J Neural Transm (2015) 122:505521

DOI 10.1007/s00702-014-1288-x

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Challenges of multimorbidity of the aging brain: a critical update

Kurt A. Jellinger Johannes Attems

Received: 4 June 2014 / Accepted: 24 July 2014 / Published online: 5 August 2014
Springer-Verlag Wien 2014

Abstract A major problem in elderly patients is the high 81 %, and mixed pathologies in 1093 %. These data
incidence of multiple pathologies, referred to as multi- clearly suggest that pathologically deposited proteins in
morbidity, in the aging brain. It has been increasingly neurodegenerating diseases mutually interact and are
recognized that co-occurrence of neurodegenerative pro- influenced by other factors, in particular cardiovascular and
teinopathies and other pathologies including cerebrovas- cerebrovascular ones, to promote cognitive decline and
cular disorders is a frequent event in the brains of both other clinical symptoms. It is obvious that cognitive and
cognitively intact and impaired aged subjects. Although other neuropsychiatric impairment in the aged result from a
clinical and neuropathological diagnostic criteria of the multimorbid condition in the CNS rather than from a single
major neurodegenerative diseases have been improved, disease and that the number of complex pathologies pro-
major challenges arise from cerebral multimorbidity, and gresses with increasing age. These facts have implications
the thresholds to cause clinical overt dementia are ill for improvement of the clinical diagnosis and prognosis,
defined. More than 80 % of aged human brains show the development of specific biomarkers, preventive strate-
neurodegenerative non-Alzheimer type proteinopathies and gies and better treatment of cerebral multimorbidity.
other pathologies which, however, frequently have been
missed clinically and are even difficult to identify at Keywords Alzheimer disease
Cerebral multimorbidity

neuropathological examination. Autopsy studies differ in Neurodegenerative disease
Proteinopathy

selection criteria and the applied evaluation methods. Cerebrovascular lesions
Mixed pathology
Therefore, irrespective of the clinical symptoms, the fre-
quency of cerebral pathologies vary considerably: Alzhei- Abbreviations
mer-related pathology is seen in 19100 %, with pure AD Alzheimers disease
Alzheimers disease (AD) in 1772 %, Lewy pathology in AGD Argyrophilic grain disease
639 % (AD ? Lewy disease 928 %), vascular patholo- Ab b-Amyloid
gies in 2893 % (10.778 % pure vascular dementia), aSyn a-Synuclein
TDP-43 proteinopathy in 639 %, hippocampal sclerosis in CAA Cerebral amyloid angiopathy
CBD Corticobasal degeneration
CERAD Consortium to Establish a Registry for
To the memory of our old friend, Prof. Siegfried Hoyer, who passed Alzheimers Disease
away after a long way as an excellent neuroscientist, in January 2014. CN Cognitively normal
CVD Cerebrovascular disease
K. A. Jellinger (&)
Institute of Clinical Neurobiology, Kenyongasse 18, CVL Cerebrovascular lesion
1070 Vienna, Austria DLB Dementia with Lewy bodies
e-mail: kurt.jellinger@univie.ac.at FTLD Frontotemporal lobe degeneration
GCI Glial cytoplasmic inclusions
J. Attems
Institute for Ageing and Health, Newcastle University, HS Hippocampal sclerosis
Newcastle upon Tyne, UK LB Lewy body

123
506
LBD Lewy body disease
MCI Mild cognitive impairment
MSA Multiple system atrophy
NACC National Alzheimers Coordinating Center
NFTs Neurofibrillary tangles
NIA National Institute on Aging
PSP Progressive supranuclear palsy
SVD Small vessel disease
TDP-43 TAR DNA binding protein 43
VaD Vascular dementia
VCI/ Vascular cognitive impairment/vascular
VaD dementia
VCI Vascular cognitive impairment
VITA Vienna trans-danube aging study
WML White matter lesion
Introduction
Due to increased life expectancy, understanding of age-
associated disorders including cognitive decline is more
and more important, since the prevalence and incidence of
dementia increase exponentially with age. In 2010, 35.6
million people worldwide lived with dementia, with around
8 million new cases every year. Numbers are expected to
double or triple every 510 years, to 135 millions in 2050,
16 millions in Europe (Prince et al. 2013). With the dis-
proportional growth of the elderly population, dementia has
become a major public health and socio-economic problem
that threatens to become the scourge of our century (Thies
and Bleiler 2013; Wimo et al. 2013). There are many
causes of dementia, however, neurodegenerative disorders
that are caused by the intra- and extra-cellular deposition of
aggregated misfolded proteins (proteinopathies) are
thought to be the most prevalent in aged people. Modern
neuropathological examinations, have demonstrated that
the brains of many elderly individuals had Alzheimer-
related pathologies, featured by neurofibrillary tangles
(NFTs) and plaques together with a large number of
coincident non-Alzheimer type pathologies (Attems and
Jellinger 2013a; Jellinger 2013, 2014; Rahimi and Kovacs
2014). Cognitively normal elderlies may have substantial
AD-related pathology (Price et al. 2009); but, in general,
the density of isocortical tangles correlates best with the
severity of cognitive impairment (Nelson et al. 2007,
2012), which, however, may or may not apply for the
oldest-old age group (Dolan et al. 2010; Purohit et al. 2008;
Sinka et al. 2010). Others emphasized that much of late life
cognitive decline is not due to common neurodegenerative
pathologies (Boyle et al. 2013; Strozyk et al. 2010).
The coexistence of multiple pathologies is referred to as
multimorbidity. With increasing age, the prevalence of
123
K. A. Jellinger, J. Attems
both cerebral and general multimorbidities increases con-
siderably (Attems and Jellinger 2013a; Marengoni et al.
2011; Rahimi and Kovacs 2014). Recent community-based
studies have clearly shown that co-occurrence of Alzhei-
mers disease (AD) and non-AD type proteinopathies as
well as other superimposed pathologies, in particular
cerebrovascular lesions (CVLs), are frequently occurring in
the brains of both cognitively unimpaired and demented
aged individuals, whereas the presence of single disease is
rather the exception than the rule (Attems and Jellinger
2013a). Multiple pathologies are suggested to interact in
promoting cognitive and other nervous symptoms in the
aged (Attems and Jellinger 2013a; Jellinger and Attems
2007, 2010; Kovacs et al. 2008). Of particular importance
is the frequent presence of confounding processes that
coexist with AD, such as cerebrovascular disease (CVD),
Lewy pathology, argyrophilic grain disease (AGD), TDP-
43 proteinopathies, and hippocampal sclerosis (HS)
(Davidson et al. 2011; Nagy et al. 1997; Nelson et al. 2007;
Rahimi and Kovacs 2014; Schneider et al. 2007a, b), which
have, however, frequently been missed clinically and could
not be identified without neuropathological examination
using modern bio/histochemical and molecular-biological
analyses.
Diagnostic criteria and challenges
Current guidelines for the clinical diagnosis of major
dementia disorders include: revised National Institute of
Neurological and Communicative Disorders and Stroke
and the Alzheimers Disease and Related Disorders Asso-
ciation (NINCDSADRDA) and European Federation of
Neurological Societies (EFNS) criteria for AD (Dubois
et al. 2010; Sorbi et al. 2012), the National Institute on
Aging-Alzheimers Association (NIA-AA) criteria for AD
(McKhann et al. 2011; Sarazin et al. 2012; Sperling et al.
2011), consensus from the Canadian Consensus Confer-
ence on the Diagnosis and Treatment of Dementia
(CCCDTD) (Chertkow et al. 2013) and the International
Working Group 2 criteria for AD (Dubois et al. 2014),
criteria for Parkinsons disease (PD)-dementia (Dubois
et al. 2007; Emre et al. 2007), dementia with Lewy bodies
(DLB) (McKeith et al. 2005), frontotemporal lobe degen-
eration (FTLD) (Josephs et al. 2011; Seltman and Mat-
thews 2012), vascular cognitive impairment/dementia
(VCI/VaD) (National Institute of Neurological Disorders
and Stroke and Association Internationale pour la
Recherche et lEnseignement en Neurosciences/NINDS-
AIREN) (Gorelick et al. 2011; Roman et al. 1993), Inter-
national Society for Vascular Behavioral and Cognitive
Disorders (VASCOG) (Sachdev et al. 2014), Diagnostic
and Statistical Manual of Mental Disorders 5th Ed. (DSM
Challenges of multimorbidity of the aging brain
V) (American Psychiatric Association 2013), and other
neurodegenerative syndromes (Lopez et al. 2011).
Current guidelines for the neuropathological diagnosis
of major dementing disorders rely on qualitative, semi-
quantitative and topographic assessment of morphological
and bio-/histochemical markers, in particular specific pro-
tein inclusions in neurons, glia and other cells (Arnold et al.
2013a; Jellinger 2010a; Kovacs et al. 2010). The classifi-
cation of neurodegenerative disorders, previously based on
the anatomical systems involved, has been replaced by
molecular-pathological ones, which may provide a basis
for the neuropathological diagnosis in the future (Fig. 1).
A definite diagnosis of AD can only be made by
neuropathological examination. Neuropathological criteria
for AD are (1) cut-off quantitative values of senile plaques
and tangles (Duyckaerts and Dickson 2011), (2) their
semiquantitative assessment and age-adjustment in the
Consortium to Establish a Registry for Alzheimers Disease
(CERAD) protocol (Mirra et al. 1991), (3) topographic
staging of neuritic AD pathology (Braak and Braak 1991),
re-evaluated recently (Alafuzoff et al. 2008; Braak et al.
2006a), (4) and the progress and distribution of b-amyloid
(Ab) deposition being different from tau pathology (Thal
et al. 2002b). The combination of CERAD and Braak
scores in the National Institute on Aging-Reagan Institute
(NIA-RI) criteria related dementia to AD-typical lesions
with high, intermediate and low likelihood (Hyman and
Trojanowski 1997), and the recently revised guidelines for
the neuropathological evaluation of AD and other diseases
consider levels of AD pathology in the brain regardless of
the clinical status of a given individual (Hyman et al. 2012;
Montine et al. 2012). They include an ABC score of
AD-related changes that incorporates histological assess-
ment of Ab deposits (A), based on the Ab phases (Thal
et al. 2002b), staging of NFTs (B), based on the Braak
staging system, and semiquantitative scoring of neuritic
Fig. 1 Molecular-pathologic classification of degenerative demen-
tias. From Jellinger (2013)
507
plaques in at least five neocortical regions (C), based on
CERAD criteria, as well as more detailed approaches for
assessing co-morbid conditions, such as Lewy body disease
(LBD), vascular brain injury, HS, and TDP-43 immuno-
reactive lesions (Montine et al. 2012). However, these new
algorithms did not consider the various clinico-pathologi-
cal subtypes of AD, e.g. tangle-predominant dementia
(TPD) (Jellinger and Attems 2007; Nelson et al. 2009;
Santa-Maria et al. 2012), recently redefined as primary
age-related tauopathy (Crary et al. 2014), the hippocam-
pal-sparing (HpSP-AD) and the limbic-predominant forms
(LP-AD) both differing from the most frequent typical AD
(Janocko et al. 2012; Murray et al. 2011, 2014).
Updated neuropathological criteria for the diagnosis of
other dementias include: three staging systems for a-syn-
ucleinopathies, in particular LBDs, one for PD (Braak et al.
2006a, b), another for dementia with Lewy bodies (DLB)
(McKeith et al. 2005), and revised guidelines for Lewy
body disease (Zaccai et al. 2008). Parkinsons disease
dementia (PDD) and DLB share many clinical and mor-
phological features that are suggested to form a continuum
within the spectrum of LB diseases, and show a variable
combination of Lewy and AD pathologies, which may act
synergistically (Clinton et al. 2010; Compta et al. 2011;
Irwin et al. 2012). In multiple system atrophy (MSA),
morphologically featured by a-synuclein (aSyn)-positive
glial cytoplasmic inclusions (GCIs), the morphological
correlates of cognitive impairment are under discussion
(Asi et al. 2014; Jellinger 2007b; Stankovic et al. 2014).
Frontotemporal lobe degeneration, the third most fre-
quent cause of dementias, includes three major clinical
subgroups, showing distinct patterns of brain atrophy (Lu
et al. 2013). The most common are: microtubule-associated
tau protein (FTLD-tau), TDP-43 (FTLD-TDP-43), and
fusion sarcoma protein (FTLD-FUS), but there is frequent
overlapping pathology (Goedert et al. 2012; Halliday et al.
2012; Josephs et al. 2011), while various pathological
phenotypes are related to genetic causes (mutations in
MAPT, progranulin, C9ORF72) (Liu et al. 2013). TDP-43
inclusions are frequently observed in cases with AD and
LB pathologies (Arai et al. 2009), as an important factor of
clinico-imaging features of AD (Josephs et al. 2014), but
also in cognitively normal seniors (Arnold et al. 2013a, b).
However, it is not clear whether these changes are a pri-
mary, secondary or coincident event (Wilson et al. 2013).
Neuronal and glial 3-repeat (R) tau deposits in FTLD with
Pick bodies differ from 4R tau in progressive supranuclear
palsy (PSP), and corticobasal degeneration (CBD), both
frequently associated with dementia (Bruns and Jo-
sephs 2013; Burrell et al. 2014), and AGD (Ferrer et al.
2008; Grinberg and Heinsen 2009). For VCI/VaD, recently
determined vascular cognitive disease (VCD), despite
several proposals (Kalaria et al. 2004; Montine et al. 2012),
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508 K. A. Jellinger, J. Attems

due to the high variability of morphological findings and
multifactorial pathogenesis, no generally accepted mor-
phological scheme for quantitating CVLs and no validated
neuropathological criteria have been established to date
(Jellinger 2014; Roman 2008). A recent staging scheme
proposing semiquantitative assessment of CVLs in four
brain regions with scores from IIV/VI (Deramecourt et al.
2012) needs further validation, and a harmonization of the
criteria and techniques for the assessment of cerebral
lesions of presumable vascular origin in cognitively
impaired is necessary (Alafuzoff et al. 2012; Pantoni et al.
2006).
Hippocampal sclerosis of aging (HSA), a causative
factor in a large proportion of elderly dementia cases
(Dickson et al. 1994), strongly associated with TDP-43
pathology (Nelson et al. 2013; Rauramaa et al. 2011),
differs morphologically from HS related to anoxia (epi-
lepsy) or AD (Cendes et al. 2014; Nelson et al. 2013;
Rauramaa et al. 2013), and shows neuropathological and
genetic deviations from typical AD (Murray et al. 2014).
Frequency of neurodegenerative lesions in the aged
brain
The frequency of neurodegenerative diseases in different
studies has been summarized recently (Rahimi and Kovacs
2014). AD-related pathology, previously suggested to be
the most frequent type of cerebral lesions in the elderly,
according to the statistical evaluation of 12 community-
based studies [Adult Changes in Thought study/ACT/
(Cholerton et al. 2013), the Baltimore Longitudinal study
of Aging/BALS/(Dolan et al. 2010; Troncoso et al. 2008),
the Cambridge City of 75s cohort/CC75C/(Brayne et al.
2009), the Honolulu-Asian Aging study/HAAS/(White
et al. 2005), the Rush Memory and Aging project/ROS/
(Dawe et al. 2011; Schneider et al. 2009), the Medical
Research Council Cognitive Function and Ageing Study/
MRC CFAS/(Matthews et al. 2009); the Oregon Brain
Aging study/OBAS/(Erten-Lyons et al. 2013a); the Reli-
gious Orders study/ROS/(Schneider et al. 2009; Wilson
et al. 2013); the Vantaa 85? study (Oinas et al. 2009;
Polvikoski et al. 2001, 2010); the Hisayama study (Fujimi
et al. 2008; Wakisaka et al. 2003); the 90? study (Rob-
inson et al. 2011); and the Vienna Trans-Danube Aging
(VITA) study (Kovacs et al. 2013)]; based on Braak,
CERAD and NIA criteria, irrespective of clinical symp-
toms, ranged from 19 to 67 %, while in some other studies
AD-pathology occurred between 42 and 100 %. However,
the frequency of pure AD, i.e. AD (Braak stages V and
VI) without essential concomitant pathologies, ranged from
12 to 72 %, the combination of AD pathology and LB
disorders from 9 to 28 % and of AD with CVLs from 19 to
93 % (Table 1).
The second most common neurodegenerative disorder is
featured by Lewy pathology with a range between 6 and
39 %, but its evaluation (detection of cortical LBs) varied
considerably, depending on the methodology (use of a-Syn
immunostaining), the regions assessed, and the use of
classification criteria for LB disorders (Aho et al. 2008;
Parkkinen et al. 2008). The implication of neocortical LBs
for cognitive decline is under discussion (Boyle et al. 2013;
Horvath et al. 2013; Kotzbauer et al. 2012), since signifi-
cant cortical Lewy pathology occurs in older people in the
absence of clinical symptoms (Byford et al. 2009; Frigerio
et al. 2011; Markesbery et al. 2009; Parkkinen et al. 2005).
However, it has been suggested that incidental Lewy body
disease (iLBD) that shows LBs and decreased tyrosine
hydroxylase reactivity in striatum similar to but much less
than PD, is a precursor to or a preclinical form of PD that
lacks parkinsonian symptoms due to a sub-threshold
pathology (DelleDonne et al. 2008; Frigerio et al. 2011).

Table 1 Mixed pathologies frequent in demented elderly

References n Pathologies (%)
AD lesions AD alone AD ? CVL AD ? LBD VaD

Nolan et al. (1998) 87 87 50 34

Lim et al. (1999) NA AD cases 36 45 22
Riley et al. (2002) AD cases 57 73/93
Petrovitch et al. (2005) (HAAS study) 333 \60 36 24 24
Fernando and Ince (2004) (MRC-CFAS (UK)) 209 (48 % dem.) 70 21 78
Andin et al. (2005) 175 (clin. VaD) 72 28
Schneider et al. (2007a, b) 141 82.7 30 38 12 12
Jellinger (2008) (retrospective) 1,700 (dem.) 83.2 41.1 24.2 9.1 10.7
Jellinger (prospective, unpubl.) 180 82.7 48.8 23.9 10.0 7.8
Kovacs et al. (2013) (other pathologies 23.2 %) 233 100 12 48.9 24 NA
NA not available

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Challenges of multimorbidity of the aging brain
Although the prevalence of HS is rather low in the
general population, it is twice as frequent in a demented
cohort (Robinson et al. 2011), but the frequency of TDP-43
pathology varies considerably among aged subjects (range
1346 %), partly due to methological and classification
differences (Wilson et al. 2013). Other neurodegenerative
diseases, such as MSA, PSP, CBD, TDP-43, Pick disease
and other FTLDs, have been less frequently reported in
aged subjects (less than 510 %) (Byford et al. 2009;
Keage et al. 2012; Kovacs et al. 2013; Polvikoski et al.
2010; Schneider et al. 2009; Wakisaka et al. 2003), but
their clinical presentation varies in relation to concomitant
pathologies (Dugger et al. 2014).
Vascular pathologies in the aging brain
Cerebrovascular pathologies have been reported in
5085 % of elderly subjects, but due to the lack of clearly
defined assessment criteria, their reported frequency varies
considerably. Of note, this association was recently found
to be stronger in cases with lower NFT pathology (Toledo
et al. 2013), similar to earlier studies on respective asso-
ciations with subcortical vascular pathology (Chui et al.
2006) and general CVD (Petrovitch et al. 2005). The
spectrum of vascular pathologies assessed at autopsy ran-
ges from small vessel disease (SVD), microinfarcts, lac-
unes, white matter lesions, cerebral amyloid angiopathy
(CAA) to large infarcts due to large vessel disease of
various extent in multi-infarct encephalopathy, cerebral
microbleeds and hemorrhages (Grinberg and Thal 2010;
Jellinger 2007a, 2008; Richardson et al. 2012; Thal et al.
2012). Multiple lacunar microinfarcts were most frequent
in Japanese dementia cases with a prevalence of 42 %,
suggesting that VaD was more frequent in the Japanese
than in Western populations (Fujishima and Kiyohara
2002). Vascular brain injury is commonly encountered in
elderly subjects with and without AD pathology (Ferrer
2010; Grinberg and Thal 2010; Jellinger 2007a). However,
subcortical SVD is increasingly recognized as a predictor
of cognitive impairment (Smallwood et al. 2012). The
NUN study suggested that individuals with NFT pathology
and one or two lacunar infarcts experienced a steeper drop
in cognitive function than those without cerebral infarcts
(Snowdon et al. 1997). On the other hand, in the Vienna
VITA study, single microinfarcts and territorial infarcts
were found in up to 33 % in both demented and non-
demented aged individuals (Kovacs et al. 2013). Several
studies discussed that the presence of multiple infarction is
more relevant for cognitive decline than the size of single
infarcts (Schneider et al. 2003; Troncoso et al. 2008; White
et al. 2002), and that subcortical lacunes and multiple
disseminated microinfarcts appear to be the most common
509
features of cognitive impairment, while large cystic
infarcts are less common (Gold et al. 2005; Jellinger
2007a; Kalaria et al. 2004; Kovari et al. 2004; Troncoso
et al. 2008). Microinfarcts are an important correlate of
age-related VCI, but are not associated with an increased
burden of AD pathology (Richardson et al. 2012; Zheng
et al. 2013). The presence of both SVD and AD pathologies
can summate, particularly at mild levels of AD pathology
(Esiri et al. 1999; Petrovitch et al. 2005), but there is no
good evidence that one promotes the other (Esiri and
Englund 2014). Evaluation of the type and topographic
pattern of CVLs in a large autopsy series of demented
subjects, in cases with pure VaD, i.e. without essential
other pathologies, showed a significantly higher frequency
of small subcortical lesions (70 %) than of large infarcts
(volume \10 ml) involving one or both hemispheres
(32.5 %). This pattern differed considerably from that in
cases with mixed dementia (AD ? vascular encephalopa-
thy), where 56.6 % revealed large, often lobar infarcts of
multiple cortical and subcortical lesions larger than
510 mm in diameter involving one or both hemispheres,
whereas lacunes and small subcortical microinfarcts were
seen in only 36 %. These data suggest different pathogenic
mechanisms between both types of disorders (Jellinger and
Attems 2010).
Recent emphasis on comorbidity of AD and CVD,
detected in 3060 % of AD brains and showing a large
variety of lesions (Jellinger and Attems 2005, 2014;
Schneider et al. 2007a, b), and many other data indicate an
association between AD and CVD. However, their role in
dementia is still under discussion and data obtained from
epidemiological and clinico-pathological studies regarding
their relation are controversial (Esiri et al. 1999; Jellinger
2008; Jellinger and Attems 2014; Rincon and Wright 2014;
Zekry et al. 2002). Small vascular and AD-related patho-
logical determinants of dementia have been demonstrated
in the oldest old (Sinka et al. 2010). In elderly patients with
subclinical AD, either critically located CVLs or cortical
microinfarcts may worsen cognitive impairment due to a
synergistic interaction between both pathologies (Esiri
et al. 2014; Iadecola 2010; Miklossy 2003), while in
advanced of full-blown stages of AD, concomitant small
vascular lesions do not significantly influence the overall
state and progression of cognitive decline that is mainly
related to the severity and extent of AD pathology over-
whelming the modest effects of CVD (Chui et al. 2006;
Esiri et al. 2014; Jellinger and Attems 2005; Jellinger
2007a). The thresholds for vascular and degenerative
lesions for distinguishing pure VaD or AD from mixed
cases have been critically discussed (Gold et al. 2007).
The burden of vascular and AD-type pathologies are
considered to be independent of each other, and are con-
sistent with an additive or synergistic effect of both types
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510
of lesions on cognitive impairment (Andin et al. 2005;
Jellinger 2007a; Kalaria et al. 2004; Launer et al. 2008;
Lim et al. 1999; Schneider et al. 2004; Strozyk et al. 2010).
An interesting finding is the inverse correlation of the
volume of white matter lesion (WML) with NFT pathol-
ogy, supporting the concept of synergistic effects and
suggesting that AD pathology might be driving the white
matter pathology (Shim et al. 2014). The variability of data
on the neuropathologies of WMLs has been emphasized
(Erten-Lyons et al. 2013b; Schmidt et al. 2011), and their
significance may be different to the state of the disease,
subjects with early AD probably being more vulnerable
than cognitively normal older adults with similar WML
burden (Burns et al. 2005). AD-related pathology alone
more frequently accounts for dementia than both macro-
scopic and microscopic infarcts (Troncoso et al. 2008). In a
recent study, global AD pathology significantly correlated
to global cognition, whereas infarct and Lewy pathologies
did not (Bennett et al. 2012).
In a population-based study in the UK, among 209
autopsies of elderly subjects, 48 % being demented, 78 %
had evidence of CVD and 70 % of AD pathology. The
proportion of multiple vascular lesions was higher in the
demented group, while only 21 % showed pure AD, was recently studied in 5,715 autopsy cases of the National
indicating that most patients had mixed disease (Fernando
and Ince 2004). In a health maintenance organization
dementia register, only 36 % of patients had AD without
any other pathologies, while 4 % had definite AD plus
coexistent CVD (Lim et al. 1999). Among 333 autopsied
men in the Honolulu Asian Aging Study (120 demented,
114 marginal, 96 normal cognition), 24 % of dementias
were linked with CVD and dementia frequency more than
doubled in AD with coexistent CVD (45 vs. 20 %). These
findings suggest that CVD is associated with a marked
excess of dementia in cases with low neuritic plaque fre-
quency (Petrovitch et al. 2005). In a retrospective series of
730 autopsy cases of AD and 535 age-matched controls,
using a 4-grade scale for the severity of CVLs, the total
prevalence of CVD in AD was significantly higher than in
controls (31.6 vs. 23.4 %) (Jellinger and Mitter-Ferstl
2003).
Retrospective examination of the prevalence of CVD in
a consecutive autopsy series of 621 autopsy-proven AD
cases and 486 age-matched NC controls, using a 4-degree
scale for cerebrovascular pathology, showed 67.8 % CVLs
in AD versus controls (29.4 %); severe CVLs [old/recent
infarcts and hemorrhages were more frequent in AD
(23.6 %) than in controls (5.4 %)]. Cortico-subcortical
infarcts and subcortical vascular lesions were more fre-
quent in AD than in controls (41.2 vs. 11.6 %). Both the
incidence and severity of CVLs, similar to the previous
study, increased with higher neuritic Braak stages (Jellin-
ger 2010b). Likewise, the prevalence and severity of CAA
123
K. A. Jellinger, J. Attems
increased from aged controls (total 30 %, 20 % severe) to
AD (total 97.7 %, among which 75 % severe). In 75 % of
AD patients, hemorrhages were associated with severe and
only in 10 % with mild to moderate CAA, while only 20 %
of cerebral infarcts were associated with severe CAA.
These studies confirmed previous ones documenting
significantly higher frequency of vascular pathology in AD
than in age-matched non-demented controls. Like in the
Einstein Aging Study in 67 patients with autopsy-proven
AD showing additional vascular pathology in 82.1 %
(Crystal and Dickson 2002), no significant differences in
the severity of cognitive decline between AD with and
without concomitant CVLs were observed, which suggests
a floor effect of high-grade AD pathology in these patients.
These studies corroborated with another study comparing a
large number of seniors showing similar age and Braak
scores but less severe dementia and more frequent histories
of stroke in AD cases with additional CVD (Jellinger
2002), but are at variance with others reporting more
severe dementia and less severe AD pathology in patients
with concomitant CVD (Esiri et al. 1999; Petrovitch et al.
2005; Snowdon et al. 1997; Zekry et al. 2002).
The contribution of CVD in neurodegenerative diseases
Alzheimers Coordinating Center (NACC) database. For
comparison, 210 unremarkable cases without cognitive
impairment and 280 cases with pure CVD were included.
The latter were older than those without CVD in all groups
except for those with HS. a-Synucleinopathies, FTLD and
prion diseases showed a lower coincident CVD than AD
patients, and those with both AD and synucleinopathies
revealed a lower burden of their relative lesions than those
without CVD in the context of comparable dementia. In
conclusion, CVD as a common finding in aged subjects
with dementia, is more common in AD than in other
neurodegenerative disorders and lowers the threshold for
dementia due to AD or synuclein pathologies (Toledo et al.
2013), confirming previous findings (Jellinger 2008;
Schneider et al. 2004; Strozyk et al. 2010; Zekry et al.
2003a).
Cerebral amyloid angiopathy is a very frequent but not
consistent feature of AD (Attems 2005; Attems et al. 2005,
2011), and is also a relevant cause for hemorrhages and
brain infarction (Tanskanen et al. 2012). Capillary CAA
can occur without the presence of general CAA in the
meningeal and cortical arteries and it allows the distinction
between two types: CAA type 1 characterized by the pre-
sence of capillary CAA with or without concomitant gen-
eral CAA, while in CAA type 2, no capillary CAA is
present (Thal et al. 2002a). The presence of capillary CAA
has been suggested to identify a subtype of AD that is
characterized by a stronger association to the APOE e4
genotype, higher Ab load and higher Braak neuritic stages
Challenges of multimorbidity of the aging brain 511

Table 2 Frequency of different neuropathological variables in community-based studies

Study (n) N AD-related pathologies a-Syn TDP-43 HS Vascular Mixed
(%) (%) pathologies pathology
Braak III CERAD NIA (%) (%)
VI (%) (%)
(%)

MAP study 425 59 15 % 13 46a 23

ROS study 539 61 21 % 46 13 49a 28
MRC CFAS 525 52 46 39 % (29 % amygdala) 70b
Cambridge 75C 224 39l 28 15 % 56c
h
Vantaa 85? 304 70 66 41 36 % 5 55a 40
Hisayama 205 62 29 % 31 10d
studyk
HAAS 439 19e 10 %k 9k 28c 39.5
ACT study 438 62 47 14 % 35c
BALS 209 56f 6 %k 44a
OBAS 125 62 44 20 % 7 46c
90? study 108 67 6 %g 31 29k 19i
j
VITA study 223 38 35 25 % (17.2 % 13 3 49 74
amygdala)
Total 3,775
Modified from Rahimi and Kovacs (2014)
a
Macroscopic and microscopic infarcts/brain infarcts
b
Any vascular disease
c
Microinfarcts/cortical microvascular lesions
d
AD ? VD
e
Pure AD cases defined as frequent NP according to CERAD or Braak stages V and VI
f
Composite AD pathology score by summing CERAD and Braak in equal measures (score [4 included)
g
DLB high likelihood
h
Braak stages IVVI with moderate or frequent NP
i
AD ? DLB/FTD
j
Vascular pathology including bleeding and ischemic lesions
k
Data only reported for demented subjects
l
Severe hippocampal NFTs

as compared to other subtypes of AD (Thal et al. 2010). A
consensus protocol for the assessment of CAA in post-
mortem brain tissue has been published recently (Love
et al. 2014).
Mixed dementia: mixed pathologies
Although no standardized criteria for mixed dementia are
currently available (Gold et al. 2007; Jellinger and Attems
2007; Jellinger 2008), this neuropathological diagnosis
should be made if more than one disease or type of lesions
is detected at postmortem brain examination. The most
frequent form is the simultaneous presence of both AD and
cerebrovascular pathology, but the co-occurrence of sev-
eral pathologies has been observed frequently. Of partic-
ular importance is the frequent presence of confounding
processes in the aged brain that coexist with AD-related
lesions, as for example CVD, Lewy pathology, AGD, TDP-
43 pathology, and HS. Of note, mixed dementia should not
be used to describe the presence of additional minimal or
limited pathologies, e.g. AD with minor CVLs (Jellinger
2008). Depending on the definition of mixed dementia/
mixed pathologies, the prevalence lies between 2 and 93 %
(Table 2) (Davidson et al. 2011; Jellinger and Attems
2010; Jellinger 2013; Nagy et al. 1997; Nelson et al. 2007;
Rahimi and Kovacs 2014; Schneider et al. 2007a, b).
Although several clinico-pathological studies used differ-
ent recruitment and neuropathological methods, they all
concluded that mixed pathologies are frequent and increase
with age (Gelber et al. 2012; Jellinger 2007a; Jellinger and
Attems 2010; Nelson et al. 2013). In a consecutive autopsy
series of 1,110 patients (mean age 83.3 5.6 years; 90 %
over age 70), the prevalence of pure AD increased from

123
512
32.3 % in the 7th decade to 45.1 % in the 9th decade but
decreased in the 10th decade to 39.2 %. By contrast, AD
with minor CVLs as well as AD ? severe CVD both
increased from 7.8 % in the 7th decade to 32.9 % in the
10th decade (Jellinger and Attems 2010). Mixed patholo-
gies increase the odds of dementia to almost ten times and
up to three times compared to patients with only one brain
pathology (Schneider et al. 2007a, b).
The rate of neuropathologically confirmed intermediate
and high likelihood AD plus any other pathology was
reported to be as almost 54 % in the Rush Memory and
Aging Project cohort (Schneider et al. 2007a, b), while in
the VITA study, the presence of mixed pathologies was
over 70 % (Kovacs et al. 2013). In a large retrospective
autopsy study of demented patient (N = 1,700, mean age
83.3 6.0 years; 52 % with the clinical diagnosis of
probable AD) 83.2 % revealed AD-related pathology, but
only 41.1 % were diagnosed as pure AD without con- ogies in non-demented elderly subjects, in particular CVLs,
comitant pathologies; 24.2 % showed additional cerebro-
vascular lesions (infarcts, hippocampal sclerosis, lacunar
state, etc.), 9.1 % additional Lewy pathology, and 2.6 %
various other concomitant brain lesions, while 10.7 % were
diagnosed as pure vascular dementia without AD- studies revealed moderately to frequent neuritic plaque
pathology superior to age-related intensity. 5.5 % of the
demented patients showed other non-AD related disorders
(other neurodegenerative diseases, like MSA, multiple
sclerosis or tumors), while in 0.9 % of the total, no
pathology other than mild age-related lesions were detected
(Jellinger 2008).
Using the NACC database, a retrospective review of 533
patients clinically diagnosed as AD, showed that the
pathological results of 199 subjects (36 %) did not meet the
criteria of definite AD. The neuropathological diagnoses of
these cases consisted of DLB (29 %), insufficient AD
(18 %), vascular disease (13 %), FTLD (12 %), and HS
(8 %) (Shim et al. 2013). These data emphasize that
continuing systematic comparisons of clinical data are
essential to clinical practice and research, and may also
lead to further improvement of the diagnostic procedure.
A recent study of 2,083 autopsy cases from the NACC
database correlating the clinical dementia rate within
2 years before death in 835 subjects showed that the cause
of mild to moderate dementia remained uncertain in 14 %.
Plaques and tangles independently correlated with cogni-
tive dysfunction, and severe SVD. CAA and HS were also
independently associated with the degree of cognitive
impairment, while concomitant CVD strongly correlated
with cognitive impairment in the sample selected to rep-
resent AD pathological continuum, confirming the uncer-
tainty of AD clinico-pathological correlations based only
on tangles and plaques (Serrano-Pozo et al. 2013).
A study across nine centers of the BrainNet Europe
Consortium evaluating neuropathological data of 3,303
123
K. A. Jellinger, J. Attems
demented subjects (mean age 74.14 12.07 years)
showed mixed pathology in 53 % of the cases, that was
most frequently seen in synucleinopathies (PD 92 %, DLB
61 %), followed by cases with vascular pathology (61 %),
AGD (61 %), and AD (43 %), less frequent in PSP (22 %),
CBD (21 %), frontotemporal lobe degeneration with
ubiquitin-positive inclusions (FTLD-U) (9 %), and Cre-
utzfeldtJakob disease (2 %). The most frequent diagnoses
in mixed cases was AD in 89.6 % (p \ 0.01), followed by
vascular pathology (52.6 %), synucleinopathy (50 %), and
AGD (11.4 %) (Kovacs et al. 2008).
In several autopsy series of oldest-old individuals, the
frequency of AD ranged from 12 to 66 %, that of vascular
dementia from 9 to 46.8 %, of DLB between 9 and 24 %,
and that of mixed pathologies between 2 and 86 % (Jel-
linger and Attems 2010).
Many studies emphasize multiple confounding pathol-
e.g. small or large infarctions, lacunes, and white matter
lesions, in up to 10 % (Davis et al. 1999; Jentoft et al.
2011; Knopman et al. 2003; Schneider et al. 2009). Eval-
uation of 336 cognitively normal (CN) seniors from four
density in 47 %; of these 6 % had Braak neuritic stages I
VI, medullary, nigral, and cortical LBs in 15, 8, and 4 %,
respectively; cerebral microinfarcts in 33 %, and high-level
microinfarcts in 10 %. The burden of brain lesions and
comorbidities varied widely within each study, but was
similar across studies (Sonnen et al. 2011).
Among 418 non-demented participants of the Religious
Order Study (age 88.5 5.3 years), 35 % showed mac-
roscopic brain infarcts, 8 % microinfarcts, 14.8 % arterio-
sclerosis, 5.7 % both, only 37.5 % being free of CVLs
(Buchman et al. 2011). Up to 75 % of CN elders had
various degrees of CAA, argyrophilic grains in up to 23 %
(Jentoft et al. 2011), LBs in up to 18 % (Jellinger and
Attems 2012; Knopman et al. 2003; Schneider et al. 2009;
White 2009), occasional HS (Jentoft et al. 2011; Schmitt
et al. 2000), and mixed pathologies in 715 % (Schneider
et al. 2009; White 2009). Among 100 non-demented
elderly, mild, moderate and severe intracranial athero-
sclerosis was present in 31, 17 and 6 %, respectively,
lacunar state in basal ganglia and/or white matter in 73 %,
HS in 3 %, LBs in 5 % but tau pathology in brainstem in
60 %, and other mixed cerebral pathologies in 6 %,
whereas only 9 % were free of CVLs (Jellinger and Attems
2012). A recent British non-demented sample (n = 53,
mean age 81.5 7.4 years) showed maximum score neu-
ritic plaques in 3294 %, NFTs in hippocampus and neo-
cortex in 81 and 30.8 %, respectively, white matter lesions
in 5583 %, SVD in 45 %, brain infarcts in 13.7 %, lac-
unes in 6 %, and cerebral hemorrhages in 10 % (Stephan
et al. 2012). A community-based autopsy series from the
Challenges of multimorbidity of the aging brain
Viennese VITA study (Fischer et al. 2002) of 233 subjects
over age 75 (range 7787 years), in addition to some
degrees of NFTs in 100 %, showed Ab deposits (68.7 %),
CVLs (48.9 %), non-AD tauopathies (23.2 %), TDP-43
proteinopathy (13.3 %), and others (inflammation, tumors,
etc., 15.1 %). Most of these lesions did not increase the
probability of the co-occurrence of others, while the
number of coincidental pathologies correlated significantly
with AD-related changes (Kovacs et al. 2013).
A recent cross-sectional study in a community-based
sample of 72 CN older individuals (mean age
74.9 5.7 years) confirmed that a substantial number
harbored neurodegeneration without Ab burden, but asso-
ciation of neurodegenerative lesions with CVD can emerge
through non-Ab pathways within regions most affected by
AD pathology (Wirth et al. 2013).
Impact of comorbidity
Data from many different autopsy studies indicate the
presence of additional lesions in otherwise well-charac-
terized cases that may fulfill the criteria for a single distinct
disorder:
1. In AD that is characterized by Ab and tau pathology,
LBs were seen in up to 43 %; AD with amygdala LBs
is considered a distinct form of aSynucleinopathy
(Uchikado et al. 2006). TDP-43 pathology is seen in up
to 43 % (Amador-Ortiz et al. 2007; Arai et al. 2009;
Bigio et al. 2010; Davidson et al. 2011; Duyckaerts
et al. 2009; Josephs et al. 2008, 2014; Rauramaa et al.
2011; Robinson et al. 2011), and severe CVLs in up to
50 % of the AD cases (Jellinger and Attems 2010).
2. In LBD that is characterized by aSyn pathology,
coincident Ab pathology is found in 95 %, considerable
tau pathology (Braak stages V/VI) in 55 %, and various
degrees of CVD in 75 % (Jellinger and Attems 2008).
Another autopsy study in investigating a cohort for the
presence of aSyn pathology reported that over 50 % of
the cases with widespread aSyn lesions did not show any
clinical symptoms (Parkkinen et al. 2008).
3. Pure VaD without additional lesions is rare (Jellinger
2007a; Jellinger and Attems 2010), and frequently
confounding, but often limited AD pathology is present.
However, since 5085 % of post mortem brains from
individuals dying over age 80, show appreciable CVLs
(Petrovitch et al. 2005), a specific problem is the impact
of CVD in relation to AD pathology (Bennett et al. 2005;
Chui 2006; Chui et al. 2006; Jellinger and Attems 2005;
Schneider et al. 2007a, b).
The high prevalence of multiple pathologies in brains of
aged individuals could reflect the simultaneous presence of
513
a single distinct neurodegenerative disease and age-related
changes that are not directly associated. For example, the
high prevalence of CVLs in AD brains of aged subjects
mirrors the prevalence of vascular disease in the aged per
se, rather than suggesting causal relationships between AD
and CVLs. However, this does not preclude the possibility
that CVLs exert influence on AD pathology itself, and it
has been suggested that CVLs lower the threshold for overt
clinical dementia, i.e. that less AD pathology is needed to
cause clinical symptoms in the simultaneous presence of
CVD (Jellinger and Attems 2007; Zekry et al. 2003a, b).
Another example for the simultaneous presence of a dis-
tinct neurodegenerative disease with age-associated chan-
ges is the co-occurrence of AD pathology in DLB
biochemical overlapping between DLB and AD, including
co-localization on aSyn and tau epitopes in LBs, suggests
that the process of LB formation is triggered, at least in
part, by AD pathology (Iseki et al. 2003). Similarly to the
presumed impact of CVLs in AD, aSyn pathology in DLB
is aggravated by AD pathology (Merdes et al. 2003; Per-
neczky et al. 2005).
The synergistic interaction between Ab, tau, aSyn and
other pathological proteins, demonstrated in in vitro and in
animal models (Giasson et al. 2003; Oddo et al. 2003)
accelerating neuropathology and cognitive decline, and
explaining overlap between synucleinopathies, tauopathies,
and other neurodegenerative disorders (Compta et al. 2011;
Wills et al. 2010) has been summarized recently (Clinton
et al. 2010; Colom-Cadena et al. 2013; Jellinger 2010a,
2012). The high prevalence of mixed pathologies con-
firmed by many autopsy studies supports the notion that a
combination of neuropathological alterations often has a
cumulative effect and, if reaching the individual threshold
for cognitive impairment, manifests as clinical dementia
(Kovacs et al. 2013; Savva et al. 2009). When discussing
the prevalence of mixed pathologies, not only their fre-
quency is important, but also that the number of combi-
nations of major alterations can be very high (Kovacs et al.
2013). It should be emphasized that in the concept for the
understanding of aging brain, both AD-related and non-AD
pathologies should be evaluated in details (Dugger et al.
2014; Nelson et al. 2013).
Conclusions and future perspectives
Currently, neuropathological assessment is based on
semiquantitative scoring of cerebral lesions, the criteria of
which have recently been standardized (Alafuzoff et al.
2008; Braak et al. 2006a, 2006b; Montine et al. 2012).
While these methods are used in routine neuropathological
diagnosis, they provide only a rough estimation of the
amount of pathology present in the brain. Algorithms for
123
514
the molecular-pathological classification of sporadic (non-
genetic) forms of neurodegenerative dementias have been
proposed (Dickson et al. 1994; Jellinger 2010a; Kovacs
et al. 2010). However, due to variable overlap, these
changes may fail to distinguish between cognitively intact
aged subjects from those with preclinical or mild to mod-
erate AD (Jicha et al. 2012; Markesbery et al. 2009; Pet-
ersen et al. 2006). These latter groups show a wide variety
in intensity and pattern of AD-related and other pathologies
(Schneider et al. 2009; Stephan et al. 2012). Although they
differ from normal aging, only a small proportion of pathological diagnosis of neurodegenerative disorders and
cognitively intact aged subjects are free of AD and other
pathologies, while the majority shows multiple pathologies
(Arriagada et al. 1992; Bennett et al. 2005; Davis et al.
1999; Jellinger and Attems 2012; Knopman et al. 2003).
Additional challenges arise from the frequent coexistence
of various pathologies in the aging brain that may have an
additive or synergistic effect (Fig. 2), although their mutual
impact often remains unclear. Community-based neuro-
pathological studies have shown that complex constella-
tions of underlying pathologies may lead to cognitive
decline and that the number and intensity of possible
constellations increased in the aging brain. However, cau-
tion is needed for the interpretation of frequency values in
view of the differences in recruitment, assessment, meth-
ods, criteria used, and brain regions examined. More
accurate quantitative assessment of various neuropatho-
logical lesions is necessary to further elucidate possible
mutual relationships between coincident pathologies as
well as their combined influence on the clinical picture.
Interdisciplinary projects/initiatives for the standardized
assessment of clinical, biomarker, and neuropathological
data are currently under way (Cairns et al. 2010; Dubois
Fig. 2 Multiple pathologies in brains of demented seniors. Full
arrows point towards the characteristic neuropathology of the
respective disease, while dotted arrows point towards neuropatho-
logical lesions that are frequently seen in addition to the main
pathological hallmark lesions. Approximate percentages are encir-
cled. AD Alzheimers disease, LBD Lewy body diseases, FTLDTDP
frontotemporal lobar degeneration with TDP-43 pathology, VaD
vascular dementia. From Attems and Jellinger (2013b)
123
K. A. Jellinger, J. Attems
et al. 2014; Jack 2012; Toledo et al. 2013; Vanderstichele
et al. 2012; Weiner et al. 2010). In the majority of cases
except those with known genetic or metabolic back-
grounds, however, pathological examination may not be
able to clarify the causes or etiology of most dementing
disorders (Jellinger 2010a), while some conservative
authors emphasized that autopsy examination of well-
studied cases of AD and other dementias still has a critical
role to play (Esiri 2010). Therefore, the reliability and
clinical relevance of the current criteria for the neuro-
other brain pathologies need better qualification, quantita-
tion and validation in order to find a way out of the chaos
regarding the histopathological diagnosis of disorders of
the aging brain. Molecular genetics, biochemistry, and
animal models, at least in part reproducing the morphology
of human brain diseases, have produced a large body of
data on the pathogenesis and pathophysiology of these
disorders, showing a complex cascade of events leading
from preclinical to fully developed neurodegeneration (de
Calignon et al. 2012; Gotz and Gotz 2009; Petiet et al.
2011). However, both their molecular backgrounds, basic
etiological factors, pathogenic interrelations of the various
concomitant pathologies, and their impact on the clinical
symptoms need further validation. Methodological issues
in evaluating multimorbidity are to be considered as well as
future research needs, especially concerning etiological
factors, combinations and clustering of chronic brain dis-
eases, and new animal models for conditions affected by
multiple disorders in order to provide further insights in the
problems of multimorbid patients (Marengoni et al. 2011).
Neuropathological studies should use a wide range of
molecular-pathological methods and should evaluate as
many brain regions as possible. Harmonized and modern
techniques are required to increase the accuracy and
reproducibility of neuropathological diagnosis in view of
the frequent co-occurrence of multiple different patholo-
gies as a basis for further personalized treatment and
neuroprotection, an enormous challenge for modern
neurosciences.
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