh tone promotes neuroplasticity and decreases
pro-INFLAM cytokines, while raising IL-4.
„ Recent study shows that chronic anti-ACh drugs increase risk
for developing AD, suggesting that ↓ ACh tone is etiologic.
Cholinergic Systems in AD
 Possible Interactions Between Cholinergic
Deficit, Infection and Synaptic Dysfunction

van Gool et. al., 2010

Proposed sequence of events in systemic infection: (A) Peripherally produced pro-inflammatory cytokines
(TNF α) enter CNS, activate microglia producing inflammatory mediators affecting neuronal fxn, causing delirium.
Cholinergic inhibition modulates microglial activation and limits severity and duration of delirium. (B) In some
situations, microglia might already be primed, which leads to over-activation on new stimuli. If cholinergic
inhibition also fails, due to pre-existing neurodegeneration or drugs with anticholinergic effects, inflammation
could spin out of control, leading to severe prolonged delirium. The green arrows indicate 4 ways in which control
could be re-established over activated microglia: (1) direct inhibition of microglial activation by anti-inflammatory
treatment (eg, minocycline); (2) inhibition of effects of cytokines (eg, anti-TNF α); augmentation of inhibitory
cholinergic control by (3) nicotine-receptor ligands or (4) cholinomimetic drugs (eg, cholinesterase inhibitors).
A Neurodegenerative Matrix – Looping Factors Driving Decline
Primary Factor Produced By Producing Clinical Correlate?
Beta Amyloid Plaque Aging, genes, ↓ BBB, Inflammation, esp. in No clear clinical
(Extracellular Aβ ) ↓ clearance, ? OS glial cells, ↑ OS correlates by itself
Central Insulin Inflammation (NFk-b) ↓ Energy, HC damage, Promotes synaptic loss
Resistance (in CNS) ↑ Kinases (→ tangles)
Small aggregate Extracellular plaques? synaptic loss and Synaptic loss (NMDA,
amyloid (Oligomeric Aβ) Β and γ secretases dysfunction, OS, INFLA AMPA), Loss of LTP
Oxidative Stress, esp. in Aging, Aβ oligomers in Apoptosis, synaptic & Appears before (&
MITO (OS) MITO, metal ions? neural loss, INFLA, Aβ after) plaques/tangling

Inflammation (INFLA) Amyloid, ↓ ACh effect Synaptic dysfunction, Contributes directly to

on glial and rAGE
Depletion of neuro- Oligomers (Aβ
(Aβ) → receptor
internalization, tau pathology
trophins/transmitters driving microtubule dysfxn
Excitotoxicity and Ca++ Oligomers (Aβ) in
dysfunction MITO
Neurofibrillary Tangling Oxidative stress (OS),
and Tau Aggregates insulin resistance
Synaptic Loss (SL) Multifactorial – many
factors listed
Neuronal Loss, Atrophy, Multifactorial – many
Apoptosis (NL) factors listed
possible apoptosis cognitive dysfunction
ACh loss → ↑ Aβ form, Synaptic dysfunction,
BDNF/NGF declines eventually SL/NL
Probable synaptic Synaptic dysfunction,
dysfunction. Apoptosis eventually SL/NL
Basal forebrain (ACh) Tracks atrophic change
loss, SL, Apoptosis (SL/NL) and ↓ cog fxn.
Shrinking brain volume Primary correlate
and ventriculomegaly for ↓ cog fxn.
Shrinking brain volume Second major biologic
and ventriculomegaly correlate, esp. later.
 Treatment of AD
More than Just ACh Rx
Although no single Rx is ‘disease-modifying,’
multi-agent Rx might be.
ACh, NMDA, Omega-3, polyphenols, exercise for now
Treatments on the Frontier?
„ Lipoic acid as an anti-inflammatory and neuroprotective treatment for
Alzheimer's disease. Maczurek A, Hager K,
K, Kenklies M, Sharman M,
M, Martins R,
R, Engel J,
J, Carlson DA,
DA, Münch G.

„ Despite extensive research into pathogenesis of AD, a neuroprotective treatment -

particularly for early stages - remains unavailable for clinical use. In this review,
we advance the suggestion that lipoic acid (LA) may fulfill this therapeutic need.
„ A naturally occurring cofactor for the mitochondrial enzymes pyruvate
dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to
have a variety of properties which can interfere with pathogenesis and/or
progression of AD.
„ LA increases acetylcholine (ACh) production by activation of choline acetyltransferase
and increases glucose uptake, supplying more acetyl-CoA for the production of ACh.
„ LA chelates redox-active transition metals, inhibiting formation of hydroxyl radicals,
scavenging reactive oxygen species (ROS), increasing levels of glutathione.
„ LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including
TNF and inducible nitric oxide synthase.
„ LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein.
„ Evidence for a clinical benefit for LA in dementia is limited. There are only two
published studies, in which 600 mg LA was given daily to 43 patients with AD
(receiving standard ACh treatment) in an open-label study over an observation
period of up to 48 months. Whereas the improvement in patients with moderate
dementia was not significant, the disease progressed extremely slowly (change in
ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild
dementia (ADAScog<15).
„ LA could be combined with other nutraceuticals such as curcumin, EGCG (green
tea) and DHA (from fish oil) to synergistically decrease oxidative stress,
inflammation, Abeta levels and plaque load and thus provide combined benefit.
 Treatment of Alzheimer’s disease
„ Cholinesterase Inhibitors & Namenda (often too late?) Start Prodromally.
„ Exercise programs (grossly underutilized).
„ Omega-3 supplementation? (some empirical support, but mixed outcomes)
„ Polyphenol ‘antioxidants’? (also underutilized). Diets high in polyphenols ↓ AD.
„ Resveratrol (rescues proteasome, partial CR effects)
„ Turmeric (Indian curried diet → ~ 1/5 incidence of AD as USA)
„ EGCG (from green tea extract) (also functions as metal chelator)
chelator)
„ Ginkgo (recent JAMA study: no efficacy in preventing AD, probably not effective in treating AD)
AD)
„ Early treatment of comorbid accelerating/aggravating conditions
(diabetes, recurrent infections, depression).
„ Extra support and daily structure, esp. reduced isolation.
„ Nicotine patches, anti-inflammatories? (esp. Ibuprofen)?
„ One study to date looking at more than two treatments and integrating
modalities!! (drugs + exercise + nutraceuticals).
„ Treatments in the pipeline?
„ Would earlier amyloid vaccination be protective (before cognitive decline)?
„ Dimebon? 1st drug to show sustained improvement for 1 year in mild to
moderate AD BUT . . . not confirmed in F/U study.) Probably not effective.
„ Iron chelators (neuroprotective in relationship to multiple aspects of AD).
„ Rasagiline – MAO-B, but with effects on OS in MITO (SOD/catalase).
Very neuroprotective/neurotrophic (↑ α secretase, ↓ apoptosis).
„ TV3326 - experimental drug (Rasagiline, plus ACh promotion).
„ AL-108 (fragment of neuroprotective peptide): efficacy in both animals and
clinical models: ↑ amnestic MCI into normal range of STM function!!
„ TNF-α blocking drug (Etanercept) may improve cognitive function.
 Multimodal treatment approaches
Integrated treatment approach improves cognitive function in demented and
clinically depressed patients.

Bragin V, Chemodanova M, Dzhafarova N, Bragin I, Czerniawski JL, Aliev G.

Stress Relief and Memory Training Center, Brooklyn, New York, USA.

The purpose of this study was to evaluate the efficacy of an integrative treatment approach
on cognitive performance. The study sample comprised 35 medically ill patients (20 male,
15 female) with an average age of 71.05, who were diagnosed with mild dementia and
depression. These patients were evaluated at baseline and at six, 12, and 24 months of
treatment, which included antidepressants (sertraline, citalopram, or venlafaxine XR, alone
or in combination with bupropion XR), cholinesterase inhibitors (donepezil, rivastigmine
or galantamine), as well as vitamins and supplements (multivitamins, vitamin E, alpha-
lipoic acid, omega-3 and coenzyme Q-10). Patients were encouraged to modify their diet
and lifestyle and perform mild physical exercises. RESULTS SHOW THAT THE
INTEGRATIVE TREATMENT NOT ONLY PREVENTED COGNITIVE
DECLINES FOR 24 MONTHS BUT EVEN IMPROVED COGNITION RELATIVE
TO BASELINE, ESPECIALLY MEMORY AND ‘FRONTAL LOBE’ FUNCTIONS.
 Impact of Lifestyle Variables
on Oxidative Stress and INFLAM?
„ Sleep, exercise and diets high in phytochemicals & Omega-3 are
anti-inflammatory and control OS. High phytochemical diets down
regulate inflammation and oxidative stress via several mechanisms.
„ Exercise promotes slow wave sleep (which is anti-inflammatory).
„ Exercise up regulates antioxidant defense mechanisms (adaptive
response to increased oxidative stress in exercising organism).
„ Social comfort decreases stress, and stress promotes inflammation.
„ High phytochemical diets also reduce glycation of protein as does
exercise. Advanced glycation end products promote inflammation.
„ Inflammation itself promotes oxidative stress.
„ Oxidative stress damages mitochondrial DNA → eventual cellular
failure and programmed cell death.
„ All lifestyle issues thus impinge on biggies of OS, INFLAM, GLYCA
and promote either LT cellular protection or cellular degradation.
 How are Modern Lifestyles → AD
(& Other Diseases Of Aging)?
EVOLUTIONARY CURRENT TECHNOLOGIC
ENVIRONMENT ENVIRONMENT
1) Intense aerobic exercise 1) Little aerobic exercise
2) High phytochemical diets 2) Low phytochemical diets
3) Omega-6/Omega-3 ratio 3) Omega-6/Omega-3 ratio
between 4:1 to 2:1 between 20:1 to 40:1
4) Calorie limitations (‘calorie 4) Unlimited calories (‘calorie
restriction’) enhancement’)
5) 9+ hours sleep (see #1) 5) 7 or less hours of sleep
6) Intimate social groups 6) Social isolation common
7) High stress related to 7) High stress related to social
homeostatic needs needs & other issues
Conclusions: We are in an alien environment from the standpoint of our genome,
one promoting inflammation, oxidative stress, glycation of proteins, and long-term
biological failure. Promotion of Diseases of Aging is a primary consequence.