Vol.2, No.4, 123-125 (2013) Advances in Alzheimer’s Disease
http://dx.doi.org/10.4236/aad.2013.24016
Cognitive assessment in Alzheimer’s disease*
Mario A. Parra
Human Cognitive Neuroscience and Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh,
Alzheimer Scotland Dementia Research Centre and Scottish Dementia Clinical Research Network, Edinburgh, UK;
Received 31 May 2013; revised 12 July 2013; accepted 20 July 2013
Copyright © 2013 Mario A Parra. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
No effective treatments are currently available to tackle
Alzheimer’s disease (AD), yet there seems to be a grow-
ing consensus in support to prevention initiatives [1-4].
This poses important challenges to the scientific com-
munity as prevention entails at least two targets, early
detection and effective treatments neither of which meets
current needs. Regarding the latter target, recent failures
in clinical trials have led to question whether the under-
taken treatments have been too little or too late [2,4].
This question seems to emerge from current under-
standing of the neuropathological changes underlying
AD, which suggests that anti-amyloid treatments might
need to be administered earlier than we thought [1].
However, to achieve this we first need to identify who
could be suitable for such prevention trials and this re-
quires early detection. Significant progress has been
made in the area of biomarkers for AD, yet available
tests still face important challenges [5-8]. Less has been
done in the area of cognitiv e markers for AD, albeit cog-
nition plays a fundamental role in the disease diagnosis,
prognosis and follow up. The present short communica-
tion aims to reflect on current approaches to cognitive
assessment in AD and the extent to which the conundrum
“too little, too late” also applies to the early detection of
cognitive impairments in this form of dementia.
Traditional assessment of cognitive functions in AD
has largely focused on episodic memory. This tendency
has been driven by neuropathological evidence which
suggests that regions within the medial temporal lobe
known to be crucial from long-term memory formation
are affected by AD since very early. However, episodic
memory, as assessed by available tests, reveals impair-
ments which characterize the rather advanced stages of
the disease. It might be that for AD-related episodic me-
mory changes to reach the pathological threshold of
these tests, substantial damage to th e hippocampus needs
to accumulate because this structure and associated func-
tions also decline as part of the normal aging process.
Distilling age-related and AD-related decline of hippo-
campal functions is a subject which requires further re-
search. Moreover, the negative results currently reported
by clinical trials might also rest, at least in part, on the
outcome measures used to assess memory functions. The
disease mechanisms tackled by available drugs (e.g.,
anti-amyloid compounds) might impact on brain regions
and functions different from those taxed by available
episodic memory tests [9-11]. Episodic memory tests
might be unveiling the impact of advanced pathological
changes (e.g., Tauopathy and tangle formation; [12]).
Memory tests capable of detecting the impact of earlier
mechanism s woul d be desi red (see Sperling et al. [13]).
In a recent hypothesis paper, Didic et al. [14] proposed
a novel approach which calls for a new conception of
memory assessment in AD. In their paper, the authors
addressed the question of which memory system is im-
paired first in AD. They suggest a model which sees the
hippocampal damage as a rather late consequence of AD.
In the model, a subhippocampal phase precedes the hip-
pocampal damage in the neurodegenerative course of AD.
Interestingly, the hippocampal phase seems to corre-
spond to the Braak’s stages III-IV while the subhippo-
campal phase reflects earlier pathological stages (I-III),
thus suggesting that memory tests capable of detecting
this phase would be more promising in the early detec-
tion of AD. They suggest that tests measuring con-
text-free memory (e.g., item memory, familiarity based
recognition) as opposed to tests measuring context-rich
memory (e.g., inter-item association, freed and cued re-
call), appear to be promising candidates (see Wolk et al.
[15] for recent evidence). This proposal is appealing as
regions supporting item memory and familiarity based
recognition fall outside the hippocampus and map well
onto areas known to be affected by amyloid-induced
changes early in the course of AD (e.g., entorhinal cortex,
perirhinal cortex, parahippocampus, and regions within
the visual ventral stream; [9,12,14]). There is now ac-
crued evidence suggesting that the neuropathological
changes accompanying AD spread through these extra-
*Mario A Parra’s work is currently supported by Alzheimer’s Society,
UK.

M. A. Parra / Advances in Alzheimer’s Disease 2 (2013) 123-125
124
hippocampal regions in the very early stages of the dis-
ease [16-22]. Of note, whereas healthy aging impacts on
the hippocampus, it seems to spare these extra hippo-
campal regions which are affected by AD [23-25]. Hence,
memory tests assessing the functions supported by these
regions would help detect early AD-related changes not
accounted for by age.
A recent methodology, namely short-term memory
binding (STMB), adheres to this new conception of
memory assessment in AD. STMB refers to the cognitive
function responsible for retaining, on a temporary basis,
intra-item features thus contributing to the formation of
objects’ identity. This function has been investigated
using a change d etection task during which the examinee
judges whether arrays of shapes, colors or shape-color
combinations presented in two sequential screens are the
same or different. STMB has proved insensitive to
healthy aging [26,27] but very sensitive to AD [28,29].
AD seems to impact on STMB much earlier than on
other memory functions [28,30]. Relative to other de-
mentias and depression, STMB declines only in AD
[31,32]. A recent fMRI study confirmed that STMB does
not rely on the hippocampus but it does recruit regions
within the visual ventral stream [33]. Interestingly, recent
studies carried out in the asymptomatic population of
carriers of the mutation E280A of the PSEN1 gene [34]
who will go on to develop familial AD with 100 % prob-
ability and who had previously shown STMB deficits at
a mean age of 35 [28,30], suggest that amyloid changes
are the most prominent pathological feature of this pre-
clinical stage [35,36]. Based on the evidence reviewed
above, the STMB task appears to be taxing the subhip-
pocampal phase of AD [4].
A shift in the concep tion of early cognitiv e assessment
of AD and of the tools necessary to undertake this task is
already due. Current revised guidelines continue to em-
phasize on tests that assess the hippocampal phase of AD
(e.g., associative learning, cued recall, etc.) despite they
detect changes late in the course of the disease and are
sensitive to a number of unwanted factors (e.g., age,
cognitive reserve, and other individual differences). Fu-
ture assessment of AD should focus on theory-driven
tests which tap into specific cognitive domains and are
insensitive to confounding factors. More effort will be
required in the forthcoming years to further investigate
the usefulness of tests of subhippocampal memory func-
tions in the prediction of AD among the elderly popula-
tion. Such tests would become screening tools to detect
individuals at risk who could then be referred to preven-
tion programs.
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