Progress in Neurobiology 97 (2012) 3851

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Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

Dening Alzheimer as a common age-related neurodegenerative process not

inevitably leading to dementia
Isidro Ferrer *
Institute of Neuropathology, University Hospital Bellvitge, University of Barcelona, Idibell, Ciberned, Spain

A R T I C L E I N F O A B S T R A C T

Article history: Since the description by Alois Alzheimer, more than 50 years have passed during which senile dementia
Received 15 January 2012 and pre-senile dementia have been considered Alzheimer disease (AD) on the basis of their common
Received in revised form 10 March 2012 neuropathological and clinical manifestations. AD now covers pre-senile dementia, senile dementia,
Accepted 13 March 2012
mild cognitive impairment and pre-clinical AD, all of them within the context of AD-related pathology.
Available online 21 March 2012
However, there is still a gray area between normal aging with AD-related pathology and AD. Here it is
proposed that Alzheimer (or alzheimer) is an age-related neurodegenerative process distinguished from
Keywords:
normal aging by the presence of senile plaques and neurobrillary tangles. Alzheimer affects about 80%
Alzheimer
of individuals aged 65 years but dementia only occurs in a small percentage of individuals at this age;
Senile plaques
Neurobrillary tangles prevalence of dementia in Alzheimer increases to 25% in individuals aged 80 years. The concepts derived
Amyloid from the b-amyloid hypothesis support b-amyloid as a conductor in the pathogenesis of familial AD and
Tau as a prodding factor in sporadic AD. Moreover, seeding of b-amyloid and truncated tau explains
Mitochondria incorporation, enhancement and perpetuation of AD-related changes. Therefore, the earliest Alzheimer
Oxidative stress changes conned to selected regions are the rst grounds and the main risk factor for developing
Atherosclerosis dementia. The term Alzheimer embraces this assumption and likens its meaning to other degenerative
Biomarkers
biological processes, such as atherosclerosis, that may eventually progress to disease. In this context, the
rst stages of Alzheimer should be considered as primary targets of therapeutic intervention in order to
prevent progression to diseased states.
2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2. Historical evolution of the concepts of AD and senile dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3. Genetic and sporadic AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
4. Neuropathological hallmarks and molecular pathology of tau b-amyloid in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5. Multi-functional subcellular failure in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6. Involvement of synapses, multiple neuronal types and systems in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7. Categorization of changes in the nervous system attributable to aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
8. Discrimination of normal brain aging from AD-related pathology and AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
9. AD, mild cognitive impairment, pre-clinical AD and biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Abbreviations: AD, Alzheimers disease; ADAD, autosomal dominant Alzheimers disease; ApoE4, apolipoprotein allele e4; APP, amyloid precursor protein; BACE, b-secretase;
CERAD, Consortium to Establish a Registry of Alzheimers Disease; CSF, cerebrospinal uid; EOAD, early onset Alzheimers disease; FAD, Familial Alzheimers disease; LOAD,
late-onset Alzheimers disease; MAPT, gene encoding microtubule associated protein tau; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders
Association; NFTs, neurobrillary tangles; PDGF, platelet-derived growth factor; PET, positron emission tomography; PICALM, phosphatidylinositol binding clathrin
assembly protein; PSEN1, presenilin-1; PSEN2, presenilin-2; PSN1, gene encoding presenilin-1; PSN2, gene encoding presenilin-2; sAD, sporadic Alzheimers disease; sMRI,
structural magnetic resonance; SPs, senile plaques.
* Correspondence address: Institute of Neuropathology, Service of Pathology, University Hospital Bellvitge, carrer Feixa LLarga sn, 08907 Hospitalet de LLobregat, Spain.
Tel.: +34 93 2607452.
E-mail address: 8082ifa@gmail.com.

0301-0082/$ see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2012.03.005
 I. Ferrer / Progress in Neurobiology 97 (2012) 3851 39

10. The b-amyloid cascade in the pathogenesis of FAD and sAD, compelling or prodding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
11. Seeding b-amyloid and abnormal tau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
12. Concluding comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

1. Introduction on chromosome 21, the presenilin-1 (PSEN1) gene on chromosome

Alzheimer disease (AD) is a human age-related biological
process which causes progressive degeneration of the brain and
which is characterized clinically by cognitive impairment and
dementia, and neuropathologically by the variable combination of
two hallmarks, neurobrillary tangles (NFTs) and senile plaques
(SPs) (Duyckaerts and Dickson, 2003; Lowe et al., 2008). The
meaning of the term AD, rst described as a pre-senile dementia,
has changed over the years, now covering pre-senile dementia,
senile dementia, mild cognitive impairment and pre-clinical AD, all
of them within the context of AD-related pathology. However,
there is still heated controversy regarding normal aging with AD-
related pathology and AD.
2. Historical evolution of the concepts of AD and senile
dementia
The concept of AD has changed over the years mainly due to
social aspects as well as to scientic developments. The average
lifespan of human beings in Western countries rarely exceeded the
sixth decade at the end of the nineteenth century and during the
rst half of the twentieth. Individuals over 65 were considered old.
Mental disorders before this age were classied with terms such as
madness, neurasthenia, presbyophrenia and hysteria, and the
principal cause of dementia was progressive general paresis due to
tertiary syphilis. Mental impairment and dementia in older
persons was considered a phenomenon of senile dementia closely
associated with the process of aging and related to vascular
disease. The study of the brains of many of these old people showed
the presence of SPs and the term pure senile dementia was
therefore introduced (Klippel and Lhermitte, 1905). The descrip-
tion by Alois Alzheimer of a relatively young woman with
dementia and numerous SPs and new lesions in her brain
described as NFTs, as shown with silver stains, was the starting
point of pre-senile dementia of Alzheimers type or AD (Alzheimer,
1907, 19091910). Although neuropathological studies promptly
revealed that (pre-senile) AD and pure senile dementia shared the
same brain lesions, NFTs and SPs, the distinction between the two
conditions was based on the social assumption of what was
considered, at that time, to be old. Even in the 1960s, pre-senile
dementia or AD and pure senile dementia were considered as
separate entities (Delay and Brion, 1962). Not until the end of that
decade was a relationship established between NFTs, SPs and the
degree of dementia (Blessed et al., 1968).
Several years of debate and vast amounts of clinical, neuro-
pathological and genetic evidence were needed to bring about the
abandonment of this dualism in favor of the view that pre-senile
dementia of Alzheimers type and senile dementia with neuro-
pathological changes consisting of accumulations of NFTs and SPs
are the same disorder appearing at different ages.
3. Genetic and sporadic AD
Genetically determined AD is triggered by dominant genetic
factors as in Down syndrome (chromosome 21 trisomy) and in
familial cases with autosomal dominant inheritance (ADAD)
caused by mutations in the amyloid precursor protein (APP) gene
14, and the presenilin-2 (PSEN2) gene on chromosome 1 (Levy
et al., 1990; van Broeckhoven et al., 1990; Chartier-Harlin et al.,
1991; Sherrington et al., 1995; Hardy, 1997; Tanzi, 1999; Bateman
et al., 2011).
Sporadic AD (sAD) is favored by: (a) individual or combined low-
penetrating genetic factors linked to apolipoprotein allele e4
(ApoE4), a2-macroglobulin, low density lipoprotein protein recep-
tor 1 (both in chromosome 12), very low density lipoprotein R
(chromosome 9), interleukin 1a (chromosome 2), clusterin (chro-
mosome 8), phosphatidylinositol binding clathrin assembly protein
(PICALM, chromosome 11) and complement component (3b/4b)
receptor 1 (CR1, chromosome 1), among others (Corder et al., 1993;
Farrer et al., 1997; Marzolo and Bu, 2009; Bu, 2009; Harold et al.,
2009; Lambert et al., 2009; Seshadri et al., 2010; Jun et al., 2010;
Hollingworth et al., 2011); (b) environmental factors such as
repeated brain trauma (i.e. dementia pugilistica) (Constanza et al.,
2011); and (c) combined metabolic systemic factors such as
atherosclerosis and cardiovascular disease, elevated serum homo-
cysteine and hypercholesterolemia at midlife, and family history of
dementia (Qiu et al., 2005; Kivipelto and Solomon, 2006; Anstey
et al., 2008; Solomon et al., 2009; Reitz et al., 2011; Ballard et al.,
2011). Interestingly, genes involved in sAD are not linked to b-
amyloid but rather to cholesterol and lipid metabolism, the immune
system, and synaptic membranes (Jones et al., 2010; Morgan, 2011).
Moreover, epigenetic factors (differences in DNA methylation) may
mediate AD in monozygotic twins (Mastroeni et al., 2009). In
consequence, AD is a multifactorial, genetically complex and
heterogeneous disorder modulated by variegated non-genetic
factors (Bertram and Tanzi, 2003; Iqbal and Grundke-Iqbal, 2010).
Approximately 16% of cases are early-onset (under 65 years of
age: EOAD) and nearly 70% of these are associated with mutations
in APP, PSN1 or PSN2 these mutations being the major cause of
familial AD (FAD) (Bird, 2008). In contrast, late-onset AD (after 65
years of age: LOAD) is largely sporadic although 40% of LOAD
patients have at least one ApoE4 allele (Bu, 2009). These gures
represent AD cases with clinical manifestations of cognitive
impairment and dementia.
4. Neuropathological hallmarks and molecular pathology of
tau b-amyloid in AD
The rst electron microscopic studies revealed the structure of
b-amyloid deposition and the presence of surrounding dystrophic
neurites lled with altered mitochondria, residual bodies and
abnormal laments in SPs, together with disorganization of the
normal cytoskeleton and accumulation of paired helical laments
such as the subcellular substrates of NFTs (Kidd, 1964; Luse and
Smith, 1964; Terry et al., 1964; Nakano and Hirano, 1999).
Biochemical characterizations of the main alterations of SPs and
NFTs appeared in the 1980s, rmly demonstrating b-amyloid as
the main component of SPs and hyper-phosphorylated tau as the
main component of NFTs (Glenner and Wong, 1984a,b; Masters
et al., 1985; Grundke-Iqbal et al., 1986; Iqbal et al., 1986; Kang
et al., 1987; Goedert et al., 1988, 1989; Delacourte et al., 1999).
Hyper-phosphorylated 3R and 4R tau isoforms, resulting from
the imbalance between hyper-activation of kinases and reduced
activation of phosphatases, together with tau truncation resulting
40 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
from the activity of different proteases, and interactions of tau with
sulphated glycosaminoglycans, are the main alteration in NFTs
(Buee and Delacourte, 2001; Ferrer et al., 2005; Goedert et al.,
2006; Avila, 2006; Wang et al., 2007, 2010; Hanger et al., 2009;
Kovacech and Novak, 2010). Modications of different subunits of
the ubiquitinproteasome system and expression of mutant
ubiquitin are additional contributory factors to impaired NFT
degradation (van Leeuwen et al., 1998; Keller et al., 2000; Cecarini
et al., 2007; Oddo, 2008; McMillan et al., 2011).
SPs are composed of variable species of b-amyloid forming: (a)
diffuse plaques accompanied with punctate alterations of neuronal
processes, and (b) neuritic plaques with a central core of b-amyloid
and a peripheral crown of dystrophic neurites lled with hyper-
phosphorylated tau, altered mitochondria and other cellular
debris. In addition, b-amyloid angiopathgy (i.e. b-amyloid
deposition in the blood vessel walls) is a common accompanying
alteration in AD (Goedert, 1996; Duyckaerts and Dickson, 2003;
Masters and Beyreuther, 2003; Lowe et al., 2008; Shepherd et al.,
2009; Markesbery, 2010; Serrano-Pozo et al., 2011).
b-amyloid deposits result from the proteolytic cleavage of the
APP precursor by b-secretases (BACEs) and g-secretases which
consist of a complex in which presenilins are one of their
components. b-amyloid is composed of several cleaved products,
mainly b-amyloid140 and b-amyloid142, which are the principal
elements of brillar b-amyloid in SPs (Hardy, 2006). Additionally,
nepresylin and insulin-degrading enzyme do not withstand
degradation of b-amyloid; and transport of b-amyloid bound to
low-density protein receptor and receptor for advanced glycation
end-products required to pass across the blood brain barrier is
partially blocked in AD, thus favoring accumulation of soluble and
insoluble b-amyloid species in brain (Deane and Zlokovic, 2007;
Jaeger and Pietrzik, 2008; Weller et al., 2008; Tseng et al., 2008; Utter
et al., 2008; Schmidt et al., 2009; Alvira-Botero and Carro, 2010;
Hawkes et al., 2011; Chalbot et al., 2011).
However, the links between b-amyloid and tau hyper-
phosphorylation are not completely understood (Small and Duff,
2008; Oddo et al., 2008; Takashima, 2009).
In addition to these basic mechanisms involved in NFTs and b-
amyloid deposition, mounting evidence points toward soluble b-
amyloid oligomers rather than brillar b-amyloid in plaques as
being causative of neurodegeneration (McLean et al., 1999; Glabe
and Kayed, 2006; Deshpande et al., 2006; Shankar et al., 2008; van
Helmond et al., 2010; Ono and Yamada, 2011). Similarly, truncated
tau appears to be toxic to neurons (Fasulo et al., 2000; Chung et al.,
2001; Gomez-Ramos et al., 2006; Filipcik et al., 2009; Lasagna-
Reeves et al., 2010; Zilkova et al., 2011).
5. Multi-functional subcellular failure in AD
Mitochondria are abnormal and dysfunctional in AD (Kidd, 1964;
Luse and Smith, 1964; Terry et al., 1964; Kish et al., 1992; Mutisya
et al., 1994; Hirai et al., 2001; Tsuji et al., 2005; Hauptmann et al.,
2006; Kim et al., 2000; Perez-Gracia et al., 2008; Moreira et al., 2007;
Coskun et al., 2011). This may result in increased oxidative stress and
damage to different molecules including nucleic acids, proteins and
lipids (Pamplona and Barja, 2007; Starkov, 2008).
b-amyloid deposition is also causative of oxidative stress (Boyd-
Kimball et al., 2005a,b; De Felice et al., 2007; Wan et al., 2011), and b-
amyloid inhibits integrated mitochondrial respiration and key
enzyme activities (Casley et al., 2002 Crouch et al., 2005). Resulting
from the cumulative effect of diverse events, increased oxidative
stress is key in the pathogenesis of AD and is the principal cause of
damage to quite a variety of substrates including mitochondrial and
energy metabolism-related proteins (Buttereld et al., 2002;
Castegna et al., 2002a,b; Choi et al., 2004, 2005; Pamplona et al.,
2005; Korolainen et al., 2006; Sultana et al., 2006, 2009; Reed et al.,
2008; Sultana and Buttereld, 2009, 2010; Terni et al., 2010).
Neuronal exhaustion is the term used for the delicate metabolic
condition resulting from the convergence of detrimental energy
production, increased oxidative damage, impaired glycolysis and
increased energy demands in AD (Ferrer, 2009). It is worth
emphasizing that altered mitochondrial function appears early in
time in AD (Terni et al., 2010), and that it precedes Alzheimer
pathology in mouse models of AD (Yao et al., 2009; Du et al., 2010).
In addition to energetic failure, other molecular pathways fail in
AD. Lipid composition of cell membranes and most particularly of
lipid rafts is modied when compared with aged-matched controls
(Pamplona et al., 2005; Martn et al., 2010; Chan et al., 2012);
alteration of lipid raft composition implies increased viscosity and
greater difculty in molecular trafc (Martn et al., 2010).
Endoplasmic reticulum stress and impairment of responses to
protein misfolding has also been demonstrated in AD (Hoozemans
et al., 2009; Salminen et al., 2009; Lee et al., 2010; Kaneko et al.,
2010). Mechanisms geared to getting rid of altered proteins and
organelles, including autophagy, are impaired in AD (Cataldo et al.,
1991; Yu et al., 2005; Nixon et al., 2005; Barrachina et al., 2006;
Cecarini et al., 2007). Impaired removal of altered proteins is
already manifested in the rst NFT, as hyper-phospohorylated,
abnormally conformed, and truncated, ubiquitinated tau species
are resistant to degradation by the ubiquitinproteasome system.
6. Involvement of synapses, multiple neuronal types and
systems in AD
Synapses are damaged in AD, resulting in a major cause of
cognitive impairment (Gonatas et al., 1967; Terry et al., 1991;
Selkoe, 2002; Arendt, 2003; Bloss et al., 2011). The mechanisms of
synaptic alteration are not fully understood but several observa-
tions have provided important pieces of information. On the one
hand, b-amyloid proto-brils are synaptotoxic (ONuallain et al.,
2010), b-amyloid impairs anterograde transport of mitochondria
and degenerates synapses in vitro (Calkins and Reddy, 2011), and
b-amyloid immunoreactivity has been detected in mitochondria in
AD (Lustbader et al., 2004; Caspersen et al., 2005; Gouras et al.,
2010). This is further supported by functional studies showing that
b-amyloid deposition is associated with default activity (Buckner
et al., 2005; Sperling et al., 2009). On the other hand, hyper-
phosphorylated tau and hyper-phosphorylated a-synuclein accu-
mulate at the synapses (Muntane et al., 2008) involving more
sophisticated alterations in combination with b-amyloid and
mitochondrial deviations connected with synaptic dysfunction.
Several cell types are vulnerable to AD including nuclei of the
brain stem such as raphe nuclei, reticular formation, locus
ceruleus, substantia nigra; amygdala; nucleus basalis of Meynert;
striatum; thalamus; hypothalamus; and claustrum, in addition to
the selective regional and laminar vulnerability of the cerebral
cortex. Different neuronal types are affected in the various regions
as revealed by several neurotransmitter, neuromodulator, neuro-
peptide, and calcium-binding protein markers. Even the cerebellar
cortex is compromised at advanced stages of the disease. Neuron
loss and cerebral atrophy are the aftermath of the degenerative
process (Hof, 2001; Vogt et al., 2001; Duyckaerts and Dickson,
2003; Lowe et al., 2008). In short, AD may be categorized as a
multi-systemic degenerative process.
Not only neurons, but also astrocytes, oligodendroglia, microglia,
blood vessels and choroid plexus are involved in disease progression.
7. Categorization of changes in the nervous system attributable
to aging
Common characteristics of the central nervous system with
aging in distinct mammalian species, including humans, involve
 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
the progressive accumulation of lipofuscin granules in the
cytoplasm of neurons and glial cells; mitochondrial alterations
(covering alterations in size and deletions in mitochondrial DNA);
increased oxidative stress and oxidative and nitrosative damage of
lipids, proteins, DNA and RNA; loss of neurons in specic regions of
the nervous system; reduced dendritic arbours and reduced post-
synaptic sites particularly in the cerebral cortex; and axonal
degeneration with axon loss (Morrison and Hof, 1997; Peters,
1999; Sandell and Peters, 2001, 2003; Hof and Morrison, 2004;
Peters et al., 2008, 2010; Kabaso et al., 2009; Bowley et al., 2010;
Dumitriu et al., 2010; Pannesse, 2011). Some of these alterations
occur in parallel with cognitive decline in rhesus monkey (Moss
et al., 1999).
In addition, b-amyloid deposits come up in old individuals in
several (but not all) species including dolphins and other cetacean,
non-human primates such as Microcebus murinus, Macaca mulatta
and Macaca arctioides, Chlorocebus aethiops, dogs and bears, among
others (Head, 2011; Mutsuga et al., 2012; Finch and Austad, 2012;
Languille et al., 2012). Phospho-tau deposits surrounding b-
amyloid plaques are common but NFTs are rare in species other
than humans (Price et al., 1991; Morelli et al., 1996; Toledano et al.,
2011). Yet protein tau accumulates in the cerebral cortex, but
lesser in the hippocampus, in a few vulnerable aged mouse lemur,
M. murinus (Giannakopoulos et al., 1997). Importantly, transcrip-
tome differences can be distinguished during brain aging from AD-
like pathology in this species (Abdel Rassoul et al., 2010). These
observations indicate that AD pathology is associated with aging
but AD pathology is not brain aging in M. murinus as only a small
percentage of old animals have AD-like pathology. Intracellular
phospho-tau lamentous inclusions occur in nerve cells, astrocytes
and oligodendrocytes of aged baboons (Schultz et al., 2000b) and
tau pathology increases with age in these primates (Schultz et al.,
2000a). Whether these changes in non-human primates are related
to normal aging or to AD is difcult to ascertain. Old C. aethiops have
abundant AD-related pathology in their brains although these
changes are not clearly accompanied by impaired cognitive
function, at least as may be determined by our current study
methods, thus suggesting that certain non-human primates may
have extensive AD-related pathology without dementia of
Alzheimer type. However, cognitive decline in old dogs correlates
with increased b-amyloid deposition and tau phosphorylation at
Ser396 in the parietal cortex and dorsal part of the hippocampus
(Yu et al., 2011). In short, although AD-related pathology occurs in
some aged mammals, it is far from clear the impact of such lesions
in cognitive performances and behavior. Moreover, lack of a
denitive categorization of dementia in non-human species
ignores the possibility of AD and has prejudged the presence of
SPs and phospho-tau deposits in neurons in these species as
normal aging.
Neuropsychological studies have demonstrated that loss of
recent memory, explicit and implicit secondary memories,
language, and sustained attention occurs with age in humans;
these changes are currently interpreted as a result of normal aging
(Coubard et al., 2011). Clinical studies have assumed that cognitive
decline does not occur before the age of 60 (Hedden and Gabrieli,
2004). However, recent work carried out on the Whitehall II cohort
of British civil servants of both sexes followed during 10 years has
demonstrated a 3.6% cognitive decline in men aged 4549 and
9.6% in those aged 6570, whereas the corresponding decline was
3.6% in women aged 4549 and 7.4% in women aged 6570,
probably increasing to 11.4% when considering cross sectional
effects (Singh-Manoux et al., 2011).
Some papers have highlighted a link between normal aging and
AD-related changes particularly in relation with b-amyloid
deposition in temporal cortex (Mormino et al., 2009; Rentz
et al., 2010) and with cortical thinning in clinically normal elderly
41
(Becker et al., 2011). However, the implication of these changes,
and the frontier between normal aging and abnormal aging
(mostly in the case of AD) have been and still are the subject of an
on-going debate that has lasted decades.
Another important point is the increased prevalence and
incidence of other pathologies of the human central nervous
system with aging, most of them potentially causative of cognitive
impairment. The old term mixed dementia, indicating a
combination of AD and vascular pathology leading to dementia
(Delay and Brion, 1962), is still valid (Vinters et al., 2000; Grinberg
and Thal, 2010), although the attribution of clinical manifestations
to each of the two pathologies is a matter for frequent discussion.
In addition, other degenerative diseases are common in old age,
such as Lewy body diseases, argyrophilic grain disease, mesial
sclerosis and pathology of TAR DNA binding protein (TDP)-43 (Ince
et al., 1998; Ince, 2001; Uchikado et al., 2006; Amador-Ortiz et al.,
2007; Ferrer et al., 2008; Zarow et al., 2008; Wilson et al., 2011).
Studies of large neuropathologically examined series in general
hospitals have demonstrated that combined neurodegenerative/
vascular pathologies, rather than single entities, are prevalent in
old age (Kovacs et al., 2008; White, 2009). A fascinating aspect is
that these combinations are not the result of mere accumulation
related to age, but rather they have a promoting or facilitating
effect upon each other. Although it would be worth writing a bit
more on this subject, a detailed description of this scenario is
beyond the scope of the present review.
8. Discrimination of normal brain aging from AD-related
pathology and AD
Several classications are based on the assumption that only a
certain number of plaques at a particular age and determinate
regions indicate AD, whereas the same number of lesions in older
individuals does not. Khachaturian and CERAD (Consortium to
Establish a Registry of Alzheimers Disease) codications are based
on the quantication of plaques by using silver or amyloid stains
(Khachaturian) or dystrophic neurites using Bielchowsky stains
(CERAD) in selected cortical regions (Kachaturian, 1985; Mirra
et al., 1991, 1994). The number of lesions depending on the age of
the patient serves to make the diagnosis of AD. Beyond the
difculty in staining and interpreting Bielchowsky stains (Alafuzoff
et al., 2008), Khachaturian and CERAD classications are not
instrumental approaches to classifying AD but rather tenets to
discriminate AD from normal aging with SPs. Moreover, these
categorizations are sustained on a problematic basis as the number
of SPs barely correlates with neurological decits whereas
dementia is more closely associated with NFTs, synaptic loss
and nerve cell loss in the cerebral cortex (Bierer et al., 1995;
Masliah and Salmon, 1999; Hof et al., 1999). These classications
have for years permeated the notion that AD is a different
condition from normal aging with SPs.
Other studies have stressed that, albeit a heterogeneous pattern
of SPs, NFTs in non-demented old people are consistently present
among individuals in the entorhinal cortex, CA1 region of the
hippocampus, and, less often, the temporal and frontal cortex
(Braak and Braak, 1991; Bussiere and Hof, 2001). These changes in
individuals with no concurrent major cognitive disability have
been largely categorized as being related to normal aging (Hof
et al., 1999).
Regardless of the clinical threshold between normal aging and
AD, it is clear that the type of lesionsNFTs and SPsand the
regional vulnerability are similar in the group of individuals who
present SPs and NFTs with aging and cases with dementia with AD-
related pathology, apart from the order of magnitude and extent of
such lesions, which are markedly greater in cases with dementia
(Arriagada et al., 1992; Morris et al., 1996; Hof et al., 1999).
42 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
A signicant advance was brought about after the study of post-
mortem aged brains by using silver methods (Braak and Braak, 1991,
1999). Systematic anatomical study of cases with AD-related
pathology has prompted a staging classication of sAD. Stages I
and II are dened by the presence of NFTs in the entorhinal cortex
(stage I) and progression to the transentorhinal cortex and mild
involvement of the CA1 region (stage II). Limbic stages III and IV
implicate the presence of NFTs in the upper and inner layers of the
entorhinal cortex, transentorhinal cortex, CA1 region of the
hippocampus, subiculum, anterodorsal thalamic nucleus, amygdala,
magnocellular nuclei of the basal forebrain (including Meynert
nucleus), tubero-mammillary nucleus (stage III), plus associated
areas of the temporal cortex, striatal neurons, raphe nucleus and
locus ceruleus (stage IV). Neocortical stages V and VI require, in
addition, NFTs in cortical association areas, claustrum, reticular
nucleus of the thalamus and substantia nigra (stage V), plus primary
sensory areas (stage VI). Similarly, SP burden and distribution allows
the classication of SP pathology into stages A (basal neocortex
including orbitary and temporal cortices), B (isocortical involvement
covering associated cortices) and C (involving in addition the
primary cortical areas). Further renements have been made with
immunohistochemistry, thus permitting a harmonization of stain-
ing in different laboratories (Braak et al., 2006a,b). Neuropathologi-
cal inquiries have also given rise to more sophisticated
classications of b-amyloid pathology in relation to SPs and b-
amyloid angiopathy (Thal et al., 2002). Phases of b-amyloid
deposition are classied as phase I: neocortex; phase 2: plus
allocortical brain regions; phase 3: plus diencephalic nuclei,
striatum, cholinergic nuclei of the basal forebrain; phase 4: plus
nuclei of the brain stem; phase 5: plus cerebellar deposition.
Stages of AD-related pathology have supported a hypothesis of
AD progression based on the putative sequence of NFT pathology
from entorhinal and transentorhinal cortex, to the hippocampus
and limbic brain, and eventually to the entire cerebral cortex.
Similarly, amyloid plaques are suggested as spreading from the
orbitary and temporal cortices to the entire brain, and nally to the
cerebellum. These seminal observations are the primordium of the
concept that AD develops from the rst tangle or amyloid plaque in
particular regions of the cerebral cortex (Ohm et al., 1995).
No similar studies have been carried out in individuals carrying
APP, PSN1 and PSN2 mutations, and we therefore have very little
information with which to formulate a tenable staging of AD-
related pathology in ADAD (Klunk et al., 2007). However, AD-
related pathology in Down syndrome is rst manifested with
widespread distribution of b-amyloid deposits, followed by NFTs
(Mann and Esiri, 1989; Leverenz and Raskind, 1998). In the same
line, b-amyloid plaques precede the appearance of NFTs in some
transgenic mice bearing mutations in APP-related proteins and
mutations in MAPT, the gene encoding protein tau (Oldo et al.,
2003; Perez et al., 2005; Ribe et al., 2005). Although limited,
available data suggest that chronology of SPs and NFTs may differ
in sAD and, at least some genetic AD and certain AD-related
models. Yet bigenic mice resulting from the crossing of PDAPP
transgenic mice carrying the APP V717F mutation driven by the
PDGF promoter with PS19 transgenic mice harbouring the P301S
mutation in MAPT routed by the prion protein promoter rst
manifest tau pathology following a pattern similar to that seen in
single PS19 transgenic mice, reminiscent of Braak staging in
humans (Hurtado et al., 2010).
Post-mortem neuropathological studies of neurologically exam-
ined cases have shown that manifestations of neurological
impairment as early memory decits and mild cognitive im-
pairment occur at stages III and IV of Braak, whereas dementia does
not appear until stage V and, more precisely, stage VI, at the time
when the brain is lled with NFTs and SPs (Braak et al., 2006a,b; Price
et al., 2009; Markesbery, 2010). However, the presence of abundant
AD-related changes does not always match with severe neurological
decits (Erten-Lyons et al., 2009; Nelson et al., 2009; Abner et al.,
2011; SantaCruz et al., 2011). Further studies are also needed to
elucidate the neuropathological and molecular correlates of
different types of dementia in AD cases (Murray et al., 2011).
The present distinction between AD (once accepted as a unique
disease) and normal aging accompanied by variable numbers of
SPs and NFTs (AD-related pathology) is circular and dependent on
the arbitrary number and extent of NFTs and SPs based on
statistical measures of what is considered normal mental
performance according to typical forms and frequencies of a
socially established behavior.
Recent proposals aimed at facilitating the neuropathological
assessment of AD recommend the selection of certain areas and
staining of sections to cover AD-related changes and concomitant
pathologies such as vascular disease, Lewy body diseases, TDP-43
inclusions, and mesial sclerosis as well (Montine et al., 2012). Yet
the ABC score suggested for AD neuropathological classication
has added little of value to previous instrumental classications
intended to substantially increase our understanding of AD.
9. AD, mild cognitive impairment, pre-clinical AD and
biomarkers
The National Institute of Neurological and Communicative
Disorders Association (NINCDS-ADRDA) criteria of 1984 (McKhann
et al., 1984) were revised in 2007 by the International Working
Group for New Research Criteria for the Diagnosis of Alzheimers
disease (Dubois et al., 2007). Subsequently, improvements
appeared as a result of annual meetings and workshops. In
contrast to NINCDS-ADRDA criteria which determined the
diagnosis of AD as probable, possible and denitive, this last
category requiring neuropathological examination of the brain, the
new criteria are mostly based on clinical, laboratory, and
neuroimaging methods (Dubois et al., 2010).
Currently, the term biomarker is used to designate variegated
signs derived from clinical probes, biochemical data and neurora-
diological techniques, formerly considered as complementary or
ancillary examinations to characterize a particular disease. Several
biomarkers are currently available for the clinical diagnosis of
dementia of Alzheimer type covering skill decrement and
degraded responses in several neuropsychological tests, reduced
levels of b-amyloid and increased ratio of phospho-tau/tau in the
CSF, increasing atrophy of certain cerebral regions such as the
hippocampus and amygdala revealed by structural magnetic
resonance imaging (sMRI) or computerized tomography, and
increased positron emission tomography (PET) signals of abnor-
mally accumulated proteins in the brain such as b-amyloid and
tau, as well as reduced glucose consumption (Jack et al., 2008;
Morris et al., 2009; Mueller et al., 2010; Vemuri et al., 2010; Dubois
et al., 2010; Jack et al., 2011a,b).
Unveiling the ordered appearance of the different biomarkers,
combining the appropriate use of several known biomarkers, and
discovering and applying new biomarkers may help at identifying
early stages of AD even before the appearance of clinical symptoms
(Jack et al., 2010; Hu et al., 2010).
Rened recommendations to diagnose dementia and mild
cognitive impairment due to AD and pre-clinical stages of AD have
recently been the objective of several guidelines published under
the patronage of the National Institute on AgingAlzheimers
Association (Jack et al., 2011a,b; Albert et al., 2011; McKhann et al.,
2011; Sperling et al., 2011). Identication of pre-clinical stages of
AD is relevant, although there is no full agreement among different
proposals. Staging categories of pre-clinical AD proposed by the
National Institute on Aging and the Alzheimers Association
Workgroup cover stage 1, described as asymptomatic cerebral
 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
amyloidosis (altered b-amyloid by PET or in the CSF); stage 2,
characterized as asymptomatic amyloidosis plus markers of
neurodegeneration (as revealed by sMRI, 18-uorodeoxyglucose
PET and altered tau/phospho-tau ratio in the CSF); and stage 3,
combining markers of amyloidosis, markers of neurodegeneration
plus subtle cognitive and behavioral decline (Sperling et al., 2011).
The new lexicon proposed by the International Working Group
for New Research Criteria for the Diagnosis of Alzheimers disease
incorporates AD (typical and atypical); pre-dementia stage of AD
(prodromal AD); and pre-clinical states of AD, grouping asymp-
tomatic at-risk state for AD (similar to pre-clinical stage 2 of the
previous proposal) and pre-symptomatic AD (carriers of mono-
genic forms of ADAD) (Dubois et al., 2010).
These clinical proposals are innovative tools that clearly
identify AD as a continuum of alterations that may lead from
mild or moderate cognitive impairment as a prodromal stage to
dementia of Alzheimer type. Moreover, these criteria also advance
the possibility of considering AD even in the absence of apparent
clinical symptoms but in the presence of positive biomarkers. In
short, the focus of biomarker research at present is not only the
identication of AD the disease but also the identication of
individuals at risk of suffering dementia of Alzheimer type.
Unfortunately, available biomarkers are still too uneven and not
precise enough to detect subtle alterations. Available biomarkers,
other than genetic tests related to ADAD, are capable of visualizing
large accumulations of certain altered proteins such as b-amyloid,
focal atrophy involving severe loss of neurons and connections,
and disturbed proportions of altered proteins discharged in the
CSF. Yet altered composition of proteins in CSF follows massive
neuronal damage as for tau or retained in the brain as a
consequence of severe impairment of b-amyloid clearance in
the blood vessel wall and CSF barriers. The available biomarkers
unfortunately do not detect the process at early stages in
neuropathological terms.
The application of biomarkers to the diagnosis of AD (excepting
gene study in ADAD) is, at present, a procedure giving witness to
the pace of progression of the degenerative process rather than a
system allowing the detection of the rst stages of such process in a
particular individual. Moreover, the ordering pattern or sequence
of positive biomarkers does not reect the real sequence of events
in sAD as revealed in post-mortem neuropathological studies. The
rst biomarker of AD identies accumulation of b-amyloid plaques
and abnormal clearance of b-amyloid in the CSF, and this is
followed by altered ratio of tau/phospho-tau in the CSF (Dubois
et al., 2010; Jack et al., 2010; Sperling et al., 2011; Ossenkoppele
et al., 2011). However, the rst pathological changes in cases with
sAD-related pathology are characterized by NFTs while b-amyloid
plaques appear later. The hierarchical ordering of current
biomarkers further reinforces the misconception that plaque
formation precedes NFT formation in sAD.
The major criticism of biomarker research is that present
clinical approaches bias the recognition of AD as a biological
process in which the majority of persons will not develop an illness
in the sense that this process may have no major impact on the
current life of the individual.
AD-related pathology, at least limited to the entorrhinal and
transentorrhinal cortices (stages III), is found in about 7080% of
neuropathologically assessed post-mortem individuals aged 65
years belonging to a non-biased general population and dying as a
result of various non-neurologically related conditions. These
values increase to about 90% in individuals aged 80 years but then
remain steady in centenarians (Braak and Braak, 1997; Braak et al.,
2011). It is worth recalling that the prevalence of dementia in AD is
approximately 1 per 100 persons between 65 and 69 years of age,
and between 25 and 50 per 100 individuals over the age of 85. The
speed of progression of AD-related pathology in relation with NFTs
43
has been estimated after the sequential study of a series of cases of
AD-related pathology; it takes about 14 years from stage II to stage
III, 13 years from stages III to IV but 5 years from stages IV to V
(Ohm et al., 1995). This means that the biological process starts at
middle age, develops slowly during the rst stages and then
progresses more rapidly at advanced stages. Individual differences
in the progression and severity of the process are not commensu-
rate to maintain the pervasive opinion that the origin of AD-related
pathology at stages I, II and III differs from the origin of AD-related
pathology stages IV, V and VI.
Moreover, it has been claimed that the multifaceted nature of
the altered neuronal function and neuronal connections in mild
cognitive impairment due to AD suggests that there is no single
event which precipitates this prodromal stage of AD (Mufson et al.,
2012).
10. The b-amyloid cascade in the pathogenesis of FAD and sAD,
compelling or prodding
The discovery that FAD is linked to mutations in APP and in other
genes encoding proteins involved in the cleavage of APP and the
production of b-amyloid, and to duplications in the genetic loading
of APP (St George-Hyslop et al., 1987; Hardy, 1997; Tanzi, 1999;
Sleegers et al., 2006; Cabrejo et al., 2006; Brouwers et al., 2006;
Bateman et al., 2011), prompted the hypothesis of the b-amyloid
cascade as the origin of AD (Hardy and Higgins, 1992; Hardy and
Selkoe, 2002, Tanzi and Bertram, 2005; Hardy, 2009). This was
supported by the fact that transgenic mice expressing mutations in
APP present b-amyloid plaques with hyper-phosphorylated tau
deposition in surrounding dystrophic neurites but not accompanied
by NFTs in their brains (Games et al., 1995; Hsiao et al., 1996;
Sturchler-Pierrat et al., 1997; Borchelt et al., 1997; Puig et al., 2004;
McGowan et al., 2006; Gotz and Ilttner, 2008; Woodruff-Pak, 2008;
Aso et al., 2011). In contrast, individuals with mutations in MAPT
develop another type of dementia accompanied by neuronal and
glial hyper-phosphorylated 4R tau inclusions but not accompanied
by SPs (Munoz and Ferrer, 2008; Dickson et al., 2011). Moreover,
transgenic mice bearing tau mutations do not reproduce the
presence of b-amyloid plaques but accumulate hyper-phosphory-
lated tau in neurons (Zhang et al., 2004; Gotz and Ilttner, 2008).
Therefore, mutations in APP-related genes give rise to incomplete
AD lacking NFTs while mutations in MAPT give rise to a tauopathy.
Generation of mice bearing both SPs and NFTs is only accomplished
following the co-expression of mutant APP together with mutant or
altered tau (Lewis et al., 2001; Oldo et al., 2003; Perez et al., 2005;
Ribe et al., 2005; Hurtado et al., 2010).
Although valid in FAD, the strict interpretation of the b-amyloid
cascade hypothesis does not completely t with the morphological
neuropathology of early stages in sAD. AD-related pathology in
sAD is rst manifested in the form of NFTs whereas it is important
to recall that no SPs are normally encountered at the rst stages of
sAD-related pathology (Braak and Braak, 1991, 1997, 1999; Braak
et al., 2011; Schonheit et al., 2004). Moreover, the distribution of
SPs at early stages of AD-related pathology does not t with the
localization of NFTs (Braak et al., 2011).
Whether b-amyloid oligomers are present years before the
appearance of tau pathology in sAD and trigger the rst alterations
in tau is not known at present. This does not rule out the possibility
that b-amyloid might accelerate tau pathology in different animal
models, and in sAD. Indeed, NFT pathology is enhanced in
transgenic mice expressing mutant tau and APP (Lewis et al.,
2001). Similarly, tau pathology is accelerated in bigenic mice
crossing PDAPP and PS19, but tau pathology does not alter b-
amyloid plaques when comparing bigenic mice with single
transgenic counterparts (Hurtado et al., 2010). These results are
in line with studies showing that b-amyloid oligomers can induce
44 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
tau phosphorylation in a mouse model (Tomiyama et al., 2010).
Consequently, these observations support the concept that b-
amyloid fuels tauopathy in sAD (Masters and Beyreuther, 2006;
Delacourte, 2006).
11. Seeding b-amyloid and abnormal tau
Recent studies have shown that b-amyloid deposition can be
stimulated by b-amyloid under certain conditions in vivo. Thus
plaque formation is accelerated in transgenic mice bearing FAD
mutations following the intracerebral injection of diluted extracts
from AD brains or from old AD transgenic mice (Walker et al., 2002;
Meyer-Luehmann et al., 2006; Walker et al., 2006). Similar results
are found following peripheral inoculation of these b-amyloid
seeds (Eisele et al., 2010).
Transgenic rats over-expressing human APP (APP21 line) do not
develop b-amyloid plaques at any point in their lifespan, but SPs and
b-amyloid angiopathy are seen in the same rats at nine months
following intra-hippocampal injection of diluted AD extracts
containing aggregated b-amyloid (Rosen et al., 2012). Similar
observations have been reported in transgenic mice over-expressing
APP, which also do not develop b-amyloid plaques during their life
span, following intra-hipocampal injection of diluted AD extracts
(Morales et al., 2011). Plaques not only develop locally but extend as
well to the cerebral cortex at a distance from the injection. These
ndings support the possibility that once the rst b-amyloid
deposits appear they may accelerate the accumulation of additional
seeding in other parts of the brain, thus contributing to the
exponential deposition of b-amyloid. Interestingly, soluble forms of
b-amyloid are particularly effective at inducing plaque formation
(Langer et al., 2011). Additional studies have established that
presence of b-amyloid seeds, and not the age of the host per se, is
critical to the initiation of b-amyloid aggregation in brain, while b-
amyloid deposition, actuated in a brain area, eventually spreads
throughout the brain (Hamaguchi et al., 2012).
These observations may apply not only to genetic-prone cases
with over-expression of APP, such as patients with Down
syndrome and with duplications in the APP locus or altered
regulatory sequences in the APP promoter region (Sleegers et al.,
2006; Cabrejo et al., 2006; Brouwers et al., 2006), but may also be
considered contributory factors in sAD.
In addition, injection of brain extract from mutant P301S tau-
expressing mice into the brain of transgenic wild-type tau-
expressing animals induces assembly of wild-type human tau into
laments and the spread of the pathology from the site of injection
to neighbouring brain regions (Clavaguera et al., 2009). In the same
line, in vitro models have also shown that introduction of small
quantities of misfolded preformed tau brils into tau-expressing
cells recruits soluble tau into lamentous inclusions reminiscent of
NFTs (Guo and Lee, 2011). Moreover, seeding differs in 3R and 4R
tau (Dinkel et al., 2011).
These observations have important consequences as they imply
that seeding and spreading of b-amyloid plaques and altered tau
species may occur, under appropriate conditions, at a cellular level
in a similar way as occurs in prion diseases under appropriate
conditions (Frost and Diamond, 2010; Aguzzi and OConnor, 2010;
Goedert et al., 2010; Jucker and Walker, 2011).
12. Concluding comments
The presence of NFTs in the inner regions of the temporal cortex
in the absence of clinical symptoms in aged individuals has been
largely considered as normal aging.
Yet these rst lesions are present in the majority of people over
65 years of age and 100% of AD cases have entorhinal and
transentorhinal pathology.
It has been largely defended that NFTs, as revealed with silver
stains, can be encountered in different conditions, but 3R/4R-tau
NFTs are practically exclusive of AD, excepting rare familial
prionopathies and a limited number of familial tauopathies due to
MAPT mutations (Munoz and Ferrer, 2008; Alzualde et al., 2010).
Moreover, 3R/4R-tau NFTs not accompanied by glial tau inclusions
and not accompanied by PrP amyloid deposition are restricted to
AD-related pathology.
The occurrence of certain numbers of NFTs in particular regions
in most people means that this process is common but not
necessarily normal. Moreover, normal aging does not exclude the
circumstance of a concomitant putative age-dependent degenera-
tive process. The fact that we cannot at present identify the clinical
consequences of NFTs in the inner temporal lobe, corresponding to
early stages of AD-related pathology (Knopman et al., 2003; Price
and Morris, 1999; Jack et al., 2010), does not mean that we should
overlook NFT lesions in these regions as a part of the AD spectrum.
Furthermore, we do not have fair criteria to consider the well-
known memory and other cognitive decits in most individuals at
pre-senile ages not resulting from AD-related alterations in the
inner temporal cortex.
Recent observations have shown the appearance of NFTs in the
dorsal raphe nucleus and locus coeruleus in the absence of cortical
tangles in young individuals (Rub et al., 2000; Grinberg et al., 2009;
Simic et al., 2009; Braak et al., 2011), suggesting that early AD-
related lesions start in the brain stem. Whether these lesions may
explain pre-cognitive decits related to AD-related pathology such
as disturbances in mood, emotion and sleep, and confusion,
depression and others already reported years before the diagnosis
of AD deserves attention (Jost and Grossberg, 1996).
One of the major setbacks to acceptance of the spectrum of AD-
related pathology as AD is the term disease which implies some
disability or disturbing health problem according to the WHO. It is
clear that cases with AD-related pathology restricted to the
entorhinal cortex, transentorhinal cortex and limited parts of the
CA1 region may not suffer AD as a disease per se. Moreover, most of
these individuals probably would have never developed signicant
cognitive impairment or dementia. Nevertheless, they are indeed
experiencing a degenerative process within the spectrum of AD.
Similarly, the spectrum or atherosclerosis covers the presence of
isolated plaques of lipid deposition in the walls of arteries and
ischemic complications linked with occlusion of arterial blood
vessels. It would hardly be acceptable to speak of normal aging in
the presence of a certain number of arterial plaques whilst
reserving the term atherosclerosis exclusively for the moment
when the arteries are clogged with fatty deposits and the process is
manifested as infarction.
One possibility for circumventing the implications of the use
disease when dealing with AD-related pathology would be to use
the common term Alzheimer (or alzheimer) at the same level that
we use the term atherosclerosis.
Under this thinking, Alzheimer is then considered an age-
related biological process in certain mammals, mainly in non-
human primates and particularly in humans, which causes
progressive degeneration of the brain neuropathologically charac-
terized by the variable combination of the neuropathological
hallmarks NFTs and SPS, and which may cause neurological
symptoms principally manifested as cognitive impairment and
dementia. This term covers early stages of AD-related pathology
with presently unavailable clinical and biomarker data, cases with
altered biomarkers without clinical signs, and cases with early or
advanced stages of mental deterioration and cognitive im-
pairment.
It may be argued that Alois Alzheimer described a disease
whereas Alzheimer may be or may not be manifested as disease. It
is worth recalling that, in a pure sense, Alois Alzheimer described
 I. Ferrer / Progress in Neurobiology 97 (2012) 3851
the terminal stage of a pre-senile dementia that was considered for
years to be different from senile dementia with AD-related
pathology. Moreover, cognitive impairment with AD-related
pathology was never envisaged by Alois Alzheimer as a prodromal
stage of pre-senile or senile dementia.
In addition to clarifying the concept of the full spectrum of AD-
related pathology, the term Alzheimer will have two important
implications. One of them is to center attention on the origin of
Alzheimer in the very early stages of AD-related pathology because
tau pathology and later b-amyloid pathology are already present
on a small scale during these rst stages. In addition, the
hypothesis of seeding, if proved to be true in humans, implies a
progression of the disease once the rst extracellular deposition of
b-amyloid brils or the intracellular accumulation of truncated tau
is initiated. The b-amyloid cascade hypothesis further supports
self-recruitment of lesions. Based on these observations, thera-
peutic strategies should be shifted, in part, to halting early changes
in addition to focusing on the middle and late stages of the process.
It must be stressed that the proposed term Alzheimer is not
synonymous with Alzheimer disease or Alzheimer dementia,
which must be contemplated in a clinical setting. Rather,
Alzheimer comprises molecular, morphological and accompanying
neuronal dysfunctions that can lead, or not, to the progression of
neurological decits. It is true, at present, that the main hallmarks
of Alzheimer are the morphological alterations NFTs and SPs, but it
may be advanced that these alterations occur in a very complex
and still poorly understood metabolic and molecular background,
including mitochondrial dysfunction and altered lipids in cellular
membranes. More precisely, NFTs and SPS can be considered as by-
products or residual products resulting from intricate processes
covering altered formation and inefcient removal of different
proteins in particular molecular and metabolic settings. Therefore,
it can be envisaged that combinations of various at risk genome/
transcriptome/proteome/lipidome/metabolomes, which make up
such predisposing molecular and metabolic backgrounds, will be
identied in the near future. Considering this rationale, the term
AD-related pathology seems confusing as it implies a relationship
but not identication with the process of Alzheimer. The
expression Alzheimer pathology seems appropriate to describe
the neuropathology of key alterations, even at the rst stages.
No less important are the social implications of the term
Alzheimer (or alzheimer) as an alternative to AD. The term AD is
associated with the idea of a terrible untreatable condition that
disrupts our minds and undermines our status as humans. In
contrast, alzheimer denotes a very common condition in old age
that only in a percentage of cases progresses to dementia. Suffering
from alzheimer does not imply a verdict of dementia, but rather
encompasses understanding that most humans at a certain age will
face a degenerative disease of the brain with similar possibilities
for treatment as atherosclerosis. The present rationale also permits
an assertive conciliation to break the hierarchical status between
normal and disease regarding degenerative processes associated
with aging.
Acknowledgment
I wish to thank T. Yohannan for editorial assistance.
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