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J Neural Transm (2015) 122:505521

DOI 10.1007/s00702-014-1288-x


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: 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

506 K. A. Jellinger, J. Attems

LBD Lewy body disease both cerebral and general multimorbidities increases con-
MCI Mild cognitive impairment siderably (Attems and Jellinger 2013a; Marengoni et al.
MSA Multiple system atrophy 2011; Rahimi and Kovacs 2014). Recent community-based
NACC National Alzheimers Coordinating Center studies have clearly shown that co-occurrence of Alzhei-
NFTs Neurofibrillary tangles mers disease (AD) and non-AD type proteinopathies as
NIA National Institute on Aging well as other superimposed pathologies, in particular
PSP Progressive supranuclear palsy cerebrovascular lesions (CVLs), are frequently occurring in
SVD Small vessel disease the brains of both cognitively unimpaired and demented
TDP-43 TAR DNA binding protein 43 aged individuals, whereas the presence of single disease is
VaD Vascular dementia rather the exception than the rule (Attems and Jellinger
VCI/ Vascular cognitive impairment/vascular 2013a). Multiple pathologies are suggested to interact in
VaD dementia promoting cognitive and other nervous symptoms in the
VCI Vascular cognitive impairment aged (Attems and Jellinger 2013a; Jellinger and Attems
VITA Vienna trans-danube aging study 2007, 2010; Kovacs et al. 2008). Of particular importance
WML White matter lesion 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)
Introduction (Davidson et al. 2011; Nagy et al. 1997; Nelson et al. 2007;
Rahimi and Kovacs 2014; Schneider et al. 2007a, b), which
Due to increased life expectancy, understanding of age- have, however, frequently been missed clinically and could
associated disorders including cognitive decline is more not be identified without neuropathological examination
and more important, since the prevalence and incidence of using modern bio/histochemical and molecular-biological
dementia increase exponentially with age. In 2010, 35.6 analyses.
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, Diagnostic criteria and challenges
16 millions in Europe (Prince et al. 2013). With the dis-
proportional growth of the elderly population, dementia has Current guidelines for the clinical diagnosis of major
become a major public health and socio-economic problem dementia disorders include: revised National Institute of
that threatens to become the scourge of our century (Thies Neurological and Communicative Disorders and Stroke
and Bleiler 2013; Wimo et al. 2013). There are many and the Alzheimers Disease and Related Disorders Asso-
causes of dementia, however, neurodegenerative disorders ciation (NINCDSADRDA) and European Federation of
that are caused by the intra- and extra-cellular deposition of Neurological Societies (EFNS) criteria for AD (Dubois
aggregated misfolded proteins (proteinopathies) are et al. 2010; Sorbi et al. 2012), the National Institute on
thought to be the most prevalent in aged people. Modern Aging-Alzheimers Association (NIA-AA) criteria for AD
neuropathological examinations, have demonstrated that (McKhann et al. 2011; Sarazin et al. 2012; Sperling et al.
the brains of many elderly individuals had Alzheimer- 2011), consensus from the Canadian Consensus Confer-
related pathologies, featured by neurofibrillary tangles ence on the Diagnosis and Treatment of Dementia
(NFTs) and plaques together with a large number of (CCCDTD) (Chertkow et al. 2013) and the International
coincident non-Alzheimer type pathologies (Attems and Working Group 2 criteria for AD (Dubois et al. 2014),
Jellinger 2013a; Jellinger 2013, 2014; Rahimi and Kovacs criteria for Parkinsons disease (PD)-dementia (Dubois
2014). Cognitively normal elderlies may have substantial et al. 2007; Emre et al. 2007), dementia with Lewy bodies
AD-related pathology (Price et al. 2009); but, in general, (DLB) (McKeith et al. 2005), frontotemporal lobe degen-
the density of isocortical tangles correlates best with the eration (FTLD) (Josephs et al. 2011; Seltman and Mat-
severity of cognitive impairment (Nelson et al. 2007, thews 2012), vascular cognitive impairment/dementia
2012), which, however, may or may not apply for the (VCI/VaD) (National Institute of Neurological Disorders
oldest-old age group (Dolan et al. 2010; Purohit et al. 2008; and Stroke and Association Internationale pour la
Sinka et al. 2010). Others emphasized that much of late life Recherche et lEnseignement en Neurosciences/NINDS-
cognitive decline is not due to common neurodegenerative AIREN) (Gorelick et al. 2011; Roman et al. 1993), Inter-
pathologies (Boyle et al. 2013; Strozyk et al. 2010). national Society for Vascular Behavioral and Cognitive
The coexistence of multiple pathologies is referred to as Disorders (VASCOG) (Sachdev et al. 2014), Diagnostic
multimorbidity. With increasing age, the prevalence of and Statistical Manual of Mental Disorders 5th Ed. (DSM

Challenges of multimorbidity of the aging brain 507

V) (American Psychiatric Association 2013), and other plaques in at least five neocortical regions (C), based on
neurodegenerative syndromes (Lopez et al. 2011). CERAD criteria, as well as more detailed approaches for
Current guidelines for the neuropathological diagnosis assessing co-morbid conditions, such as Lewy body disease
of major dementing disorders rely on qualitative, semi- (LBD), vascular brain injury, HS, and TDP-43 immuno-
quantitative and topographic assessment of morphological reactive lesions (Montine et al. 2012). However, these new
and bio-/histochemical markers, in particular specific pro- algorithms did not consider the various clinico-pathologi-
tein inclusions in neurons, glia and other cells (Arnold et al. cal subtypes of AD, e.g. tangle-predominant dementia
2013a; Jellinger 2010a; Kovacs et al. 2010). The classifi- (TPD) (Jellinger and Attems 2007; Nelson et al. 2009;
cation of neurodegenerative disorders, previously based on Santa-Maria et al. 2012), recently redefined as primary
the anatomical systems involved, has been replaced by age-related tauopathy (Crary et al. 2014), the hippocam-
molecular-pathological ones, which may provide a basis pal-sparing (HpSP-AD) and the limbic-predominant forms
for the neuropathological diagnosis in the future (Fig. 1). (LP-AD) both differing from the most frequent typical AD
A definite diagnosis of AD can only be made by (Janocko et al. 2012; Murray et al. 2011, 2014).
neuropathological examination. Neuropathological criteria Updated neuropathological criteria for the diagnosis of
for AD are (1) cut-off quantitative values of senile plaques other dementias include: three staging systems for a-syn-
and tangles (Duyckaerts and Dickson 2011), (2) their ucleinopathies, in particular LBDs, one for PD (Braak et al.
semiquantitative assessment and age-adjustment in the 2006a, b), another for dementia with Lewy bodies (DLB)
Consortium to Establish a Registry for Alzheimers Disease (McKeith et al. 2005), and revised guidelines for Lewy
(CERAD) protocol (Mirra et al. 1991), (3) topographic body disease (Zaccai et al. 2008). Parkinsons disease
staging of neuritic AD pathology (Braak and Braak 1991), dementia (PDD) and DLB share many clinical and mor-
re-evaluated recently (Alafuzoff et al. 2008; Braak et al. phological features that are suggested to form a continuum
2006a), (4) and the progress and distribution of b-amyloid within the spectrum of LB diseases, and show a variable
(Ab) deposition being different from tau pathology (Thal combination of Lewy and AD pathologies, which may act
et al. 2002b). The combination of CERAD and Braak synergistically (Clinton et al. 2010; Compta et al. 2011;
scores in the National Institute on Aging-Reagan Institute Irwin et al. 2012). In multiple system atrophy (MSA),
(NIA-RI) criteria related dementia to AD-typical lesions morphologically featured by a-synuclein (aSyn)-positive
with high, intermediate and low likelihood (Hyman and glial cytoplasmic inclusions (GCIs), the morphological
Trojanowski 1997), and the recently revised guidelines for correlates of cognitive impairment are under discussion
the neuropathological evaluation of AD and other diseases (Asi et al. 2014; Jellinger 2007b; Stankovic et al. 2014).
consider levels of AD pathology in the brain regardless of Frontotemporal lobe degeneration, the third most fre-
the clinical status of a given individual (Hyman et al. 2012; quent cause of dementias, includes three major clinical
Montine et al. 2012). They include an ABC score of subgroups, showing distinct patterns of brain atrophy (Lu
AD-related changes that incorporates histological assess- et al. 2013). The most common are: microtubule-associated
ment of Ab deposits (A), based on the Ab phases (Thal tau protein (FTLD-tau), TDP-43 (FTLD-TDP-43), and
et al. 2002b), staging of NFTs (B), based on the Braak fusion sarcoma protein (FTLD-FUS), but there is frequent
staging system, and semiquantitative scoring of neuritic 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
Fig. 1 Molecular-pathologic classification of degenerative demen- determined vascular cognitive disease (VCD), despite
tias. From Jellinger (2013) several proposals (Kalaria et al. 2004; Montine et al. 2012),

508 K. A. Jellinger, J. Attems

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

Challenges of multimorbidity of the aging brain 509

Although the prevalence of HS is rather low in the features of cognitive impairment, while large cystic
general population, it is twice as frequent in a demented infarcts are less common (Gold et al. 2005; Jellinger
cohort (Robinson et al. 2011), but the frequency of TDP-43 2007a; Kalaria et al. 2004; Kovari et al. 2004; Troncoso
pathology varies considerably among aged subjects (range et al. 2008). Microinfarcts are an important correlate of
1346 %), partly due to methological and classification age-related VCI, but are not associated with an increased
differences (Wilson et al. 2013). Other neurodegenerative burden of AD pathology (Richardson et al. 2012; Zheng
diseases, such as MSA, PSP, CBD, TDP-43, Pick disease et al. 2013). The presence of both SVD and AD pathologies
and other FTLDs, have been less frequently reported in can summate, particularly at mild levels of AD pathology
aged subjects (less than 510 %) (Byford et al. 2009; (Esiri et al. 1999; Petrovitch et al. 2005), but there is no
Keage et al. 2012; Kovacs et al. 2013; Polvikoski et al. good evidence that one promotes the other (Esiri and
2010; Schneider et al. 2009; Wakisaka et al. 2003), but Englund 2014). Evaluation of the type and topographic
their clinical presentation varies in relation to concomitant pattern of CVLs in a large autopsy series of demented
pathologies (Dugger et al. 2014). 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
Vascular pathologies in the aging brain (volume \10 ml) involving one or both hemispheres
(32.5 %). This pattern differed considerably from that in
Cerebrovascular pathologies have been reported in cases with mixed dementia (AD ? vascular encephalopa-
5085 % of elderly subjects, but due to the lack of clearly thy), where 56.6 % revealed large, often lobar infarcts of
defined assessment criteria, their reported frequency varies multiple cortical and subcortical lesions larger than
considerably. Of note, this association was recently found 510 mm in diameter involving one or both hemispheres,
to be stronger in cases with lower NFT pathology (Toledo whereas lacunes and small subcortical microinfarcts were
et al. 2013), similar to earlier studies on respective asso- seen in only 36 %. These data suggest different pathogenic
ciations with subcortical vascular pathology (Chui et al. mechanisms between both types of disorders (Jellinger and
2006) and general CVD (Petrovitch et al. 2005). The Attems 2010).
spectrum of vascular pathologies assessed at autopsy ran- Recent emphasis on comorbidity of AD and CVD,
ges from small vessel disease (SVD), microinfarcts, lac- detected in 3060 % of AD brains and showing a large
unes, white matter lesions, cerebral amyloid angiopathy variety of lesions (Jellinger and Attems 2005, 2014;
(CAA) to large infarcts due to large vessel disease of Schneider et al. 2007a, b), and many other data indicate an
various extent in multi-infarct encephalopathy, cerebral association between AD and CVD. However, their role in
microbleeds and hemorrhages (Grinberg and Thal 2010; dementia is still under discussion and data obtained from
Jellinger 2007a, 2008; Richardson et al. 2012; Thal et al. epidemiological and clinico-pathological studies regarding
2012). Multiple lacunar microinfarcts were most frequent their relation are controversial (Esiri et al. 1999; Jellinger
in Japanese dementia cases with a prevalence of 42 %, 2008; Jellinger and Attems 2014; Rincon and Wright 2014;
suggesting that VaD was more frequent in the Japanese Zekry et al. 2002). Small vascular and AD-related patho-
than in Western populations (Fujishima and Kiyohara logical determinants of dementia have been demonstrated
2002). Vascular brain injury is commonly encountered in in the oldest old (Sinka et al. 2010). In elderly patients with
elderly subjects with and without AD pathology (Ferrer subclinical AD, either critically located CVLs or cortical
2010; Grinberg and Thal 2010; Jellinger 2007a). However, microinfarcts may worsen cognitive impairment due to a
subcortical SVD is increasingly recognized as a predictor synergistic interaction between both pathologies (Esiri
of cognitive impairment (Smallwood et al. 2012). The et al. 2014; Iadecola 2010; Miklossy 2003), while in
NUN study suggested that individuals with NFT pathology advanced of full-blown stages of AD, concomitant small
and one or two lacunar infarcts experienced a steeper drop vascular lesions do not significantly influence the overall
in cognitive function than those without cerebral infarcts state and progression of cognitive decline that is mainly
(Snowdon et al. 1997). On the other hand, in the Vienna related to the severity and extent of AD pathology over-
VITA study, single microinfarcts and territorial infarcts whelming the modest effects of CVD (Chui et al. 2006;
were found in up to 33 % in both demented and non- Esiri et al. 2014; Jellinger and Attems 2005; Jellinger
demented aged individuals (Kovacs et al. 2013). Several 2007a). The thresholds for vascular and degenerative
studies discussed that the presence of multiple infarction is lesions for distinguishing pure VaD or AD from mixed
more relevant for cognitive decline than the size of single cases have been critically discussed (Gold et al. 2007).
infarcts (Schneider et al. 2003; Troncoso et al. 2008; White The burden of vascular and AD-type pathologies are
et al. 2002), and that subcortical lacunes and multiple considered to be independent of each other, and are con-
disseminated microinfarcts appear to be the most common sistent with an additive or synergistic effect of both types

510 K. A. Jellinger, J. Attems

of lesions on cognitive impairment (Andin et al. 2005; increased from aged controls (total 30 %, 20 % severe) to
Jellinger 2007a; Kalaria et al. 2004; Launer et al. 2008; AD (total 97.7 %, among which 75 % severe). In 75 % of
Lim et al. 1999; Schneider et al. 2004; Strozyk et al. 2010). AD patients, hemorrhages were associated with severe and
An interesting finding is the inverse correlation of the only in 10 % with mild to moderate CAA, while only 20 %
volume of white matter lesion (WML) with NFT pathol- of cerebral infarcts were associated with severe CAA.
ogy, supporting the concept of synergistic effects and These studies confirmed previous ones documenting
suggesting that AD pathology might be driving the white significantly higher frequency of vascular pathology in AD
matter pathology (Shim et al. 2014). The variability of data than in age-matched non-demented controls. Like in the
on the neuropathologies of WMLs has been emphasized Einstein Aging Study in 67 patients with autopsy-proven
(Erten-Lyons et al. 2013b; Schmidt et al. 2011), and their AD showing additional vascular pathology in 82.1 %
significance may be different to the state of the disease, (Crystal and Dickson 2002), no significant differences in
subjects with early AD probably being more vulnerable the severity of cognitive decline between AD with and
than cognitively normal older adults with similar WML without concomitant CVLs were observed, which suggests
burden (Burns et al. 2005). AD-related pathology alone a floor effect of high-grade AD pathology in these patients.
more frequently accounts for dementia than both macro- These studies corroborated with another study comparing a
scopic and microscopic infarcts (Troncoso et al. 2008). In a large number of seniors showing similar age and Braak
recent study, global AD pathology significantly correlated scores but less severe dementia and more frequent histories
to global cognition, whereas infarct and Lewy pathologies of stroke in AD cases with additional CVD (Jellinger
did not (Bennett et al. 2012). 2002), but are at variance with others reporting more
In a population-based study in the UK, among 209 severe dementia and less severe AD pathology in patients
autopsies of elderly subjects, 48 % being demented, 78 % with concomitant CVD (Esiri et al. 1999; Petrovitch et al.
had evidence of CVD and 70 % of AD pathology. The 2005; Snowdon et al. 1997; Zekry et al. 2002).
proportion of multiple vascular lesions was higher in the The contribution of CVD in neurodegenerative diseases
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 Alzheimers Coordinating Center (NACC) database. For
and Ince 2004). In a health maintenance organization comparison, 210 unremarkable cases without cognitive
dementia register, only 36 % of patients had AD without impairment and 280 cases with pure CVD were included.
any other pathologies, while 4 % had definite AD plus The latter were older than those without CVD in all groups
coexistent CVD (Lim et al. 1999). Among 333 autopsied except for those with HS. a-Synucleinopathies, FTLD and
men in the Honolulu Asian Aging Study (120 demented, prion diseases showed a lower coincident CVD than AD
114 marginal, 96 normal cognition), 24 % of dementias patients, and those with both AD and synucleinopathies
were linked with CVD and dementia frequency more than revealed a lower burden of their relative lesions than those
doubled in AD with coexistent CVD (45 vs. 20 %). These without CVD in the context of comparable dementia. In
findings suggest that CVD is associated with a marked conclusion, CVD as a common finding in aged subjects
excess of dementia in cases with low neuritic plaque fre- with dementia, is more common in AD than in other
quency (Petrovitch et al. 2005). In a retrospective series of neurodegenerative disorders and lowers the threshold for
730 autopsy cases of AD and 535 age-matched controls, dementia due to AD or synuclein pathologies (Toledo et al.
using a 4-grade scale for the severity of CVLs, the total 2013), confirming previous findings (Jellinger 2008;
prevalence of CVD in AD was significantly higher than in Schneider et al. 2004; Strozyk et al. 2010; Zekry et al.
controls (31.6 vs. 23.4 %) (Jellinger and Mitter-Ferstl 2003a).
2003). Cerebral amyloid angiopathy is a very frequent but not
Retrospective examination of the prevalence of CVD in consistent feature of AD (Attems 2005; Attems et al. 2005,
a consecutive autopsy series of 621 autopsy-proven AD 2011), and is also a relevant cause for hemorrhages and
cases and 486 age-matched NC controls, using a 4-degree brain infarction (Tanskanen et al. 2012). Capillary CAA
scale for cerebrovascular pathology, showed 67.8 % CVLs can occur without the presence of general CAA in the
in AD versus controls (29.4 %); severe CVLs [old/recent meningeal and cortical arteries and it allows the distinction
infarcts and hemorrhages were more frequent in AD between two types: CAA type 1 characterized by the pre-
(23.6 %) than in controls (5.4 %)]. Cortico-subcortical sence of capillary CAA with or without concomitant gen-
infarcts and subcortical vascular lesions were more fre- eral CAA, while in CAA type 2, no capillary CAA is
quent in AD than in controls (41.2 vs. 11.6 %). Both the present (Thal et al. 2002a). The presence of capillary CAA
incidence and severity of CVLs, similar to the previous has been suggested to identify a subtype of AD that is
study, increased with higher neuritic Braak stages (Jellin- characterized by a stronger association to the APOE e4
ger 2010b). Likewise, the prevalence and severity of CAA 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
Vantaa 85? 304 70 66 41 36 % 5 55a 40
Hisayama 205 62 29 % 31 10d
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
VITA study 223 38 35 25 % (17.2 % 13 3 49 74
Total 3,775
Modified from Rahimi and Kovacs (2014)
Macroscopic and microscopic infarcts/brain infarcts
Any vascular disease
Microinfarcts/cortical microvascular lesions
Pure AD cases defined as frequent NP according to CERAD or Braak stages V and VI
Composite AD pathology score by summing CERAD and Braak in equal measures (score [4 included)
DLB high likelihood
Braak stages IVVI with moderate or frequent NP
Vascular pathology including bleeding and ischemic lesions
Data only reported for demented subjects
Severe hippocampal NFTs

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

512 K. A. Jellinger, J. Attems

32.3 % in the 7th decade to 45.1 % in the 9th decade but demented subjects (mean age 74.14 12.07 years)
decreased in the 10th decade to 39.2 %. By contrast, AD showed mixed pathology in 53 % of the cases, that was
with minor CVLs as well as AD ? severe CVD both most frequently seen in synucleinopathies (PD 92 %, DLB
increased from 7.8 % in the 7th decade to 32.9 % in the 61 %), followed by cases with vascular pathology (61 %),
10th decade (Jellinger and Attems 2010). Mixed patholo- AGD (61 %), and AD (43 %), less frequent in PSP (22 %),
gies increase the odds of dementia to almost ten times and CBD (21 %), frontotemporal lobe degeneration with
up to three times compared to patients with only one brain ubiquitin-positive inclusions (FTLD-U) (9 %), and Cre-
pathology (Schneider et al. 2007a, b). utzfeldtJakob disease (2 %). The most frequent diagnoses
The rate of neuropathologically confirmed intermediate in mixed cases was AD in 89.6 % (p \ 0.01), followed by
and high likelihood AD plus any other pathology was vascular pathology (52.6 %), synucleinopathy (50 %), and
reported to be as almost 54 % in the Rush Memory and AGD (11.4 %) (Kovacs et al. 2008).
Aging Project cohort (Schneider et al. 2007a, b), while in In several autopsy series of oldest-old individuals, the
the VITA study, the presence of mixed pathologies was frequency of AD ranged from 12 to 66 %, that of vascular
over 70 % (Kovacs et al. 2013). In a large retrospective dementia from 9 to 46.8 %, of DLB between 9 and 24 %,
autopsy study of demented patient (N = 1,700, mean age and that of mixed pathologies between 2 and 86 % (Jel-
83.3 6.0 years; 52 % with the clinical diagnosis of linger and Attems 2010).
probable AD) 83.2 % revealed AD-related pathology, but Many studies emphasize multiple confounding pathol-
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- e.g. small or large infarctions, lacunes, and white matter
vascular lesions (infarcts, hippocampal sclerosis, lacunar lesions, in up to 10 % (Davis et al. 1999; Jentoft et al.
state, etc.), 9.1 % additional Lewy pathology, and 2.6 % 2011; Knopman et al. 2003; Schneider et al. 2009). Eval-
various other concomitant brain lesions, while 10.7 % were uation of 336 cognitively normal (CN) seniors from four
diagnosed as pure vascular dementia without AD- studies revealed moderately to frequent neuritic plaque
pathology superior to age-related intensity. 5.5 % of the density in 47 %; of these 6 % had Braak neuritic stages I
demented patients showed other non-AD related disorders VI, medullary, nigral, and cortical LBs in 15, 8, and 4 %,
(other neurodegenerative diseases, like MSA, multiple respectively; cerebral microinfarcts in 33 %, and high-level
sclerosis or tumors), while in 0.9 % of the total, no microinfarcts in 10 %. The burden of brain lesions and
pathology other than mild age-related lesions were detected comorbidities varied widely within each study, but was
(Jellinger 2008). similar across studies (Sonnen et al. 2011).
Using the NACC database, a retrospective review of 533 Among 418 non-demented participants of the Religious
patients clinically diagnosed as AD, showed that the Order Study (age 88.5 5.3 years), 35 % showed mac-
pathological results of 199 subjects (36 %) did not meet the roscopic brain infarcts, 8 % microinfarcts, 14.8 % arterio-
criteria of definite AD. The neuropathological diagnoses of sclerosis, 5.7 % both, only 37.5 % being free of CVLs
these cases consisted of DLB (29 %), insufficient AD (Buchman et al. 2011). Up to 75 % of CN elders had
(18 %), vascular disease (13 %), FTLD (12 %), and HS various degrees of CAA, argyrophilic grains in up to 23 %
(8 %) (Shim et al. 2013). These data emphasize that (Jentoft et al. 2011), LBs in up to 18 % (Jellinger and
continuing systematic comparisons of clinical data are Attems 2012; Knopman et al. 2003; Schneider et al. 2009;
essential to clinical practice and research, and may also White 2009), occasional HS (Jentoft et al. 2011; Schmitt
lead to further improvement of the diagnostic procedure. et al. 2000), and mixed pathologies in 715 % (Schneider
A recent study of 2,083 autopsy cases from the NACC et al. 2009; White 2009). Among 100 non-demented
database correlating the clinical dementia rate within elderly, mild, moderate and severe intracranial athero-
2 years before death in 835 subjects showed that the cause sclerosis was present in 31, 17 and 6 %, respectively,
of mild to moderate dementia remained uncertain in 14 %. lacunar state in basal ganglia and/or white matter in 73 %,
Plaques and tangles independently correlated with cogni- HS in 3 %, LBs in 5 % but tau pathology in brainstem in
tive dysfunction, and severe SVD. CAA and HS were also 60 %, and other mixed cerebral pathologies in 6 %,
independently associated with the degree of cognitive whereas only 9 % were free of CVLs (Jellinger and Attems
impairment, while concomitant CVD strongly correlated 2012). A recent British non-demented sample (n = 53,
with cognitive impairment in the sample selected to rep- mean age 81.5 7.4 years) showed maximum score neu-
resent AD pathological continuum, confirming the uncer- ritic plaques in 3294 %, NFTs in hippocampus and neo-
tainty of AD clinico-pathological correlations based only cortex in 81 and 30.8 %, respectively, white matter lesions
on tangles and plaques (Serrano-Pozo et al. 2013). in 5583 %, SVD in 45 %, brain infarcts in 13.7 %, lac-
A study across nine centers of the BrainNet Europe unes in 6 %, and cerebral hemorrhages in 10 % (Stephan
Consortium evaluating neuropathological data of 3,303 et al. 2012). A community-based autopsy series from the

Challenges of multimorbidity of the aging brain 513

Viennese VITA study (Fischer et al. 2002) of 233 subjects a single distinct neurodegenerative disease and age-related
over age 75 (range 7787 years), in addition to some changes that are not directly associated. For example, the
degrees of NFTs in 100 %, showed Ab deposits (68.7 %), high prevalence of CVLs in AD brains of aged subjects
CVLs (48.9 %), non-AD tauopathies (23.2 %), TDP-43 mirrors the prevalence of vascular disease in the aged per
proteinopathy (13.3 %), and others (inflammation, tumors, se, rather than suggesting causal relationships between AD
etc., 15.1 %). Most of these lesions did not increase the and CVLs. However, this does not preclude the possibility
probability of the co-occurrence of others, while the that CVLs exert influence on AD pathology itself, and it
number of coincidental pathologies correlated significantly has been suggested that CVLs lower the threshold for overt
with AD-related changes (Kovacs et al. 2013). clinical dementia, i.e. that less AD pathology is needed to
A recent cross-sectional study in a community-based cause clinical symptoms in the simultaneous presence of
sample of 72 CN older individuals (mean age CVD (Jellinger and Attems 2007; Zekry et al. 2003a, b).
74.9 5.7 years) confirmed that a substantial number Another example for the simultaneous presence of a dis-
harbored neurodegeneration without Ab burden, but asso- tinct neurodegenerative disease with age-associated chan-
ciation of neurodegenerative lesions with CVD can emerge ges is the co-occurrence of AD pathology in DLB
through non-Ab pathways within regions most affected by biochemical overlapping between DLB and AD, including
AD pathology (Wirth et al. 2013). 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
Impact of comorbidity presumed impact of CVLs in AD, aSyn pathology in DLB
is aggravated by AD pathology (Merdes et al. 2003; Per-
Data from many different autopsy studies indicate the neczky et al. 2005).
presence of additional lesions in otherwise well-charac- The synergistic interaction between Ab, tau, aSyn and
terized cases that may fulfill the criteria for a single distinct other pathological proteins, demonstrated in in vitro and in
disorder: animal models (Giasson et al. 2003; Oddo et al. 2003)
accelerating neuropathology and cognitive decline, and
1. In AD that is characterized by Ab and tau pathology,
explaining overlap between synucleinopathies, tauopathies,
LBs were seen in up to 43 %; AD with amygdala LBs
and other neurodegenerative disorders (Compta et al. 2011;
is considered a distinct form of aSynucleinopathy
Wills et al. 2010) has been summarized recently (Clinton
(Uchikado et al. 2006). TDP-43 pathology is seen in up
et al. 2010; Colom-Cadena et al. 2013; Jellinger 2010a,
to 43 % (Amador-Ortiz et al. 2007; Arai et al. 2009;
2012). The high prevalence of mixed pathologies con-
Bigio et al. 2010; Davidson et al. 2011; Duyckaerts
firmed by many autopsy studies supports the notion that a
et al. 2009; Josephs et al. 2008, 2014; Rauramaa et al.
combination of neuropathological alterations often has a
2011; Robinson et al. 2011), and severe CVLs in up to
cumulative effect and, if reaching the individual threshold
50 % of the AD cases (Jellinger and Attems 2010).
for cognitive impairment, manifests as clinical dementia
2. In LBD that is characterized by aSyn pathology,
(Kovacs et al. 2013; Savva et al. 2009). When discussing
coincident Ab pathology is found in 95 %, considerable
the prevalence of mixed pathologies, not only their fre-
tau pathology (Braak stages V/VI) in 55 %, and various
quency is important, but also that the number of combi-
degrees of CVD in 75 % (Jellinger and Attems 2008).
nations of major alterations can be very high (Kovacs et al.
Another autopsy study in investigating a cohort for the
2013). It should be emphasized that in the concept for the
presence of aSyn pathology reported that over 50 % of
understanding of aging brain, both AD-related and non-AD
the cases with widespread aSyn lesions did not show any
pathologies should be evaluated in details (Dugger et al.
clinical symptoms (Parkkinen et al. 2008).
2014; Nelson et al. 2013).
3. Pure VaD without additional lesions is rare (Jellinger
2007a; Jellinger and Attems 2010), and frequently
confounding, but often limited AD pathology is present.
Conclusions and future perspectives
However, since 5085 % of post mortem brains from
individuals dying over age 80, show appreciable CVLs
Currently, neuropathological assessment is based on
(Petrovitch et al. 2005), a specific problem is the impact
semiquantitative scoring of cerebral lesions, the criteria of
of CVD in relation to AD pathology (Bennett et al. 2005;
which have recently been standardized (Alafuzoff et al.
Chui 2006; Chui et al. 2006; Jellinger and Attems 2005;
2008; Braak et al. 2006a, 2006b; Montine et al. 2012).
Schneider et al. 2007a, b).
While these methods are used in routine neuropathological
The high prevalence of multiple pathologies in brains of diagnosis, they provide only a rough estimation of the
aged individuals could reflect the simultaneous presence of amount of pathology present in the brain. Algorithms for

514 K. A. Jellinger, J. Attems

the molecular-pathological classification of sporadic (non- et al. 2014; Jack 2012; Toledo et al. 2013; Vanderstichele
genetic) forms of neurodegenerative dementias have been et al. 2012; Weiner et al. 2010). In the majority of cases
proposed (Dickson et al. 1994; Jellinger 2010a; Kovacs except those with known genetic or metabolic back-
et al. 2010). However, due to variable overlap, these grounds, however, pathological examination may not be
changes may fail to distinguish between cognitively intact able to clarify the causes or etiology of most dementing
aged subjects from those with preclinical or mild to mod- disorders (Jellinger 2010a), while some conservative
erate AD (Jicha et al. 2012; Markesbery et al. 2009; Pet- authors emphasized that autopsy examination of well-
ersen et al. 2006). These latter groups show a wide variety studied cases of AD and other dementias still has a critical
in intensity and pattern of AD-related and other pathologies role to play (Esiri 2010). Therefore, the reliability and
(Schneider et al. 2009; Stephan et al. 2012). Although they clinical relevance of the current criteria for the neuro-
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 other brain pathologies need better qualification, quantita-
pathologies, while the majority shows multiple pathologies tion and validation in order to find a way out of the chaos
(Arriagada et al. 1992; Bennett et al. 2005; Davis et al. regarding the histopathological diagnosis of disorders of
1999; Jellinger and Attems 2012; Knopman et al. 2003). the aging brain. Molecular genetics, biochemistry, and
Additional challenges arise from the frequent coexistence animal models, at least in part reproducing the morphology
of various pathologies in the aging brain that may have an of human brain diseases, have produced a large body of
additive or synergistic effect (Fig. 2), although their mutual data on the pathogenesis and pathophysiology of these
impact often remains unclear. Community-based neuro- disorders, showing a complex cascade of events leading
pathological studies have shown that complex constella- from preclinical to fully developed neurodegeneration (de
tions of underlying pathologies may lead to cognitive Calignon et al. 2012; Gotz and Gotz 2009; Petiet et al.
decline and that the number and intensity of possible 2011). However, both their molecular backgrounds, basic
constellations increased in the aging brain. However, cau- etiological factors, pathogenic interrelations of the various
tion is needed for the interpretation of frequency values in concomitant pathologies, and their impact on the clinical
view of the differences in recruitment, assessment, meth- symptoms need further validation. Methodological issues
ods, criteria used, and brain regions examined. More in evaluating multimorbidity are to be considered as well as
accurate quantitative assessment of various neuropatho- future research needs, especially concerning etiological
logical lesions is necessary to further elucidate possible factors, combinations and clustering of chronic brain dis-
mutual relationships between coincident pathologies as eases, and new animal models for conditions affected by
well as their combined influence on the clinical picture. multiple disorders in order to provide further insights in the
Interdisciplinary projects/initiatives for the standardized problems of multimorbid patients (Marengoni et al. 2011).
assessment of clinical, biomarker, and neuropathological Neuropathological studies should use a wide range of
data are currently under way (Cairns et al. 2010; Dubois 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


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