Deciphering the mechanism underlying late-onset Alzheimer disease.

TLDR: The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.

Abstract: Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.

Full text

ZurichOpenRepositoryand
Archive
UniversityofZurich
UniversityLibrary
Strickhofstrasse39
CH-8057Zurich
www.zora.uzh.ch
Year:2012
Decipheringthemechanismunderlyinglate-onsetAlzheimerdisease
Knuesel,Irene;Krstic,Dimitrije
Abstract: Despitetremendousinvestmentsinunderstandingthecomplexmolecularmechanismsunder-
lyingAlzheimerdisease(AD),recentclinicaltrialshavefailedtoshowecacy.Apotentialproblem
underlying these failuresis the assumption that themolecular mechanism mediatingthe genetically
determinedformof thediseaseisidenticaltotheoneresultinginlate-onsetAD.Here, weintegrate
experimentalevidenceoutsidethe’spotlight’ofthegeneticdriversofamyloid-฀(A฀)generationpublished
duringthepasttwodecades,andpresentamechanisticexplanationforthepathophysiologicalchanges
thatcharacterizelate-onsetAD.Weproposethatchronicinammatoryconditionscausedysregulation
ofmechanismstoclearmisfoldedordamagedneuronalproteinsthataccumulatewithage,andconcomi-
tantlyleadtotau-associatedimpairmentsofaxonalintegrityandtransport.Suchchangeshaveseveral
neuropathologicalconsequences:focalaccumulationofmitochondria,resultinginmetabolicimpairments;
inductionofaxonalswellingandleakage,followedbydestabilizationofsynapticcontacts;depositionof
amyloidprecursorproteininswollenneurites,andgenerationofaggregation-pronepeptides;furthertau
hyperphosphorylation,ultimatelyresultinginneurobrillarytangleformationandneuronaldeath. The
proposedsequenceofeventsprovidesalinkbetweenA฀andtau-relatedneuropathology,andunderscores
theconceptthatdegeneratingneuritesrepresentacauseratherthanaconsequenceofA฀accumulation
inlate-onsetAD.
DOI:https://doi.org/10.1038/nrneurol.2012.236
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-74263
JournalArticle
PublishedVersion
Originallypublishedat:
Knuesel,Irene; Krstic,Dimitrije(2012).Decipheringthemechanismunderlyinglate-onsetAlzheimer
disease.NatureReviews.Neurology,9(1):25-34.
DOI:https://doi.org/10.1038/nrneurol.2012.236

NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
25
Institute of
Pharmacology and
Toxicology, University
of Zurich,
Winterthurerstrasse
190, CH‑8057, Zurich,
Switzerland (D. Krstic,
I.Knuesel).
Correspondence to:
I. Knuesel
knuesel@
pharma.uzh.ch
Deciphering the mechanism underlying
late-onset Alzheimer disease
Dimitrije Krstic and Irene Knuesel
Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying
Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these
failures is the assumption that the molecular mechanism mediating the genetically determined form of the
disease is identical to the one resulting in late‑onset AD. Here, we integrate experimental evidence outside
the ‘spotlight’ of the genetic drivers of amyloid‑β (Aβ) generation published during the past two decades,
and present a mechanistic explanation for the pathophysiological changes that characterize late‑onset AD.
We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or
damaged neuronal proteins that accumulate with age, and concomitantly lead to tau‑associated impairments
of axonal integrity and transport. Such changes have several neuropathological consequences: focal
accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage,
followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites,
and generation of aggregation‑prone peptides; further tau hyperphosphorylation, ultimately resulting in
neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between
Aβ and tau‑related neuropathology, and underscores the concept that degenerating neurites represent a cause
rather than a consequence of Aβ accumulation in late‑onset AD.
Krstic, D. & Knuesel, I. Nat. Rev. Neurol. 9, 25–34 (2013); published online 27 November 2012;
doi:10.1038/nrneurol.2012.236
Introduction
Alzheimer disease (AD) is the most common type of
age-related dementia, affecting approximately 24million
people worldwide, with the number of patients doub ling
every 20years as a consequence of the ageing popula tion.
1
This pandemic scenario will have not only a pro found
health and emotional influence on affected indivi-
duals and their families, but will also place a substantial
econom ic burden on society.
The disease is characterized by progressive loss of cog-
nitive abilities, severe neurodegeneration, and promi-
nent neuroinflammation.
2
Neuropathological hall marks
include proteinous aggregates in the form of senile
plaques, which are enriched in amyloid-β (Aβ) pep tides,
and neurofibrillary tangles (NFTs), consisting of hyper-
phosphorylated tau.
3
Dominant genetic effects of muta-
tions in amyloid precursor protein (APP), presenilin-1
(PS1) or PS2 are responsible for the early-onset or fa milial
form of AD. These mutations have been shown to pro-
foundly alter APP metabolism, favouring the produc-
tion of aggregation-prone Aβ species, and such findings
formed the basis of the ‘amyloid cascade hypothesis’ of
AD pathogenesis.
4
This broadly accepted hypo thesis
states that the generation of neurotoxic Aβ peptides
by β-secretase and γ-secretase constitute the cause of
AD pathophysiology, with all other disease hallmarks
develop ing as a consequence of this event.
Although the amyloid cascade hypothesis is likely to
hold true for the familial form of the disease, increas-
ing evidence suggests that the mechanisms underlying
late-onset AD—the sporadic disease form that accounts
for the vast majority of AD cases—could be different.
5
For example, in addition to the ε4 allele of the apolipo-
protein E gene (APOE)
6
—a well-known risk factor for
AD—recent genome-wide association studies identi-
fied significant correlations between polymorphisms
in genes of the innate immune system and incidence of
late-onset AD.
7,8
By contrast, no such correlation was
found between polymorphisms in genes encoding APP
or γ-secretase and incidence of late-onset AD.
9
Together
with the observation that inflammatory mediators are
abundantly present in affected brain areas
10,11
and plasma
of patients with AD,
12
these newly identified risk factors
imply that alterations in innate immunity might have
a key role in the disease aetiology, rather than being a
passive reaction to Aβ-related neuropathology.
In this article, we integrate experimental data focused
on neuroinflammation with several other neuropatho-
logical aspects of the disease that have so far been con-
sidered to be secondary to Aβ-mediated neurotoxicity,
and propose a sequence of neuropathological events
that could lead to development of late-onset AD. This
model unites many of the previously proposed mecha-
nisms underlying AD into a comprehensive view of
how the neuropathology could evolve over decades. We
first present the results that have provided the rationale
Competing interests
The authors declare no competing interests.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved

26
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
for this hypothesis, which are then complemented by
broader literature and experimental evidence from
animal and human studies.
Inflammation hypothesis of AD
Rationale
A large body of evidence has implicated inflammatory
mediators and the innate immune system of the brain in
the aetiology of AD, as discussed below. The precise role
of inflammatory processes in the disease pathophysio-
logy has, however, been controversial, ranging from a
possible disease cause, to a by-product of the disease, or
even a beneficial response.
13
Our previous findings in mice showed that systemic
administration of the viral mimic polyriboinosinic–
polyribocytidilic acid (PolyI:C) during late gestation trig-
gered the expression of several inflammatory cytokines
in the foetal brain,
14
evoked a reduction in adult neuro-
genesis in the offspring that was accompanied by working
memory impairments,
14,15
and led to accelerated depo-
sition of aggregated proteins in the brains of the aged
offspring.
16
More recently, we demonstrated that upon
second immune stimulation with PolyI:C in adulthood,
prenatally challenged animals developed an AD-like
pheno type.
17
The ageing-associated progression of disease
in these mice was in striking similarity to that described
in patients with AD.
2
In addition, systemic immune chal-
lenge in adult transgenic AD mice led to a strong aggra-
vation of the AD-like pathology,
17
in agreement with the
observation that both acute and chronic inflammation
are associated with an increase in cognitive decline in
patients with AD.
18
Alterations in critical inflammatory
mediators might, therefore, represent a process associated
with the onset and progression of the disease in humans,
as already suggested by Sheng et al. in 1996.
19
The model
In wild-type mice, ageing is associated with increased
deposition of proteins in the brain parenchyma, and
this phenomenon is highly conserved among various
species.
16,20
Using 3D immunoelectron microscopy in
aged wild-type mice we found that, surprisingly, these
extracellular depositions originated from intracellular
spheroid-like varicosities
20
and were immunoreactive for
Key points
■ Despite tremendous investments in basic and clinical research, no cure or
preventive treatment for Alzheimer disease (AD) exists
■ A re‑evaluation of the current view of the mechanisms underlying late‑onset AD
pathology is a prerequisite for future translational approaches
■ Inflammatory processes are strongly correlated with AD onset and progression
in humans, and could have a pivotal role in disease aetiology
■ Chronic inflammation coupled with neuronal ageing induces cellular stress
and concomitant impairments in basic neuronal functions
■ Inflammation‑induced hyperphosphorylation and missorting of tau might
represent one of the earliest neuropathological changes in late‑onset AD
■ Molecular changes underlying late‑onset AD involve impairments in
cytoskeleton stability and axonal transport, which could trigger axonal
degeneration and formation of senileplaques and neurofibrillary tangles,
resulting in neuronal death
N-terminal and Aβ-containing APP fragments.
21
Some of
these structures had a budding-like morphology and con-
tained organelles, but many were detached from neurons
and/or were being engulfed by microglia and astrocytes
(Figure1, step1).
20,21
This phenomenon could, therefore,
conceivably reflect a conserved neuroprotective strategy
of postmitotic neurons to overcome age-related accumu-
lation of misfolded, damaged or aberrantly cleaved pro-
teins.
20
In line with this suggestion, a prenatal immune
challenge with its chronic elevation of proinflammatory
cytokines
17
accelerated the formation of these axonal bud-
dings, and induced the accumulation of mitochondria
and other organelles within these varicosities (Figure1,
step 2).
20
A strikingly similar budding phenomenon has
also been observed in aged rhesus monkeys,
22
which serve
as a primate model of late-onset AD.
23
Chronic inflammation and cellular stress to neurons
during ageing—owing to infection, disease, or age-
related changes—induce hyperphosphorylation and
mis sorting of tau,
17
which in turn is expected to destabi-
lize the microtubule–actin networks and impair axonal
trans port.
24
Such changes might cause the protein extru-
sion mechanism to decline or fail completely, thereby
inducing focal axonal swellings and concomitant accu-
mulation of mitochondria and other organelles (Figure1,
step3).
25,26
Disturbed energy metabolism in the axon
could induce further tau phosphorylation,
27
an additional
neuropathological event that probably facilitates the
formation of paired helical filaments (PHFs; precursor
elements of neurofibrillary tangles), as seen in double-
immune-challenged mice.
17
This outcome would lead to
further impairments in axonal transport, complete trans-
port blockade, and ultimately axonal leakage (Figure1,
step 4; Figure2a).
28
Loss of synaptic contacts and decline
in cognitive performance constitute additional structural
and functional consequences of axonal transport impair-
ments
(Figure1, step 4).
17,29
A chronic inflammatory state
also increases APP levels,
17
which may be followed by
accumulation of this protein in swollen axons
(Figure1,
steps 2–4; Figure2b).
28
In parallel with its effect on neurons, chronic sys-
temic inflammation induces a prominent activation, or
‘priming’, of microglial cells and extensive astrogliosis
(Figure1, step 3).
17
Recruitment of microglia towards
degenerative and/or leaking axons and axonal varicosi-
ties could, therefore, lead to over-activation of micro-
glia and production of local inflammatory ‘hot spots’
that would also be expected to negatively affect nearby
neurons (Figure1, step 5). Support for this scenario is
provided by our findings in double-immune-challenged
mice in which individual accumulations of APP seem
to involve groups of several adjacent neurites, which are
surrounded by activated microglia.
17
Finally, these APP
accumulations might represent a seed for other aggrega-
tion-prone peptides (Figure1, step 5), as demonstrated
in immune-challenged transgenic AD mice.
17
On the basis of recent observations in the brains of
patients with AD,
28
we propose that axonal leakage and
release of intracellular contents—especially from dense
auto phagolysosomal vesicles
30,31
(Figure2c–e)—including
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
27
accumulated APP
28
(Figure2b,f) into the extra cellular
matrix (Figure2a,b) leads to substantial local production
of aggregation-prone protein fragments. This scena rio is
in agreement with the abundant presence of APP cleav-
age enzymes, such as cathepsin-D
31
(Figure2e), and the
enrichment of various truncated Aβ fragments
32
and
diverse non-Aβ fragments of APP
33,34
in senile plaques.
In addition, electron micro scopy of human senile plaques
revealed, in accordance with this proposal, an abun-
dance of mitochondria and other organelles, as well as
degenerated neurites, in the plaque core.
33,35
Finally, the
pro inflammatory environment and concomitant loss of
axons might lead to formation of NFTs and neuronal cell
death (Figure1, step6). This suggestion is in agreement
with the observation that formation of NFT-like struc-
tures in AD transgenic mice—importantly, in the absence
of mutant human tau—was accompanied by aggravated
Aβ deposition, prominent neuroinflammation and con-
siderable shrinkage of cortical areas.
36
Loss of synaptic
contacts combined with persistent inflammation-induced
cellular stress probably contributes to initiation of the
patho physiology in interconnected brain areas and the
spread of the pathology across brain networks.
In the following sections, we summarize additional
experimental data from the existing literature that
support each of the proposed steps of the model.
Inflammation—a key player
Support for a key role for systemic inflammation in the
aetiology of AD was first provided by a meta-analysis of
17 epidemiological studies, which indicated that non-
steroidal anti-inflammatory drugs might decrease the
a
Healthy ageing
Step 1
Healthy aged neuron
Axonal varicosities
Bud-off granules
Microglia
Microglial priming
Aged neuron
and chronic or repeated
inflammatory stress
pTau
Step 3
APP APP APP
Axonal transport impairments
Axonal varicosities
Axonal swellings and accumulation of APP
APP
APP
APP
Tau
pTau
Step 4
PHF
Tau
hyperphosphorylation
Synaptic loss
APP APP APP
APP
APP
pTau
Axonal leakage
Step 5
Aberrant processing
of APP
Diffuse plaque
formation
Impaired clearance of
dystrophic neurites and debris
PHF
APP
APP
Pathological ageing
b
Step 2
Axonal varicosities
APP synthesis
Tau phosphorylation
APP
APP
Tau
APP
pTau
Healthy aged neuron
and inflammatory stress
Step 6
APP
APP
Neurofibrillary
tangles
Senile
plaques
Neuroinflammation
Proinflammatory
cytokines
Caspase
activation
Astrogliosis
Hyperreactive microglia
Inflammatory
stress
Organelle
Cellular
proteins
Aβ
Figure 1 | The inflammation hypothesis of late‑onset
Alzheimer disease. a | During healthy ageing, a conserved
protein extrusion mechanism compensates for ageing‑
dependent failures in protein clearance and degradation
(step 1). Cellular stress to ageing neurons accelerates
formation of varicosities and their extrusion into the
extracellular matrix, where they are phagocytosed by
surrounding glia (step 2). If aged neurons experience
chronic inflammation, tau becomes hyperphosphorylated
and is missorted to somatodendritic compartments, which
impairs axonal transport (steps 2 and 3).
b | Consequently, stress‑induced APP accumulates in
axonal compartments and in larger swellings (step 3).
Chronic inflammation also ‘primes’ microglia to
subsequent immune challenges (step 3). Blockade of
axonal transport leads to synaptic destabilization or loss,
and is accompanied by formation of PHFs in neurites and
membrane leakage at axonal swellings (step 4). Axonal
leakage exposes cellular proteins to lysosomal
proteinases, promoting formation of neurotoxic peptides.
Hyperreactive microglia cannot properly remove dystrophic
neurites, and create a toxic proinflammatory environment
that affects surrounding neurons. Senile amyloid‑β plaques
begin to form (step 5). In response to neuritic
degeneration, caspase activation triggers formation of
neurofibrillary tangles (step 6). Imbalances in excitatory–
inhibitory neurotransmission and the neurotoxic
proinflammatory environment initiate pathology in
interconnected brain areas. Abbreviations: APP, amyloid
precursor protein; PHF, paired helical filament.
◀
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved

28
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
risk of AD.
37
This view is supported by two key findings
from retrospective epidemiological studies: first, plasma
levels of the inflammatory proteins C-reactive protein,
α1-antichymotrypsin and IL-6 are increased long before
clinical onset of AD and dementia;
38,39
and second, epi-
sodes of infections are strongly correlated with increased
a
b
c
d
e
f
DAPI/N-APP/Aβ
Figure 2 | Axonal swellings and leakage as a trigger of senile plaque formation in patients with Alzheimer disease.
a | Experimental support that evolution of senile plaques starts with axonal swelling and varicosities (top row, arrows) and
leakage from dystrophic axons (bottom row, arrows) in the cortex. b | Immunostaining of the cortex reveals small (left panels)
and medium‑sized (right panels) plaque‑like accumulations (arrows) enriched for hyperphosphorylated tau (upper panels)
and APP and/or amyloid‑β (lower panels). c | Autophagic vacuoles (arrowheads) loaded with proteins accumulate in
dystrophic neurites. d | Immunogold staining shows enrichment of cathepsin‑D, the APP‑degrading enzyme, in autophagic
vacuoles in swollen neurites. e,f | Dense staining of cathepsin‑D within late‑stage senile plaques (e) overlaps with staining of
accumulated amyloid‑β (f). Abbreviation: APP, amyloid precursor protein. Parts a and b are reproduced, with permission, from
Springer © Xiao, A. W. etal. Neurosci. Bull. 27, 287–299 (2011). Parts c and e are reproduced, with permission, from Elsevier
Ltd © Nixon, R. A. & Yang, D. S. Neurobiol. Dis. 43, 38–45 (2011). Part d is reproduced, with permission, from Wolters Kluwer
Health © Nixon, R. A. etal. J.Neuropathol. Exp. Neurol. 64, 113–122 (2005). Part f is reproduced from Krstic, D. etal.
J.Neuroinflammation 9, 151 (2012), which is published under an open‑access license by Biomed Central.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved

Frequently asked questions

Q1. What are the contributions in "Deciphering the mechanism underlying late-onset alzheimer disease" ?

Here, the authors integrate experimental evidence outside the ’ spotlight ’ of the genetic drivers of amyloid-฀ ( A฀ ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. The authors propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. The proposed sequence of events provides a link between A฀ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A฀ accumulation in late-onset AD. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments ; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts ; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides ; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. 

Q2. What is the role of microglia in the formation of degenerated neurites?

in AD, a hyperreactive microglial state and increased secretion of proinflammatory mediators, combined with downregulated phagocytic functions, might lead to inefficient clearance of degenerated neurites. 

Q3. What are the main factors that trigger the pathological cascade described here?

In addition, traumatic head injury, micro-strokes and other vascular dysfunctions associated with increased risk of AD probably trigger the pathological cascade described here via secondary neuroinflammatory reactions. 

Q4. What is the role of axonal leakage in triggering senile plaque?

Membrane leakage at the sites of axonal swellings could serve as a seed for the formation of senile plaques, thereby triggering an innate immune response of the brain. 

Q5. what is the phosphorylation of tau in Alzheimer’s disease?

Regulation of mitochondrial transport and inter‑microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer’s disease. 

Q6. What is the axonopathy induced by kinesin light chain 1?

138 Moreover, genetic ablation of kinesin light chain 1, which induces an age-dependent axonopathy, is accompanied by tau hyperphosphorylation, as evaluated using several AD-specific tau antibodies. 

Q7. What is the role of NFTs in the formation of senile plaques?

132The observation that neuritic plaques develop gradually in the projection areas of NFT-bearing neurons133 indicates that NFTs develop in neurons whose neurites are involved in the formation of senile plaques. 

Q8. what is the axonal transport in mice with apolipoprotein E4?

Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. 

Q9. what is the role of a ps challenge in aging mice?

C. J., Huang, Y., Wynne, A. M. & Godbout, J. P. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro‑ inflammatory IL‑1β and anti‑inflammatory IL‑10 cytokines. 

Q10. What is the axonal structure of senile plaques?

a | Experimental support that evolution of senile plaques starts with axonal swelling and varicosities (top row, arrows) and leakage from dystrophic axons (bottom row, arrows) in the cortex. 

Q11. What is the role of microglia in clearing degenerated neurites?

81,82 Microglia might instead be primarily recruited to clear the fragmented and/or apoptotic neurons and neurites within the senile plaques,83 as occurs during neurodevelopment. 

Q12. what is the role of cathepsins in Alzheimer’s disease?

125. Schechter, I. & Ziv, E. Cathepsins S, B and L with aminopeptidases display β‑secretase activity associated with the pathogenesis of Alzheimer’s disease. 

Q13. What is the main reason for the existence of extra cellular A plaques?

The authors argue, therefore, that extra cellular Aβ plaques originate from intracellular APP accumulations and are secondary to degeneration of neurons. 

Q14. What is the effect of inflammation on the formation of axonal buddings?

In line with this suggestion, a prenatal immune challenge with its chronic elevation of proinflammatory cytokines17 accelerated the formation of these axonal buddings, and induced the accumulation of mitochondria and other organelles within these varicosities (Figure 1, step 2).20 

Q15. What is the main cellular stressor after 80 years of life?

The authors suggest naming this integrated view of how the neuropathology evolves over decades ‘the in flammation hypothesis of AD’, as inflammation induced by infection, disease, or age-related changes could be the main cellular stressor after 80 or more years of life. 

Q16. what is the molecule and cellular characterization of the agerelated neuroinflammatory processes occurring?

Molecular and cellular characterization of the age‑related neuroinflammatory processes occurring in normal rat hippocampus: potential relation with the loss of somatostatin GABAergic neurons. 

Q17. What is the role of axonal swellings in Alzheimer disease?

This view is supported by two key findings from retrospective epidemiological studies: first, plasma levels of the inflammatory proteins C-reactive protein,α1-antichymotrypsin and IL-6 are increased long before clinical onset of AD and dementia;38,39 and second, episodes of infections are strongly correlated with increaseda bcdef DAPI/N-APP/AβFigure 2 | Axonal swellings and leakage as a trigger of senile plaque formation in patients with Alzheimer disease. 

Q18. What is the potential problem underlying lateonset AD?

A potential problem underlying thesefailures is the assumption that the molecular mechanism mediating the genetically determined form of thedisease is identical to the one resulting in late‑onset AD.