REVIEWS

A systemic view of Alzheimer disease

insights from amyloid metabolism
beyond the brain
Jun Wang1*, Ben J.Gu2*, Colin L.Masters2 and Yan-Jiang Wang1
Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently
incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research
into this disease has conventionally focused on the CNS. However, several peripheral and
systemic abnormalities are now understood to be linked to AD, and our understanding of how
these alterations contribute to AD is becoming more clearly defined. This Review focuses on
amyloid (A), a major hallmark of AD. We review emerging findings of associations between
systemic abnormalities and A metabolism, and describe how these associations might interact
with or reflect on the central pathways of A production and clearance. On the basis of these
findings, we propose that these abnormal systemic changes might not only develop secondary to
brain dysfunction but might also affect AD progression, suggesting that the interactions between
the brain and the periphery have a crucial role in the development and progression of AD. Such
asystemic view of the molecular pathogenesis of AD could provide a novel perspective for
understanding this disease and present new opportunities for its early diagnosis and treatment.

1
Department of Neurology
and Centre for Clinical
Neuroscience, Daping
Hospital, Third Military
Medical University,
10 Changjiang branch road,
Daping, Chongqing, 400042,
China.
2
The Florey Institute,
The University of Melbourne,
30 Royal Parade, Parkville,
Victoria 3052, Australia.
*These authors contributed
equally to this work.
Correspondence to
Y.-J.W.and C.L.M.
yanjiang_wang@tmmu.edu.cn;
c.masters@florey.edu.au
doi:10.1038/nrneurol.2017.111
Published online 29 Sep 2017
The global burden of Alzheimer disease (AD), already
the most common type of dementia, is expected to
increase still further owing to population ageing. AD not
only causes severe distress for patients and caregivers,
but also results in a large economic burden on society.
Current major challenges in AD include the lack of reli-
able biomarkers for its early diagnosis, as well as the lack
of effective preventive strategies and treatments1,2. Thus,
increased understanding of the molecular pathogenesis
of AD could lead to the development of improved
diagnostic and therapeutic strategies.
AD is conventionally regarded as a CNS disorder.
However, increasing experimental, epidemiological and
clinical evidence has suggested that manifestations of
AD extend beyond the brain. These systemic alterations
might not be simply secondary effects of the cerebral
degeneration seen in AD, but could reflect underlying
processes linked to progression of the disease. AD
pathogenesis is complex, involving abnormal amyloid-
(A) metabolism, tau hyperphosphorylation, oxidative
stress, reactive glial and microglial changes, and other
pathological events. Given that A is a major hallmark
of AD and a fertile area of research in this disease, this
Review focuses on the systemic role of A in AD. We dis-
cuss the communication between peripheral and central
pools of A, and describe interactions between systemic
abnormalities and AD pathogenesis in the brain. We
review emerging findings of associations between sys-
temic abnormalities and A metabolism, and describe
how these associations might interact with or reflect on
the central pathways of A production and clearance.
On the basis of these findings, we suggest that inter
actions between the brain and the periphery might have
a crucial role in the development and progression ofAD.
A biogenesis and catabolism
A steady accrual of data from laboratories and clinics
is providing increasing support for the concept that an
imbalance between the production and clearance of A is
a very early (and often initiating) factor in AD3. Normal
metabolism of A and maintenance of the homeostatic
balance between A production and clearance is, there-
fore, essential to maintain brain health. Infact, physio-
logical metabolism of A occurs not only in the brain
but also in the periphery, and c ommunication between
these regions is possible (FIG.1).
Central and peripheral production of A
A is derived from the proteolytic cleavage of amyloid
precursor protein (APP), which is expressed not only in
brain cells, including neurons, astrocytes and microglia,
but also in peripheral organs and tissues, such as the

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Key points These factors might also help to explain why A

An imbalance between the production and clearance of amyloid (A) is an early,
often initiating, factor in Alzheimer disease (AD)
Peripheral systems are suggested to be involved in A production and clearance
The central and peripheral pathways of A metabolism communicate with each other,
and work synergistically to clear A from the brain
Increasing experimental, epidemiologic and clinical evidence suggests that AD
manifestations extend beyond the brain, and that AD pathogenesis is closely
associated with systemic abnormalities
The systemic abnormalities in patients with AD might not be secondary to the
cerebral degeneration; instead, they might reflect underlying disease processes
A systemic view of AD provides a novel perspective for understanding the role of A
in AD pathogenesis and offers opportunities for the development of new treatments
and diagnostic biomarkers for AD
aggregates are mainly deposited in the brain and cere
bral vessel walls, and only rarely in peripheral organs
(although detection of A aggregates has been claimed
in skin, subcutaneous tissue, intestinal tissues, and
heart)1315. The aggregation (oligomerization and fibrillo
genesis) of A peptides is determined by the relative
proportions of A species, their concentrations, the pH,
temperature and ionic strength of solution, and incuba-
tion time16. In the periphery, therefore, an increased pro-
portion of A40 might lead to sequestration of A42 in a
stable mixed formation, thereby preventing its oligomer-
ization and aggregation17, whereas an increased propor-
tion of A42 in the brain might render A42 susceptible
to aggregation.

Central and peripheral clearance of A

adrenal gland, kidney, heart, liver, spleen, pancreas, mus-
cles, and various blood and endothelial cells4,5. A levels
(in both peripheral tissues and the brain) are known to
be lower in cognitively normal elderly individuals than
in patients with AD (TABLE1). The accumulation of A
aggregates in elderly patients with and without AD is an
important factor that could influence the ratio of A42
to A40 in both brain and periphery. Given that skeletal
muscle represents about one-quarter of body weight in
humans and is just one of many peripheral sources of A,
peripherally derived A is likely to represent a substantial
proportion of the total. However, levels and profiles of the
dominant A species in brain and periphery still need to
be measured in young people without A deposition in
future studies, for comparison purposes.
Important differences have been found between the
central and peripheral pools of A. First, A42, which is
the most aggregation-prone and most neurotoxic form
of A, is the dominant molecular species in the brain,
whereas A40 is dominant in the periphery, although the
mechanism underlying this difference is still unclear.
Differential expression of APP isoforms in the brain and
periphery is one possible explanation. APP695 is the domi
nant species produced by neurons, whereas APP751 and
APP770 are the dominant species produced by peripheral
cells, including platelets and leukocytes6. Another possi-
ble explanation is that the tissue microenvironment dif-
fers between the CNS and periphery, which could result
in differential processing of APP by secretase and gen-
eration of different A species4,5. Second, levels of A in
the central pool are higher than those in the peripheral
pool. Concentrations of A in cerebrospinal fluid (CSF)
are at least 515 times higher than those in plasma7,8. One
possible interpretation is that APP processing in periph-
eral cells probably occurs via cleavage (rather than the
cleavage used in neurons)9,10, resulting in decreased
peripheral production of A. Another explanation for
the lower A levels in the periphery is that the periphery
contains abundant Abinding proteins (lipoproteins and
albumin)11 and Abinding cells, such as erythrocytes12,
which all contribute to A transportation and clearance.
Additionally, the high volume of the circulatory system
and the blood-dilution effect efficiently reduce systemic
A concentrations.
The failure to clear A (especially A42) is an important
cause of sporadic AD, which accounts for 99% of AD
cases. Understanding how A is physiologically cleared
from the brain is, therefore, essential. Several poten-
tial pathways could clear A from the brain: phago-
cytosis, endocytosis and macropinocytosis by various
cells (such as microglia, perivascular macrophages,
astrocytes, oligodendroglia and neurons); proteolytic
degradation by various enzymes (including neprilysin,
insulin-degrading enzyme (IDE) and matrix metallo-
proteinases); and efflux of A to the peripheral circula-
tion, via transportation across the bloodbrain barrier
(BBB) and bloodCSF barrier, interstitial fluid bulk flow
and CSF egress pathways, including arachnoid villi and
glymphaticlymphatic pathways18 (FIG.1). Some endo
genous inhibitors of A aggregation, such as the secreted
ectodomain of tumour necrosis factor receptor super-
family member 16 (also known as low affinity neuro-
trophin receptor p75NTR)19 and the Nterminal domain
of myelin basic protein20, prevent A deposition in the
brain and f acilitate its efflux into the circulation.
How A is cleared in the periphery is poorly under-
stood. Previous studies have suggested that ~60% of
brain A is cleared via transportation to the periph-
ery 21,22. Our group has demonstrated, in a mouse model
of AD, that brain-derived A can be physiologically
cleared in the periphery, and that a singular peripheral
system can remove ~40% of the A produced in the
brain23. These findings indicate that peripheral clearance
has a crucial role in removing brain-derived A, and sug-
gest that effective peripheral A clearance can improve
the efficacy of A efflux from the brain. In fact, several
peripheral tissues or organs participate in A catabolism
and constitute potential A clearance pathways. These
include uptake and phagocytosis or endocytosis by
monocytes, macrophages, neutrophils, lymphocytes, and
hepatocytes24,25; excretion via bile or urine26,27; proteo-
lytic degradation by Adegrading enzymes28; and clear-
ance from blood mediated by Abinding proteins and
cells, such as erythrocytes, albumin, antithrombin III
andlipoproteins, including apolipoproteinE (ApoE) and
apolipoproteinJ (ApoJ)11,12. These centraland periph-
eral pathways might interact with each other andwork
synergistically to clear A from thebrain.

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Brain
A production A clearance

Degradation clearance ISF bulk ow clearance

(by microglia, astrocytes, (CSF sink, perivascular
neurons, etc., or by drainage or glymphatic
A-degrading enzymes) pathways)

CNS clearance
Neuron
CNS pool

A in ISF A in CSF

Astrocyte
A Aggregation and deposition
(mainly A42)
CSF absorption clearance
BBB clearance (arachnoid villi, BCSFB,
(LRP1, P-glycoprotein, etc) lymphatic pathway)

Microglia
Inux Eux
Blood
A production A clearance

BBB entrance
(RAGE)
Degradation clearance
(phagocytosis by blood
cells and degradation
Monocytes Neutrophils A-degrading by enzymes)
enzymes

Blood ow clearance
A (by RBCs, lipoproteins,
(mainly A42) albumin, etc)

Peripheral clearance
RBC Lipoproteins Albumin
Peripheral pool

Platelets

Peripheral organs or tissues

A production A clearance

Osteoblasts

A Macrophages Liver Kidney

Skin broblasts (mainly A42)
Degradation clearance Degradation clearance
(by macrophages in tissues) (by hepatocytes) Excretion with urine
Excretion with bile

Skeletal muscle cells

Figure 1 | Physiological metabolism of A in the brain and periphery. Amyloid (A) is generated by neurons,
Nature Reviews | Neurology
microglia and astrocytes in the brain, and by platelets, skin fibroblasts, osteoblasts, and skeletal muscle cells in the
periphery. The CNS and peripheral pools of A can interact; some A peptides in the CNS are cleared via phagocytosis or
proteolytic degradation, whereas others are released into the blood via the bloodbrain barrier (BBB), interstitial fluid (ISF)
bulk flow or cerebrospinal fluid (CSF) egress pathways. Some A peptides in blood are phagocytosed, including by
monocytes or neutrophils, some are degraded by A-degrading enzymes, and some are transported by carriers (such as
erythrocytes, albumin and lipoproteins) to peripheral organs or tissues, where they are degraded by macrophages or
hepatocytes, or excreted via the liver or kidney. BCSFB, bloodCSF barrier; RAGE, receptor for advanced glycation end
products; RBC, red blood cell.

Communication between A pools
Brain-derived A can be transported into the periph-
eral pool via the BBB, bloodCSF barrier, arachnoid
villi or glymphaticlymphatic pathway. Several trans-
porters mediate A flow out of the brain across the
BBB, including LDL-related protein1 (LRP1) and ATP-
dependent efflux transporter P-glycoprotein29. The
arachnoid villi absorb A in the CSF and mediate its
release into the circulation30. The glymphaticlymphatic
pathway, which consists of the glymphatic pathway in

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Table 1 | Amounts of A in the CNS and periphery processes in the AD brain can also drive these systemic
disorders, forming feedback loops. Mechanisms that
Source of A Cognitively normal Patients with Alzheimer Refs might underlie the effects of systemic abnormalities or
elderly individuals disease
alterations on A metabolism are outlined in TABLE2.
Brain grey matter Here, we discuss the interactions between A metabo
Total A* 3.2g/g 13.1g/g 5,168 lism in the brain and periphery, and place them in a
systemic context.
A40 0.2g/g 0.6g/g 5
A42 0.78g/g 6.1g/g 5 Disorders of systemic immunity
Packed quiescent platelets One of the primary pathways of A clearance in the
84.0ng/ml Not available 5
brain is phagocytosis or endocytosis by professional
A40
phagocytes and microglia, as well as by astrocytes,
A42 1.7ng/ml Not available 5 oligodendrocytes and neurons. Accumulations of
Packed activated platelets A in the periphery can similarly be phagocytosed
A40 56.8ng/ml Not available 5 by monocytes and neutrophils in the blood, and by
macrophages in tissues41. Of note, in transgenic mice
A42 1.6ng/ml Not available 5 with AD, expression of A scavenger receptors and
Skeletal muscle Adegrading enzymes in circulating mononuclear
A40 29.8ng/g 37.8ng/g 5 phagocytes decreases substantially as these mice age42,
and the phagocytic functions of these cells are impaired
A42 10.2ng/g 15.7ng/g 5
in both mice and humans with AD4345. Infusion of
*Includes A40, A42 and shorter peptides (An40, An42).Suggested to be the primary source of monocytes derived from peripheral human umbilical
soluble A (which is mainly A40) in the circulation169,170. A might also be generated by skin
fibroblasts and osteoblasts5,171173, although these findings have not yet been confirmed. cord blood reduces the A burden and improves cog-
A,amyloid. nitive deficits in a mouse model of AD46, implying that
peripheral mononuclear phagocytes have an important
role in A clearance. Promoting the phagocytic func-
the brain and the CNS lymphatic vessels (discovered in tion of peripheral blood monocytes or promoting the
2015)31,32, might also transport A from the brain to the recruitment of peripheral macrophages into the brain
periphery for clearance18,33. However, the glymphatic might, therefore, improve A clearance in the brain47,
lymphatic pathway and arachnoid villi are unidirec- although the existence of conflicting data48 renders this
tional; they only mediate A efflux from the CNS to approach controversial.
theperiphery 18. In this regard, a cluster of genes associated with the
Whether peripherally generated A can enter the risk of sporadic AD (including CD33, CR1, MS4A6A,
brain and exert neurotoxic effects there remains poorly MS4A4E, ABCA7 and TREM2)49,50 encode proteins that
understood. In the absence of a relevant transport are involved in innate immunity. Variants in these genes,
mechanism, systemic amyloidosis might not neces especially in TREM2 and CD33, are associated with
sarily lead to AD. However, peripheral inoculation compromised phagocytic function of peripheral mono-
of Acontaining brain extracts induces cerebral A cytes or macrophages and altered A accumulation in
deposition in both mice and humans, suggesting that AD brains24,51. Interestingly, CR1 (encoding complement
peripherally generated A is able to enter the brain and receptor1, also known as CD35) is expressed primarily
participate in the pathogenesis of AD3437. Receptor for in peripheral leukocytes and erythrocytes, but not in any
advanced glycation end products (RAGE) has been sug- braincells.
gested to transport A across the BBB, from the blood In regard to adaptive immunity, much attention
into the brain38. Expression of the AGER gene (encoding has been focused on autoimmunity and autoreactive
RAGE) is upregulated in the AD brain vasculature39,40, antibodies related to the pathogenesis of AD, includ-
indicating that influx of peripheral A into the brain ing naturally occurring antibodies and autoantibodies.
is increased in AD. The contribution of peripherally These autoreactive antibodies are ubiquitous in human
derived A to amyloidosis in the AD brain needs to be blood and CSF, and profiles of these antibodies are
determined in future studies. altered in patients with AD5256. Identification of the
A decline in peripheral A clearance might also most antigenic epitopes targeted by human antibodies
impede efflux of A from the brain to the periphery, against A aggregates could lead to development of an
and thereby attenuate central clearance of A. Moreover, effective immunotherapy for AD. Aducanumab, derived
the influx and efflux of A might result in equilib- from a naturally occurring human autoantibody against
rium between the central and peripheral pools of A. Cu 2+modified A aggregates (which are the most
Mechanisms that might regulate this equilibrium need neurotoxic A species in the AD brain), showed prom-
to be understood. ise in clearing brain A deposits and improving cogni-
tion in a 2016 phaseIb trial57. Lymphocytes (including
Systemic abnormalities in AD Bcells, Tcells and natural killer cells) also participate
An increasing number of studies indicate that a series in A clearance via immunoglobulin-mediated adaptive
of systemic abnormalities can exacerbate the progres- phagocytosis58,59. Future studies will help to elucidate
sion of AD (FIG.2). In turn, the downstream effects of the crosstalk between innate immunity and adaptive

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Disorders of systemic immunity

Phagocytic function of mononuclear
phagocytes Blood abnormalities
Altered proles of autoreactive antibodies APP expression on platelets
AD risk variants in immunity-associated Altered APP isoform ratio and APP
genes: CD33, CR1, ABCA7, MS4A6A, processing pattern in platelets
MS4A4E, TREM2 Quantity and A-binding ability of RBC
Albumin , A-degrading enzymes

Cardiovascular disease Respiratory and sleep disorders

Myocardial function OSA and COPD are associated with
Ejection fractions increased plasma A levels, which are
Cerebral blood ow velocities negatively correlated with pulmonary
PI and RI in BA, LTICA, RTICA function
Intramyocardial deposits of A
Renal dysfunction
Hepatic dysfunction Serum A levels are positively correlated
Plasma A levels are positively correlated with impaired renal function
with impaired hepatic function
A in liver tissue
Microbiota disturbance and infection
Disturbance of microbiome
Metabolic disorders Plasma LPS and antibodies to
Glucose metabolism anaerobes
Decits in insulin and IGF signalling
LDL-C , HDL-C
Membrane uidity of platelets and Systemic inammation
leukocytes Plasma proinammatory cytokines ,
including TNF, IL-1, IL-6, CRP
AD risk variants in lipid-metabolism- Infectious burden
associated genes: APOE, BIN1, APOJ,
SORL1, PICALM, PLD3

Figure 2 | Systemic abnormalities in AD. Various systemic abnormalities have been found in patients with Alzheimer
Nature Reviews | Neurology
disease (AD). Red boxes highlight AD risk variants in genes related to innate immunity, phagocytosis of amyoid- (A)
byimmune cells, and lipid metabolism in periphery and brain, respectively, which were identified in genome-wide
association studies and candidate-gene studies of sporadic AD. APP, amyloid precursor protein; BA, basilar artery; COPD,
chronic obstructive pulmonary disease; CRP, Creactive protein; HDL-C, HDL-cholesterol; IGF, insulin-like growth factor;
LDL-C, LDL-cholesterol; LPS, lipopolysaccharide; LTICA, left terminal internal carotid artery; OSA, obstructive sleep
apnoea; PI, pulsatility index; RBC, red blood cells; RI, resistance index; RTICA, right terminal internal carotid artery;
TNF,tumour necrosis factor.

immunity, and to discover how the interaction of identification of these protective components could be
these two immune systems might synergistically affect of importance in understanding the pathogenesis of AD
ADpathogenesis. and in developing systemic rejuvenation therapies6871.

Blood abnormalities Metabolic disorders

Besides monocytes and leukocytes, other blood com-
ponents are also involved in A metabolism. Increased
expression of APP, altered APP isoform ratios and pro-
cessing patterns, and enhanced secretase activity are
observed in platelets from patients with AD6062, and
these changes could result in overproduction of A
in the periphery. Blood levels of albumin, an A car-
rier, are reduced in patients with AD63. The quantity
and function of erythrocytes (another A carrier) are
also altered in such patients, and their erythrocytes
show compromised binding of A64,65. In addition, the
activity of Adegrading enzymes in serum is thought
to be decreased in AD28. These changes impede A
transportation and clearance in the periphery.
Some anti-ageing molecules, such as growth and dif-
ferentiation factor11, granulocytemacrophage colony
stimulating factor, and metalloproteinase inhibitor2,
have been identified in blood from young mice and
in human umbilical cord plasma66,67. Whether levels
of these anti-ageing molecules are reduced in patients
with AD, and whether they are pathophysiologically
relevant to this disease, remain unknown. However,
Diabetes mellitus. How diabetes mellitus affects A
catabolism and AD risk is not yet well understood. Patients
with diabetes mellitus are estimated to be 1.42.0fold
more likely than healthy individuals to develop AD72,73,
although these claims need to be verified in patients with
biomarker-confirmed AD. In patients with diabetes mel-
litus, insulin resistance substantially compromises the
positive effects of insulin on both cognition and hepatic
clearance of circulating A74,75, resulting in ADlike alter-
ations in the brain. Moreover, excess insulin can competi-
tively inhibit IDE-mediated A degradation76. Some other
pathological features of diabetes mellitus including
oxidative stress, BBB disruption and reduced cell energy
supply can also affect A generation and clearance77,78.
In addition, amylin (a misfolded protein deposited in the
pancreas in patients with type2 diabetes mellitus) can
enter the brain, where it accelerates and exacerbates the
misfolding and aggregation of A79. However, atheroscle-
rosis and small vessel disease (discussed in more detail
below) can be important causes of cognitive dysfunction in
patients with diabetes mellitus80, and should be considered
in the differential diagnosis of AD in this setting.

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Table 2 | Potential mechanisms of systemic abnormalities that affect A metabolism

Abnormality Potential mechanisms Refs
Disorders Reduced expression of A phagocytic receptors and Adegrading enzymes, and decreased phagocytic function in 4145
of systemic mononuclear macrophages and neutrophils, might impede A degradation and clearance
immunity
Increased levels of pathogenic autoreactive antibodies and decreased levels of protective antibodies could influence 5254
A generation, clearance and deposition
Lymphocytes produce immunoglobulins that bind to A and form immune complexes, such as AIgG and AIgM, 58,59
which undergo clearance via phagocytosis
Blood Increased APP expression, altered APP isoform ratios and APP processing patterns, and enhanced secretase activity 6062
abnormalities in platelets could promote overproduction of A in the periphery
Altered quantity and function of erythrocytes, and compromised adherence of A to erythrocytes, might hinder A 64,65
transportation and clearance
Reduced levels of albumin (an A carrier) in blood might hinder A transportation and clearance 63
Decreased activity of Adegrading enzymes could impede A degradation and clearance 28
Metabolic Excess insulin in diabetes mellitus competitively inhibits insulin-degrading enzyme-mediated A degradation 76
disorders
Insulin resistance compromises intracellular translocation of LRP1 to the plasma membrane in hepatocytes, potentially 74
hindering hepatic clearance of circulating A
Increased oxidative metabolism of glucose might cause BBB disruption, further impeding A clearance 77
Changes in mitochondrial function and mitochondria-derived free radicals could affect A generation and degradation 78
Amylin interacts with A by cross-seeding, which could accelerate or exacerbate the misfolding and aggregation of A 79
in the brain
ApoE is an A chaperone; the ApoEA complex facilitates A clearance via autophagy, BBB transportation, enzymatic 83,84
degradation and glymphatic pathways
Low cholesterol levels could shift APP processing out of the lipid raft region, where cleavage is preferred; high 85,86
cholesterol levels might disrupt the BBB through inflammation or other pathways
Abnormal membrane lipid components might affect membrane fluidity, which is involved in membrane APP 8790
processing, cellular phagocytosis and endocytosis, which all affect A generation and clearance
Cardiovascular The association between cardiovascular diseases and AD might be attributable to common risk factors or concomitant 96,97
diseases diseases, such as diabetes mellitus, hypertension, hypercholesterolemia and stroke
Cardiac systolic function drives blood flow, which is responsible for the transportation of A and its chaperones; 98
cardiac systolic dysfunction, reflected by reduced ejection fractions, could impair A clearance
Reduced cerebral blood flow could cause hypoxia, promoting A generation via upregulating BACE1 100,101,
174,175
Reduced cerebral blood flow and hypoxia could lead to an energy deficiency in cells of the neurovascular unit, 102
breaking down the BBB and impairing clearance of A
Hepatic Hepatic dysfunction might cause reduced hepatocyte uptake and degradation of A directly from the blood 108
dysfunction
Hepatic dysfunction might result in dysregulation of Arelated protein and lipid metabolism, thereby impairing A 11,108
transportation and clearance
Hepatic dysfunction could lead to reduced A excretion in bile 26
Renal Renal dysfunction could result in reduced A excretion in urine 112,113
dysfunction
Respiratory Hypoxia in respiratory diseases might induce A overproduction via upregulation of BACE1 174,175
and sleep
disorders Sleep fragmentation in patients with sleep-disordered breathing or obstructive sleep apnoea might cause increased 121,125,
neuronal activity, leading to elevated A production and aggregation; increased wakefulness might also increase 126
sympathetic output, suppressing glymphatic clearance of A and tau
Inflammation and immune responses in respiratory diseases might affect A generation and clearance 122
Disturbance of Some micro-organisms or their products can enter the brain and cause local damage, either via direct pathogenic 128,131
microbiota and action or through neuroinflammation and oxidative effects
infection
Some microbiota or pathogens could inhibit autophagy, leading to impaired degradation of A and phosphorylated tau 131
Some microbiota, pathogens and their products could damage the BBB and thereby impede A clearance 131
Systemic Proinflammatory cytokines in blood could enter the CNS (via the BBB or neural afferent pathways such as the vagus 130,134,
inflammation nerve) and participate in AD pathogenesis either directly in the CNS or via inducing immune responses 135
Acute local inflammatory responses might promote recruitment of monocytes and macrophages into the brain, 47
facilitating clearance of cerebral A
A, amyloid; APP, amyloid precursor protein; AD, Alzheimer disease; ApoE, apolipoprotein E; BBB, bloodbrain barrier; LRP1, LDL receptor-related protein1.

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Lipid and lipoprotein risk factors. Some evidence Hepatic dysfunction

suggests that abnormal lipid metabolism is associ-
ated with an increased risk of AD81. Several potential
AD risk genes (including APOE, BIN1, CLU, SORL1,
PICALM and PLD3) encode proteins linked to lipid
metabolism82. Among these, ApoE is known to partici-
pate in A production, aggregation, and clearance in an
isoform-dependent manner 83,84.
Cholesterol levels in the brain can affect A syn-
thesis, clearance and neurotoxicity. High serum chol
esterol levels are associated with an increased cerebral
burden of A85,86. Abnormal cholesterol levels could
reflect unmeasured genetic factors or dietary patterns
that might affect the pathogenesis of AD85,86. Cell mem-
brane fluidity is strongly affected by its lipid composi-
tion, and increased membrane fluidity of platelets and
leukocytes has been reported in patients with AD, as
well as in individuals with Down syndrome (who have
a greatly increased risk of developing dementia and
AD)8790. Cell membrane fluidity also influences the
processing of APP and cellular phagocytosis, both of
which might affect A generation and clearance. Ahigh
dietary intake of polyunsaturated fatty acids such as
docosahexaenoic acid, which maintain membrane flu-
idity, have a beneficial effect on cognition in patients
with AD91,92. The study of membrane fluidity inAD
might provide insights into the alteration of mem-
brane-dependent biological functions related to A,
such as phagocytosis, endocytosis, m acropinocytosis
and autophagy.
Cardiovascular disease
Emerging evidence indicates that cardiovascular dis-
ease (CVD) is a major comorbidity in patients with
sporadic AD. A low cardiac index and heart failure are
both associated with dementia, and perhaps also with
AD9395. However, as CVD and AD are both complex
and multifactorial age-related diseases, the association
between them might be attributed partly to shared
risk factors, such as diabetes mellitus, hypertension,
hypercholesterolemia and stroke96,97.
The presence of compromised myocardial func-
tion and intramyocardial deposits of A in patients
with AD suggests that peripheral A accumulation
could affect heart function in patients with AD15,98.
In addition, cardiac systolic dysfunction could affect
A generation and clearance in the brain as a result
of reduced cerebral blood flow 99102. Regional cerebral
blood flow and glucose uptake or metabolism are con-
sistently decreased in Apositive patients with AD103,
and correlate inversely with AD severity 104. Indeed,
some degree of cerebral small vessel disease almost
always accompanies AD. Increased stiffness of small
vessel walls might attenuate A clearance via the BBB,
interstitial fluid bulk flow and glymphatic pathways,
thereby accelerating AD105,106. However, a clear under-
standing of the interaction between CVD and AD is
lacking. Most of the evidence points to CVD being an
independent risk factor for cognitive impairment, and
having an additive rather than synergistic effect on the
AD neurodegenerative process.
The liver is the major organ responsible for system-wide
metabolic regulation, protein synthesis and metabolic
detoxification. Circulating A is predominantly cleared
by either degradation in hepatocytes or direct excretion
in bile; several peptide clearance experiments have sug-
gested that soluble A has a short half-life of 2.5min to
2.5h in the circulation26,107. LRP1 is thought to mediate
the uptake of A by hepatocytes25. The liver might also
indirectly influence A clearance by regulating albu-
min levels and Arelated lipid metabolism. Plasma A
levels inversely correlate with liver function, suggesting
that hepatic dysfunction attenuates peripheral A clear-
ance108. Liver tissue from patients with AD contains less
A than that from healthy individuals, which implies
that the Aclearance function of liver is compromised
in patients withAD5.
Whether liver dysfunction also increases the A load
in the brain remains unknown; however, treatments that
enhance LRP1mediated A uptake by the liver alleviate
both the burden of A in the brain and cognitive impair-
ment74,109. These observations suggest that improving the
A clearance capacity of the liver is a potential systemic
therapeutic approach forAD.
Renal dysfunction
Soluble A is a normal component of human urine27.
In addition, animal experiments have shown that, after
intracranial or intravenous infusion of 125I-labelled A,
radioactivity is subsequently detected in the kidney and
urine23,110. These findings indicate that the kidney might
participate in physiological clearance of A by filtering
A from blood to urine. Conversely, renal dysfunction
probably leads to impaired peripheral A clearance.
Insupport of this notion, serum A levels inversely cor-
relate with measures of renal function (estimated glo-
merular filtration rate and creatinine levels) in patients
with chronic kidney disease111,112. Moreover, human
kidney donors have decreased estimated glomerular
filtration rates and increased circulating levels of A113,
suggesting that the reduction in renal function reserve
associated with having a single kidney also attenuates
peripheral A clearance.
Whether renal dysfunction increases A burden in
the brain or facilitates AD processes remains unknown.
Renal dysfunction increases the risk of both cognitive
impairment and dementia114, and this association could
involve AD pathogenetic pathways. However, kidney
transplantation can reduce plasma A levels113, and
haemodialysis alleviates A deposition in the brain of
patients with chronic kidney disease115. These observa-
tions suggest that improvement of renal function is a
promising approach to AD prevention and treatment.
Respiratory and sleep disorders
Patients with AD have an increased incidence of respira-
tory disorders, such as bronchopneumonia, obstructive
sleep apnoea (OSA) and sleep-disordered breathing 116,117.
In addition, sleep-disordered breathing is associated
with an increased risk of mild cognitive impairment or
dementia and with earlier onset of AD118120.

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Compared with healthy control individuals, patients
with OSA or chronic obstructive pulmonary disease
exhibit higher blood levels of A, which negatively
correlate with pulmonary function121,122. OSA is also
associated with altered levels of AD biomarkers in CSF,
including decreased levels of A42 and elevated levels
of phosphorylated tau123. OSA and chronic obstructive
pulmonary disease could contribute to AD processes
via hypoxia, inflammation, or sleep disruption124. Sleep
disruption has been suggested to increase A produc-
tion and aggregation, suppress glymphatic clearance
of AD pathogenic proteins (tau as well as A) and
aggravate oxidative stress, inflammation and synaptic
damage125,126.
Gut microbiota disturbance and infection
The establishment of the gutbrain axis revealed a clear
association between the gastrointestinal microbiota and
cognition127. Gram-negative bacterial species (such as
Escherichia coli K99) are the predominant sources of
bacteria-derived factors in normal human brains, and
levels of these molecules are increased in AD brains, along
with levels of the bacterial cell wall component lipopoly-
saccharide128. Lipopolysaccharide colocalizes with A in
plaques in AD brains128, suggesting that Gram-negative
bacteria are associated with AD pathogenesis. Probiotic
supplementation is associated with improved cognition
in patients with AD129, which further supports a role for
the gut microbiota in AD development.
In addition to its relationship with normal microbial
flora, emerging evidence indicates that AD is associ
ated with exposure to an ever-increasing number of
pathogens130,131. Moreover, a high infectious burden is
associated with increased serum levels of A and pro
inflammatory cytokines in patients with AD and in
healthy controls130. However, the underlying mechanisms
through which the microbiota or pathogens influence
AD remain to be determined. Whether the microbiota
or pathogens contribute to AD development, or whether
an increased infectious burden is a c onsequence of AD,
also remains unknown.
Systemic inflammation
Chronic reactive gliosis and microgliosis are neuro
inflammatory responses that are important contributors
to AD pathology. These processes might participate in
a positive feedback loop of A deposition, neurofibril-
lary tangle formation, and damage to synapses and
neurons. Several studies have shown that other condi-
tions involving chronic systemic inflammation, such as
rheumatoid arthritis and periodontitis, are associated
with an increased risk of AD132,133. These conditions are
also associated with elevated levels of Creactive pro-
tein and proinflammatory cytokines, such as tumour
necrosis factor, IL6 and IL1. These proinflammatory
molecules could participate in AD pathogenesis either
directly, by affecting brain A metabolism (via entry to
the CNS through the BBB or neural afferent pathways
such as the vagus nerve)134,135 or indirectly, by affect-
ing A metabolism in the periphery. In this regard, the
results of observational studies show that NSAID use is
associated with a reduced risk of AD136. These findings
suggest that chronic systemic inflammation promotes
the AD process.
By contrast, acute systemic inflammatory responses
seem to protect against AD at least in animal models
by recruiting monocyte-derived macrophages into
the brain, where they clear cerebral A47. However,
most studies in this area have not been repeated, and
their results have not yet been validated in patients with
biomarker-confirmedAD.
A systemic approach to understanding AD
The close interaction between the brain and the
periphery, in terms of A metabolism, provides novel
insights into the pathogenesis of AD, and could lead to
new approaches to the diagnosis and treatment of AD,
based on systems biology and systems neurophysiology
paradigms.
Pathogenesis
Our current understanding of the role of A in AD
focuses on its contribution to brain pathology and symp-
toms. However, as already discussed, this view might
not be the whole story. First, although A peptides are
generated in the brain, a considerable amount of A is
also generated in peripheral systems. Second, A can be
cleared from peripheral organs or tissues as well as
from the brain by professional phagocytes, which can
transmigrate through the BBB. Third, A deposits have
been detected in the periphery although this claim
has not yet been replicated and its pathophysiological
relevance remains unknown. Last, a series of systemic
abnormalities are both driven by and contribute to AD
progression. On the basis of these findings, we propose
that AD might not be solely a brain disorder, in the sense
that systemic factors might interact with the brain to
modify the AD process.
As discussed, the central and peripheral A pools
interact with and influence each other. For exam-
ple,therate of peripheral catabolism of A seems to
affect the rate of A efflux from the brain, and periph-
erally derived A can enter the brain and accelerate the
progression of cerebral AD pathology 34,35. Therefore, we
hypothesize that the peripheral pool of A is not simply
associated with AD, but is causally linked to this disease.
Indeed, interactions between the brain and the periphery
might have a crucial role in the natural history of AD,
and elucidation of the effects of peripheral processes on
AD development could lead to improved understand-
ing of its pathogenesis. The crucial questions to answer
would be precisely how the brain and periphery interact
with each other to affect AD progression, and whether
interventions that target systemic factors can modulate
the pathogenesis or development ofAD.
Diagnosis
Several PET radiotracers can be used to detect A in the
brain, and a few biomarkers for AD have been validated
for diagnostic use, including CSF levels of A42, total tau
and phosphorylated tau. However, these approaches are
either invasive or expensive, and are impractical for the

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Box 1 | Novel peripheral biomarkers for AD Technical advances by the AD Neuroimaging

Potential biomarkers related to Alzheimer disease (AD) are continually being
discovered, and might enable prediction of mild cognitive impairment and progression
to AD, especially when combined with APOE genotyping and assessment for systemic
dysfunctions linked to AD.
Exosome cargo proteins
Exosomes are cell-derived vesicles that are highly enriched in biological fluids. They
carry amyloid precursor protein (APP), amyloid- (A) and tau, and might facilitate
intercellular communication and propagation of A and tau pathologies. Plasma
exosome cargoes could have prognostic value in AD158; astrocyte-derived exosomes
contain higher levels of soluble A42 and proteins of the A42-generating pathway (such
as secretase 1, secretase, soluble APP and soluble APP) and phosphorylated tau cation of novel peripheral biomarkers for AD diagno-
than do neuron-derived exosomes. Levels of secretase 1 and soluble APP in
astrocyte-derived exosomes are higher in patients with AD than in healthy controls159.
Blood proteins
A new high-throughput multiplex protein biochip can identify patients with AD with an
accuracy of 92% when used to screen platelet lysates160. Another study found that a
panel of serum proteins has diagnostic value161, although the sensitivity and specificity
of this test need improvement. Individual blood proteins, including biomarkers of
neurodegeneration (such as neurofilament light protein, neuron-specific enolase and
heart fatty acid binding protein) and glial activation biomarkers (such as YKL40
andmonocyte chemotactic protein 1) also exhibit potential for AD diagnosis and
prognostication162165. Leukocyte surface protein phenotyping and functional
phenotyping might also prove useful; leukocyte surface expression of P2X7 is
decreased in patients with AD and is linked to altered phagocytic function
ofmonocytes45.
Autoantibodies
Autoantibodies have emerged as effective and noninvasive biomarkers for early
diagnosis and staging of AD. A panel of blood antibodies can differentiate patients
withmild cognitive impairment from controls with 100% accuracy55.
Blood RNA profiles
Circulating RNA profiles have diagnostic potential in AD. An exosomal microRNA
signature exhibits high sensitivity and specificity for the detection of early AD, and
shows concordance with neuropsychological and neuroimaging data166; TRPC6 mRNA
levels in blood cells were reduced in patients with AD and mild cognitive impairment,
and were related to brain A burden and A42 levels in cerebrospinal fluid167.
early diagnosis of patients without obvious cognitive
complaints. The search for peripheral blood or plasma
biomarkers for AD that reflect ADrelated processes in
the brain has, therefore, received considerable attention.
However, owing to the complexity of blood compo-
nents, the accurate measurement of plasma levels of A
or tau is very challenging. A study published in 2017 did
not find a statistically significant difference inplasma
levels of free A between patients with AD and age-
matched controls137, and similarly negative results have
been published for plasma tau levels138. However, these
results do not indicate the end of the road for AD bio-
marker studies139. With the development of advanced
and highly sensitive techniques that are able to promote
efflux of A and tau from the brain, and accurately
measure their levels even when bound to other serum
proteins, researchers might eventually find a method
to monitor cerebral A accumulation. In addition,
misfolded oligomeric species of A and tau proteins
have been detected in CSF and suggested as potential
biomarkers for AD140,141. If these misfolded protein spe-
cies also prove to be present in blood, they might be
useful for AD diagnosis, although no published reports
yetexist.
Initiative have enabled the use of microarrays to detect
serum antiA autoantibodies with 100% accuracy 55;
however, this promising technique requires validation in
large independent cohorts. This approach is particularly
interesting in the light of the promising results obtained
with aducanumab, the first human antiA autoantibody
to be developed for clinical trials57. In addition to A
and tau, secretase1 (encoded by BACE1, an enzyme
involved in A production) has been suggested as a
potential biomarker for AD142. In general, the identifi-
sis and prognosis represents a promising and rapidly
expanding research direction. (BOX1)
Treatment
Currently, effective agents for AD prevention or treat-
ment are lacking. The traditional concept one target,
one treatment inevitably ignores the complexity of AD
pathogenetic mechanisms143. After the failure of over
100 clinical trials of monotherapies targeting A, multi
targeted therapies that address various aspects of AD
pathogenesis at different disease stages are needed144. We
argue that a comprehensive strategy targeting both brain
and peripheral (systemic) abnormalities might be more
effective than strategies that target CNS abnormalities
alone. As discussed, many comorbidities of (and risk
factors for) AD such as diabetes mellitus, metabolic
disorders, cardiovascular diseases, and hypertension
are systemic disorders.
Many attempts have been made to prevent AD via
peripheral interventions, and some have been associ-
ated with beneficial outcomes. Improvements in overall
population health have led to a decreased incidence and
prevalence of dementia over the past 1030years145148,
perhaps through improved management of cardiovas-
cular risk factors145148. For example, administration
of statins (which reduce peripheral blood cholesterol
levels) to healthy middle-aged individuals was associ-
ated with a reduced dementia risk in one large-scale
prospective cohort study 149; statins have also decreased
the brain burden of A in experimental models of
AD150, although the results of most studies of statin
treatment in patients with AD have been disappoint-
ing 151. Furthermore, treatment with continuous positive
airway pressure for sleep-disordered breathing or OSA
might delay the onset of mild cognitive impairment
and slow or even improve cognitive decline in patients
with AD120,152,153. These observations support the view
that systemic management of an individuals known
comorbidities or risk factors, with the aim of maintain-
ing bodily homeostasis, might help to prevent or slow
the progression ofAD.
Active removal of excess peripheral A seems to be
a particularly promising therapeutic strategy for AD23.
Plasma albumin exchange both improves cognition
and decreases the A burden in patients with AD154.
Peritoneal dialysis reduces blood A levels in humans
and also attenuates AD pathology in an AD mouse
model155; patients who have undergone haemodialysis
exhibit a reduction in A deposition in the brain115.

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Approaches to improve peripheral A clearance via
enhancing phagocytosis45, proteolytic degradation and
excretion155,156, and identification of rejuvenation factors
in blood68, are other promising systemic therapeutic
strategies forAD157.
Conclusions
AD might be not only a brain disorder, but also a systemic
disease with widespread abnormalities beyond the brain.
Thus, systemic factors might interact with brain-related
factors to modify the AD process. AD diagnosis and
treatment should have a corresponding focus not only on
pathological changes in the brain but also on peripheral
abnormalities, which vary among individuals. Identifying
these peripheral abnormalities might offer new oppor-
tunities for diagnosis of early AD and lead to the design
of specific treatment strategies for individuals with pre-
clinical, prodromal or frank AD. In conclusion, the sys-
temic view of AD proposed in this Review provides a
novel perspective for understanding the pathogenesis of
this disease, and fosters new opportunities for its early
diagnosis and successful management.

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Acknowledgements
The authors research work is supported by the National
Natural Science Foundation of China (grants 81471296 and
81625007to Y.-J.W., and grant 81600949to J.W.), and the
Chinese Ministry of Science and Technology (grant
2016YFC1306401 to Y.-J.W.). The authors thank Dr J. Pia-
Crespo and Dr H. Xu at Sanford Burnham Prebys Medical
Discovery Institute, USA, for critical reading of the paper.
Author contributions
All authors contributed to researching data for the article,
discussion of the content, writing the article, and to review
and/or editing of the manuscript before submission.
Competing interests statement
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claims in published maps and institutional affiliations.
Review criteria
Articles for inclusion in this Review were identified by
searches of the PubMed database using the following terms:
Alzheimer disease, amyloid beta, peripheral clearance,
innate immunity, adaptive immunity, macrophage,
monocyte, phagocytosis, blood, circulation, plasma,
platelet, erythrocyte, exosome, diabetes, insulin,
amylin, apolipoprotein E, cholesterol, lipid, lipo
protein, cerebrovascular diseases, heart failure, cerebral
blood flow, hypoperfusion, hypoxia, liver, hepatic func
tion, kidney, renal function, respiratory, sleep, micro
biome, gastrointestinal microbiota, gut flora, infection,
biomarker, diagnosis, therapy, treatment, prevent.
Only articles published in English were retrieved. Full-text
papers were available for most of the articles that were
chosen for review, and the reference lists of these articles
were searched for further relevant material.

NATURE REVIEWS | NEUROLOGY VOLUME 13 | OCTOBER 2017 | 623

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