Anna Giulia Cattaneo
DBSM, University of Insubria. Varese, Italy.
Decreased or altered memory and cognitive functions are a
quite common feature in older individuals, often limited to
a range that permits a good adaptation to private and social
life. In this case the impaired function is commonly considered
as an expression of a “physiological aging process of
the brain”. The problem starts when the initial mild
impairment progresses to a true dementia. The possibility
to prevent this destructive event, and the timing for intervention,
are unknown and represent an important matter of studies in
In older individuals the more frequent cause of dementia
is by far Alzheimer disease (AD, 50% of total cases), followed
by vascular dementia (10-20%). Causes of dementia can occur
pure, but they are often mixed each other. When the pathological
conditions are at least in part reversible, a satisfactory
clinical recovery and acceptable welfare can be reached by
cure; in other cases the addition of two or more causes of
dementia leads to even fatal consequences. This is the case,
as an example, of the Alzheimer disease (AD) associated with
cerebral amyloid angiopathy (CAA) . Individuals became prone
to small, multifocal intracerebral haemorrhages or white matter
ischemia, which can dramatically deteriorate their global
cognitive and perceptional attitudes, and even be fatal in
a short period.
The second most frequent cerebral degenerative disease in
aged subjects is the dementia with Lewis bodies, but the vascular
(not always pure) dementia is the second most prevalent lesion
after Alzheimer, increasing by age after the 6th decade, and
reaching 10% of all dementia after the 8th decade. No clear
sex-linked differences are shown in multicentric studies.
Cognitive changes associated with aging involve a number
of functions (memory, speed of mental processes, attention,
language and visual or spatial functions) along a continuum
from a state of minor memory changes through mild cognitive
impairment (MCI) to dementia. Despite the fact that MCI cannot
be considered diagnostic of an earlier stage of Alzheimer
disease (in fact a significant number of cases do not progress
to true dementia nor develop AD), MCI can lasts for years
as the only sign of future AD. At the present, no prediction
can be done about progression of MCI to AD: prediction and
prevention possibilities are a field of intensive studies.
The first step is a reliable way for diagnosing and staging
Alzheimer: history of a disease
In 1906-7 the German physician Alois Alzheimer described
a new type of progressive dementia in a 51 years aged woman.
The clinical and necroscopic neurohistological features (neurofibrillary
tangles and senile neuritic plaques) of the disease seemed
to be not described before, and the disease became known with
the eponym derived from its founder and proposed by Emil Kraepelin
in 1910. The Alzheimer disease (AD), or the senile dementia
of Alzheimer type (SDAT) will be subsequently recognized as
the largest form of senile and pre-senile dementia.
Further knowledge about AD lasted until recently. In 1963
the ultramicroscopic structure of tangles has been demonstrated,
and a basic disorder of central cholinergic innervations postulated
by Davies and Maloney in 1976 and by Coyle, Price and DeLong
in 1983. The National Institute of Aging further dictated
criteria for research (1984) and diagnosis (1985). Amyloidal
deposits, genetic findings (amyloid’s precursor gene
mutation, association with familial apolipoprotein E4 late
onset, presenilin 1 and 2 genes, identification of beta-secretase)
and development of transgenic mouse model of AD were discovered
only in the two last decades.
Diagnostic criteria for senile dementia have changed from
early statements (Roth M J Ment Sc 1955; Slater E & Roth
M 1969), when the s.c. arteriosclerotic psychosis and its
manifestations have been described, up to the more recent
criteria (proposed in 1984 by the NINCDS-ADRDA, the National
Institute of Neurological and Communicative Disorders - Alzheimer’s
Disease and Related Disorders Association). These clinical
research criteria appear to be highly accurate, approaching
90% true prediction, and can be integrated by more sophisticated
techniques, like neuroimaging, genomics, proteomics, histopathological
findings. An accurate staging of the disease and individuation
of underlying causes can improve perspectives for a better
treatment and prevention.
1. Standardized techniques for neuropsychological
1.1 Hachinski Score (Hachinski et al., Lancet, 1974): AD
1.2 McKeit criteria: dementia with Lewy’s bodies (dementia
2. Staging system:
2.1 Braak system, based on the involvement of different
brain regions. Stages I and II (transentorhinal) are presymptomatic
and can last for years.
2.2 Mini-Mental State Exam
2.3 Global Clinical State
3. Descriptive findings:
3.1 Microscopic: insoluble deposits of tau-protein in
neurons (tangles) and in neurites surroundings the senile
plaques, focal deposits of amyloid (hydrophobic fragment
of a transmembrane glycoprotein) forming the core of the
plaque. In more severe cases, amyloid angiopathy is present.
3.1 Macroscopic (necropsy): diffuse, non-evenly distributed
atrophy in the brain. The primary sensorimotor areas are
relatively spared in comparison with other regions. Tangles
and plaques are relatively few in these regions, despite
the lack of knowledge between the causative relationships
between histological changes and cognitive impairment.
3.3 Imaging: Computerized Tomography (CT) and Magnetic Resonance
Imaging (MRI) fairly discriminate between AD and vascular
dementia; they could lead to erroneous or unclear diagnosis
in AD. On the contrary, functional imaging like PET (Positron
Emission Tomography) scan seems to be more useful.
3.4 While no pathognomonic EEG features can be found in
AD, this simple and relatively non expensive means for diagnosis
can be helpful in excluding other causes of dementia and
cognitive impairment, like those due to metabolic or pharmacological
agents, or to epileptic focuses.
3.5 Molecular markers are described further.
Molecular markers for AD (click on the
links, please. All names are linked to the OMIM (Online Mendelian
Inheritance in Man) of the Johns Hopkins University, describing
the genetic loci and their products), and the 3-D structures
are linked to their original site.
The molecules listed below can play a significant role in
AD development, when modified by a genetic mutation or by
a chemical reaction (see the free radicals)
Presenilin 1 (chromosome 14, locus 14q24.3)
Presenilin 2 (chromosome 1, locus 1q31–q42)
PS1 and PS2 are localized in nuclear structures, both in the
interphase and during mitotic events membrane, and in membranes
of the endoplasmic reticulum (ER) and Golgi. PS1 is primarily
expressed in cortical and hippocampus neurons, the areas in
the brain more vulnerable by AD. Both molecules seem to have
enzymatic activity (gamma-secretase acting on APP, see below),
have similar dimensions (467 and 448 Aa) and several transmembrane
domains. A number of mutations of Presenilin 1 and 2 are associated
to early-onset (before age 65 years) AD, and mutation at –48
position of presenilin1 gene seems to be involved both in
familial and sporadic AD.
ApoE (epsilon 4 allele) (chromosome 19, locus 19q13.2).
Apolipoprotein E is found in humans four isoforms, epsilon
4 seeming to be associated to AD. The zygosis for this allele
is associated with the time of symptoms appearance (earlier
in homozygotic and intermediate in heterozygotic). Its role
of “pathologic chaperone” seems to be possible
in the development of AD and cerebral degeneration: apoE epsilon
4 facilitates aggregation and deposition of amyloid insoluble
4. Amyloid beta A4 Precursor Protein (APP) (chromosome
21, locus 21q21): its isoforms are responsible for the deposition
of plaque core in AD and in AD associated with Down syndrome.
Mutations at the cleavage site for the enzymes (alpha-, beta-,
and gamma- secretase) are responsible for production of toxic
molecules and cerebral aggregates, but only mutations near
the beta- and gamma- cleavage site are associated with AD.
The cleavage in these sites produces A 42 and A 40 proteins
respectively. The first represents only 10% of catabolic product
of APP, is relatively insoluble, it hardly passes through
the brain barrier, and is the major component of senile plaques.
The second is the major product of APP splicing, is incorporated
in mature plaques and represents the most abundant component
in amyloid deposits. It is soluble and able to pass through
the brain barrier. Alpha cleavage prevents their excess.
Protein tau (chromosome 17, locus 17q21.1). The role
of this microtubule-associated protein is very important not
only in AD, but in a quite large number of cerebral degenerative
diseases known as tauopathies. Two different single-nucleotide
polymorphisms have been described in association with AD,
one of which located in the same gene responsible for frontotemporal
dementia with Parkinsonism. Modified tau proteins share inadequacy
of their transmembrane domains, and the resulting molecules
aggregates as fibrillary proteins in tangles
6. Free radicals (molecules damaged from
Most prominent markers of this damage are lipoproteins, because
of free radicals are chemically unstable and difficult to
measuring. Oxidation of immunoglobulin G, and increasing levels
of 8-hydroxy-2'-deoxyguanosine (8-OHdG, a marker of oxidative
damage to DNA) are recently proposed markers. In addition,
the oxidative state of the tissue under examination must be
taken into account.
The known 3-D structures, derived from crystallographic deposited
(at the PDB) features, are reported below. The contents of
PDB are in the public domain. Online and printed resources
are welcome to include PDB data and images from the Structure
Explorer pages, as long as they are not for sale as commercial
items themselves, and their corresponding citations are included.
No figures are shown for presenilins.
1. apoE epsilon 4: Wilson, C. Weisgraber,
K.H. Wardell, M.R. Mahley, R.W. Agard, D.A. Structural Basis
for Altered Function in the Common Mutants of Human Apolipoprotein-E
To be Published, Deposition: 1991-08-22 Release: 1992-10-15
2. APP: Hynes, T.R. Randal, M. Kennedy,
L.A. Eigenbrot, C. Kossiakoff, A.A. X-ray crystal structure
of the protease inhibitor domain of Alzheimer's amyloid beta-protein
precursor. Biochemistry v29 pp.10018-10022 , 1990
3. Protein tau: Wintjens, R. Wieruszeski,
J.M. Drobecq, H. Rousselot-Pailley, P. Buee, L. Lippens, G.
Landrieu, I. 1H NMR study on the binding of Pin1 Trp-Trp domain
with phosphothreonine peptides. J.Biol.Chem. v276 pp.25150-25156
Protein tau (complexed with PIN1
WW domain): protein tau is orange , red and light
Predictive data and risk factors.
AD is by far a sporadic disease, only 10% of cases having
a familial distribution type. These forms of the disease are
associated to known gene mutations or to chromosomal aberrations.
Presenilin 1 gene mutation is responsible for 70% of all familial
cases, presenilin 2 of 20%, APP of 3%; the remaining 7% is
represented by early-onset (before 65 years of age) cases:
they are also associated to mutations at one of the previously
cited loci, or to chromosomal aberration, like the AD associated
to Down’s syndrome (chromosome 21). AD seems to warrant
the longer survival after symptoms or diagnosis, in comparison
with vascular and mixed dementia: the calculated life quotient
(ratio between estimated and expected survival) is 0.78 vs.
0.57, respectively (no differences have been shown between
pure vascular and mixed dementia).
Established risk factors have been recognized in sporadic
AD, the most important being advancing age, followed by the
apoE genotype (and namely the zygosis for the epsilon 4 allele,
chromosome 19, locus 19q13.2) and the family history. Gender
and head injury are postulated but still uncertain risk factors.
Microtubules associated protein tau, found in neurofibrillary
tangles, is present not only in AD, but in a wide number of
brain degenerative diseases, so called tauopathy. A gene located
on chromosome 17 (locus 17q21.1) is responsible for protein
tau encoding: focal mutations are responsible for the production
of altered protein unable to bound to microtubules.
Detection and measurement of biomarkers in CSF (a poorly invasive
procedure) have been partially evaluated in view of obtaining
an early diagnosis of AD. Protein tau > 560 pg/ml associated
with A beta 42 < 1125 pg/ml identify AD patients with greater
than 85% specificity; protein tau < 560 pg/ml associated
with A beta 42 > 1125 pg/ml identify normal control with
greater than 85% specificity. (Galasko D, Clark C, Chang L,
et al. ,1997, Neurology , 632-635).
True prevention and cure for pure AD, (or mixed vascular)
are highly expected finding from research in the field of
cerebral aging, and a variety of hypothesis have been done,
on the basis of epidemiology studies and supposed pathogenesis.
The first and most prominent way to obtain a remission in
demented subjects remains a correct diagnosis and treatment
of associated and treatable causes of dementia (like depression,
Parkinson, metabolic and pharmacological conditions).
Another approach concern detecting possible markers of early
damage before the progression into a clear demented status,
in search of future efficacious preventive measures and treatment.
A number of similar markers have been proposed, and namely:
environmental pollutants (Al and Si in drinking water, heavy
metals and redox metals, iron included, between others), free
radicals toxicity and low antioxidant status measured in serum,
malnutrition and lifestyle. Their removal, or the supplement
with antagonists, has been claimed to be useful in therapy.
A number of pharmacological treatments have been proposed,
1. Dietary supplementation with antioxidant agents (carotenoids,
omega-3 fatty acids, alfa-lipoic acid, coenzyme Q10, non-steroidal
antinflammatory drugs, selenium and vitamins: C, A., E). This
approach appears to be well tolerated and counter-effects
free, while not evenly effective. Association with ACE-inhibitors,
hormone replacement (both in men and in women, as appropriate)
has been proposed as helping.
2. Modulation with cholinergic agents is a causative treatment.
3. The administration of symptomatic therapy (antipsychotic,
antidepressant, sedative drugs) does not seem to be useful
in contrasting progression of cognitive impairment when no
concomitant pathologies are present
4. Metal chelators gave contrasting results, and it has been
claimed that their efficacy is conditioned by ability to act
even on Fe
5. Therapy with statins is costly and gives contrasting results
6. Immunotherapy against APP splicing products has been recently
stopped in a clinical controlled trial because of the development
of immunoencephalitis in 6% of subjects.
7. The helpful role of growth and nerve growth factors administration,
and even of somatostatin and glucagons, has been proposed
Unfortunately, we do not have well tolerated, approved and
standardized measures that have been proved effective in AD’s
treatment and prevention, and an excess of cost often charges
clinical trials. However, good clinical practice should not
forget the emerging data, especially when great tolerance
and minimal side effects are associated with a possible amelioration.
Structural studies on secretases, especially beta- (BACE
1 and 2) open a promising, new perspective for the future
treatment of brain degenerative changes by means of specific
inhibitors at their functional site.
Mitochondrion is a district of the eucariote cell maximally
exposed to the oxidative risk. It is a major site responsible
for apoptosis, and hosts a number of active oxidative processes.
On the contrary, its DNA is poorly protected from the damage
due to free radicals and hydroperoxide production by histone
proteins, and age-related deletions have been recognized in
the brain and in muscles.
Another promising approach is represented by the development
of animal models, in which alterations present in AD and other
conditions of brain degeneration can be studied isolated from
the complex and often confounding structure present in humans
being. From their simplicity, a new integrated and more clear
understanding of the entire phenomenon in humans can be expected.
|Gli editoriali più recenti