Early neuropsychological detection of Alzheimer's disease

European Journal of Clinical Nutrition (2014), 1–8 © 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn REVIEW Early neuropsychological detection of Alzheimer's disease C Bastin1,2 and E Salmon1,3 Lifestyle modification offers a promising way of preventing or delaying Alzheimer’s disease (AD). In particular, nutritional interventions can contribute to decrease the risk of dementia. The efficacy of such interventions should be assessed in individuals thought to be prone to AD. It is therefore necessary to identify markers that may help detecting AD as early as possible. This review will focus on subtle neuropsychological changes that may already exist in the predementia phase, and that could point to individuals at risk of dementia. Episodic memory decline appears consistently as the earliest sign of incipient typical AD. An episodic memory test that ensures deep encoding of information and assesses retrieval with free as well as cued recall appears as a useful tool to detect patients at an early stage of AD. Beyond the memory domain, category verbal fluency has been shown to decline early and to predict progression to AD. Moreover, in line with current diagnosis criteria for prodromal AD, combining neuropsychological scores and neuroimaging data allows a better discrimination of future AD patients than neuroimaging or neuropsychological data alone. Altogether, the detection of cognitive changes that are predictive of the typical form of probable AD already in the predementia stage points to at risk people who are the best target for therapeutic interventions, such as nutrition or physical exercise counseling or dietary interventions. European Journal of Clinical Nutrition advance online publication, 3 September 2014; doi:10.1038/ejcn.2014.176 INTRODUCTION Alzheimer’s disease (AD) is characterized by severe cognitive deficits, which worsen and affect an increasingly broad range of domains as the disease progresses. Although there exist some atypical forms starting with language, visuospatial or executive dysfunction, the most common syndromic presentation consists of memory impairment together with cognitive dysfunction in at least one other domain (language, reasoning, visuospatial abilities and so on).1 Importantly, clinically evident dementia is preceded by a period lasting presumably one or more decades during which amyloid and tau proteins accumulate in the brain.2 Moreover, during the predementia period, cognitive deficits already exist. A recent study suggested that abnormal amyloid deposition could be detected about 17 years, hippocampal atrophy around 4 years and cognitive impairment 3 years before a clinical diagnosis of AD is made.3 Given that neuropathology has reached a critical point when dementia occurs, the predementia period is considered the best target for therapeutic interventions (e.g., Reiman et al.4). Among possible interventions, besides pharmaceutical treatment, cognitive rehabilitation and lifestyle modifications appear as promising avenues for preventing or delaying dementia onset. In particular, lifestyle modifications, such as nutritional interventions, physical activity training and stimulating leisure activities, have received an increasing interest in recent years. They are thought to contribute to build a reserve allowing individuals to resist longer to Alzheimer neuropathology5 and to reduce AD risk factors such as hypertension, obesity, diabetes, oxidative stress and so on. For instance, healthy nutritional habits, including the consumption of omega-3based fatty acids and antioxidant vitamins, seem to reduce the risk of dementia in late life.6–8 Moreover, interventions proposing the adoption of the Mediterranean diet, sometimes in combination with supplement nutrients, may lead to an attenuation of cognitive decline.9–11 As these promising preventive and/or therapeutic approaches become available, future work should evaluate their efficacy in individuals who are in the predementia phase of AD. Currently, research on the detection of the earliest signs of AD points to several kinds of biomarkers: genetic biomarkers (e.g., APOEε4), neuroimaging biomarkers (e.g., cerebral atrophy, hypometabolism, amyloid deposition), cerebrospinal fluid biomarkers (e.g., tau and amyloid levels) and cognitive markers (i.e., neuropsychological measures). In this review, we will focus on cognitive markers that may contribute to early detection of AD and hence to identify the best candidates to therapeutic interventions. It should be noted that the reviewed neuropsychological predictors apply to the typical form of AD, that is, dementia with prominent and initial memory deficits.1 REVIEW METHODS The process of selection of articles is illustrated in Figure 1. Articles dealing with predictors of AD were searched for by means of an initial Pubmed search with the following criteria and keywords: ((memory AND longitudinal AND Alzheimer's disease) AND (prodromal OR conversion OR preclinical)), (mild cognitive impairment AND (Alzheimer's disease OR dementia) AND neuropsychology AND (prediction OR longitudinal)), and (Alzheimer's disease AND conversion AND neuropsychology). Further search through the bibliography of reviews and meta-analyses led to 84 additional publications focusing on neuropsychological predictors of dementia. After excluding references related to animal studies, non-Alzheimer dementia, treatment outcomes, cognitively normal individuals with APOE ε4 genotype and depression, we reviewed 1 Cyclotron Research Center, University of Liège, Liège, Belgium; 2Fund for Scientific Research, F.R.S.-FNRS, Brussels, Belgium and 3Memory Clinic, CHU Liège, Belgium. Correspondence: Dr C Bastin, Cyclotron Research Center, University of Liege, Allée du 6 Août, B30, Liège 4000, Belgium. E-mail: Christine.Bastin@ulg.ac.be Received 9 July 2014; accepted 28 July 2014 Cognitive markers of Alzheimer’s disease C Bastin and E Salmon 2 Figure 1. Selection of reports included in the review. 216 publications describing work on neuroimaging and/or neuropsychological indicators of AD. From these, the current review included those that describe longitudinal assessments (i.e., involving at least two neuropsychological assessments over a follow-up period of minimum 1 year) of healthy older subjects or patients with mild cognitive impairment (MCI), with statistics evaluating the predictive power of neuropsychological measures in the discrimination between subjects who progress to AD and those who remained either cognitively normal or with MCI. APPROACHES FOR EARLY NEUROPSYCHOLOGICAL DETECTION OF DEMENTIA Two main approaches have been used to identify the cognitive markers of future development of AD, both having in common the reliance on longitudinal assessments of participants. Whereas one approach consists in population-based studies that follow large cohorts of community-dwelling normal older participants, the other focuses on patients with MCI. Large-scale population studies recruit healthy participants in the community and test them repeatedly with a more or less extensive neuropsychological battery. These longitudinal studies follow the participants for several years (e.g., from 4 years for the Bronx Aging Study12 to 22 years for the Framingham study13). During the course of the follow-up, a proportion of the population develops AD. It is therefore possible to identify the cognitive functions that were impaired in the prodromal phase in the future AD patients in comparison to participants who remained normal, and hence to picture the chronological sequence of these cognitive impairments.14,15 Alternatively, researchers can point to the earliest cognitive changes in preclinical AD by detecting the point in time at which the slope of decline in a neuropsychological task becomes steeper in future AD patients than in stable healthy participants.16–18 In the past 15 years, research on the predementia stage of AD has particularly focused on people with MCI. Initial criteria for MCI were the presence of subjective memory complaints and objective memory deficits, without other cognitive impairment, with relatively preserved functioning in daily life and no dementia.19 However, it soon appeared that MCI is a heterogeneous entity and that the different clinical MCI subtypes do not have the same prognosis. In particular, a distinction has been made between the amnestic forms of MCI (either single domain if only memory is European Journal of Clinical Nutrition (2014) 1 – 8 affected, or multiple domain if other cognitive functions are also deficient) and non-amnestic forms of MCI (single-domain or multiple domain).20 Given that the annual rate of progression to AD among patients with amnestic forms of MCI is much higher than that in healthy older people (6.5% versus less than 1%, respectively21) whereas non-amnestic MCI patients more frequently progress to non-AD dementia,20 the amnestic form of MCI has been considered as a clinical manifestation of incipient AD or the prodromal phase of AD. Nevertheless, all amnestic MCI patients are not to develop AD dementia symptoms. It is therefore necessary to find specific markers that would indicate whether a patient is likely or not to become demented in the near future. This motivated longitudinal studies that selected groups of MCI patients either in the community or in clinical settings and evaluated them regularly until they develop AD or for follow-up periods that typically vary between 1 and 4 years. Performance from the initial cognitive assessment is then retrospectively analyzed to find the measure that best discriminates between MCI patients who remained stable throughout the follow-up period and those who progressed to AD. Other studies have also investigated the issue of cognitive markers of AD in other at-risk people, such as carriers of the APOE ε4 allele (see Caselli et al.22 for a review). The current review will, however, focus on longitudinal studies in large cohorts from the population and in MCI patients. NEUROPSYCHOLOGICAL ASSESSMENTS THAT BEST PREDICT AD Typically, longitudinal assessments of cohorts of healthy older adults or of patients with MCI involve a more or less extensive battery of standard neuropsychological tests. The cognitive domains that are usually evaluated comprise episodic memory (memory for new information personally experienced in a specific context), working memory (to maintain a small quantity of information for a very brief period of time), executive functions (high-order functions that facilitate adaptation to new or complex situations, when highly practiced cognitive abilities no longer suffice), language and semantic memory (such as fluent word retrieval), and visuospatial abilities. Comparison between studies is made difficult because of the variety of tests that have been used, the heterogeneity of the population investigated (in terms of sample size, characterization of MCI patients, follow-up duration), the diversity of the cognitive testing (either several memory tests versus only one, the number of other neuropsychological scores) and the use of different statistical approaches (logistic regression analyses, survival analyses and so on). Therefore, only general trends can be drawn from current research on the earliest sign of cognitive decline in the predementia stage of AD. Among the cognitive domains that are evaluated with standard neuropsychological batteries, episodic memory was consistently identified as the first domain to decline in population-based studies of preclinical AD (see Table 1). In the majority of longitudinal studies of MCI patients, measures of episodic memory also emerge as the best predictors of progression to AD.23–51 This seems to be true for verbal episodic memory as well as for visual episodic memory, when the latter is evaluated. The memory decline initiates many years before the clinical diagnosis of AD. For instance, future AD patients may present with subtle episodic memory deficits compared with stable healthy individuals for as long as 9–10 years before the emergence of the first clinical symptoms.13,15,52 Furthermore, it has been suggested that, although episodic memory is affected very early, performance plateaus for several years before showing an abrupt decline 2 or 3 years before dementia onset.53 Standard tests of episodic memory consist in presenting a list of items (e.g., words or pictures) and subsequently evaluating © 2014 Macmillan Publishers Limited © 2014 Macmillan Publishers Limited Table 1. Population-based longitudinal studies testing for the cognitive measures that predict future development of Alzheimer’s disease Study Cohort name N Masur et al.12 Bronx Aging Study 31764 Framingham study North Manhattan Aging Project 1045 443 139 205 532 1043 264 603 88 Linn et al. Jacobs et al.76 Howieson et al.54 Small et al.72 Small et al.55 Elias et al.13 Grober et al.61 Chen et al.56 Chen et al.89 Kungsholmen project Kungsholmen project Framingham Study Einstein Aging Study Monongahela Valley Independent Elders Survey Monongahela Valley Independent Elders Survey Bronx Aging Study (55) (41) (16) (26) (73) (106) (32) (120) Follow-up duration Earlier emerging cognitive impairments 4 years Verbal and visual episodic memory, working memory, category fluency (2 years before diagnosis) Verbal episodic memory, working memory Verbal episodic memory, language, abstract reasoning Verbal episodic memory (2.8 years before diagnosis) Verbal and visual episodic memory; phonemic fluency (3 years before diagnosis) Verbal episodic memory (6 years before diagnosis) Verbal episodic memory and abstract reasoning (10 years before diagnosis) Verbal episodic memory (5 years before diagnosis) Verbal episodic memory, executive function (1.5 year before diagnosis) 13 years 4 years 5 years 3 years 6 years 22 years 10 years 10 years Berlin Aging Study Canadian Study of Health and Aging Amieva et al.52 PAQUID 1255 (215) 9 years Amieva et al.70 Grober et al.17 PAQUID Baltimore Longitudinal Study of Aging 3777 (350) 1006 (92) 14 years 15 years 444 (134) 25 years 1160 (60) 2071 (462) 5 years 16 years 121 (32) 627 (48) 825 (29) 7.5 years 12 years 13 years Constructional praxis, verbal episodic memory, category fluencya Verbal episodic memory Verbal and visual episodic memory, verbal fluency, visuospatial ability Bäckman et al. Saxton et al.14 90 Kungsholmen project Cardiovascular Health Study European Journal of Clinical Nutrition (2014) 1 – 8 Johnson et al.92 Auriacombe et al.93 Wilson et al.18 Riley et al.71 Rabin et al.94 Schmid et al.57 3C study Religious Orders Study & Rush Memory and Aging Project UK-ADC Einstein Aging study BASEL 10 years 488 (75) 19 years 120 (15) 693 (72) 6 years 8 years 187 (15) 5-years: 551 (77) 10 years: 263 (47) 4 years 5 and 10 years Cognitive markers of Alzheimer’s disease C Bastin and E Salmon Rapp et al.91 Tierney et al.15 Verbal episodic memory and executive function (decline between 3.5 and 1.5 years before diagnosis)a Verbal episodic memory (7–8 years before diagnosis); Performance IQ (2 years before diagnosis)a Verbal episodic memory (6 years before diagnosis) Verbal and visual episodic memory (5–8 years before diagnosis); category fluency and executive function (3.5–5 years before diagnosis) Attention, executive function, verbal episodic memory 5 years before diagnosis: verbal episodic memory, category fluency, information. 10 years before diagnosis: verbal episodic memory Visual episodic memory, category fluency, abstract reasoning, global cognition (9 years before diagnosis)a Category fluency; abstract reasoning (12 years before diagnosis)a Verbal episodic memory (7 years before diagnosis); executive function (2–3 years before diagnosis)a Visuospatial function (3 years before diagnosis), global cognition (2 years), memory (1 year)a Verbal episodic memory Semantic memory, working memory (6 years before diagnosis)a Hall et al.16 551 (68) Abbreviation: N, number of participants (number of progression to AD). aAnalysis of change point (time at which the rate of decline changes). 3 Cognitive markers of Alzheimer’s disease C Bastin and E Salmon 4 memory for these items by either asking the participants to recall as many studied items as possible or to identify among propositions those items that were studied (recognition). For recall tests, participants may have to retrieve studied items without any support (free recall) or to retrieve studied items on the basis of some cue, such as the semantic category to which the item belongs (cued recall). Several tests assess recall immediately after the study phase (immediate recall) and then again after 20 or 30 min (delayed recall). Recall measures are more often cited as good cognitive markers of future AD than recognition scores. Moreover, many population-based studies and MCI follow-up studies point toward the usefulness of scores of delayed recall as excellent predictors of progression to AD.12–15,23,25,34,36,39,41,43,45,47,48,54–57 As mentioned above, the question of which memory test and which measure are the best has currently no definitive answer given the heterogeneity of the tests that have been used in the different studies. Nevertheless, assuming that the different memory tests do not have the same sensitivity and specificity, a few studies have tried to compare the predictive accuracy of several memory tests, in an attempt to find the one that would be particularly appropriate for identifying early AD among MCI patients.27,37,42 The Free and Cued Selective Reminding test (and its longer versions avoiding ceiling effects in healthy subjects, the Double Memory test58 and the RI-48 test in French language59) was found to best discriminate between AD or MCI patients and healthy subjects, and also between MCI patients who will progress to AD and MCI patients who will remain stable, when compared with other standard memory tests. In the Free and Cued Selective Reminding test, participants are shown 16 items (e.g., grapes) presented four at a time on a card. For each card, the participants have to point and name aloud each item after its unique category cue (e.g., fruit) has been provided. When all four items of a card have been identified, immediate cued recall of those four items is tested. Once all four items have been successfully recalled (or for a maximum of three trials), the next card is presented following the same procedure until all 16 items have been studied. After a brief retention interval of 20 sec, three recall trials are proposed, each consisting of free recall followed by cued recall (e.g., what was the fruit?) for items that have not been spontaneously recalled. After 30 min, free and cued delayed recall is assessed. The advantage of the Free and Cued Selective Reminding test (and RI48 test) has been explained by the fact that it provides cognitive support at both encoding and retrieval. Indeed, in these tests, cognitive support consists of controlled encoding of materials by relating the items to their respective semantic category followed by a cued recall test where the categories serve as cues. This would facilitate performance of participants whose main difficulties concern the initiation of memory strategies (e.g., healthy older participants, demented patients with frontal lesion), but not performance of participants who have genuine difficulties with memory encoding and storage (e.g., AD patients).60,61 Consistently, cued recall in the Free and Cued Selective Reminding test (as well as Double Memory test and RI48) is better than free recall in differentiating AD from healthy aging and other forms of dementia like frontotemporal dementia, Huntington’s disease or Parkinson’s disease.62 Building upon these findings, a revision of the research criteria for MCI has been proposed to better define prodromal AD:63 an episodic memory deficit taking the form of ‘recall deficit that does not improve significantly or does not normalize with cueing or recognition testing and after effective encoding of information has been previously controlled’ is considered the core diagnostic criteria. The predominance of episodic memory deficits as cognitive markers of incipient typical AD has been interpreted as reflecting the early pathological involvement of the medial temporal lobe in the course of Alzheimer’s dementia.64 In line with this view, the cued recall score of the Free and Cued Selective Reminding test European Journal of Clinical Nutrition (2014) 1 – 8 was related to medial temporal glucose metabolism65 and total recall score (i.e., free+cued recall) of the Free and Cued Selective Reminding test was found to correlate with hippocampal volume in patients with AD.66 Also, tasks like Paired Associates Learning and face-name associative memory, that rely on the hippocampus for encoding relational bounds between pieces of information,67 have a very good discriminative power for detecting MCI patients who will develop AD.24,26,44 This is consistent with the idea that hippocampus-dependent tasks are sensitive to early cerebral changes in AD. As stressed by Gainotti et al.,68 to propose an operational criteria of the best neuropsychological predictors of conversion to AD, one needs not only to identify specific memory tests that are the most efficient predictors, but also to define the most appropriate cutoff scores for discriminating at-risk individuals. Ideally, stringent cutoff scores should be used, as stricter measures seem to provide better prediction of conversion.69 As an illustration, in addition to showing the adequacy of the Free and Cued Selective Reminding test as predictor of AD, Sarazin et al.37 proposed a free recall score of 17/48 (corresponding to the sum of free recall scores for the three trials) together with a total score over the three trials of 40/48 as optimal cutoff score to discriminate MCI patients with a high probability of progressing to AD within 36 months (90%). Beyond the episodic memory domain, poor verbal fluency performance is put forward as a good predictor of future AD in several population-based studies (Table 1) and a few MCI followup studies.25,31,43,49 In particular, category verbal fluency (e.g., to provide as many animals exemplars as possible in 2 min) predicts significant progression to AD,12,14,15,17,52,70,71 whereas phonemic verbal fluency (e.g., to provide as many words starting with the letter F as possible in 2 min) was less frequently identified as a cognitive marker of AD.57,72 The relative sequence of the decline of episodic memory and category fluency is controversial, as some studies indicated that memory impairment arises first,14,15,17 whereas another work reported initial disruption of category fluency preceding memory decline by a few years.70 Category fluency tasks are multi-determined, involving mainly semantic memory and executive functions like flexibility and inhibition. Hence, it is not clear whether predementia impairment in these tasks reflect early emergence of executive or semantic difficulties. In favor of an early executive impairment is the observation that category fluency has been found to decline together with a measure of flexibility (Trail Making Test).14,17 Moreover, a qualitative analysis of response production during a category fluency task in individuals who were to develop AD 5 years later showed that difficulties concerned switching between subcategories during word production (e.g., to cite farm animals, then insects, birds and so on) which is an executive ability rather than accessing many items within one subcategory that measures semantic memory storage.73 However, given that an executive decline would also affect phonemic fluency, the semantic account has sometimes been favored,68,74 notably in light of the severe semantic memory deficits found in MCI patients.74 Moreover, Wilson et al.18 suggested that semantic memory deficits may even precede episodic memory decline in the predementia period, a finding paralleling the very initial decline of category fluency put forward by Amieva et al.70 Other early neuropsychological predictors of AD have also been described, such as visuospatial abilities,57,71,75 abstract reasoning,13,52,70,76 recognition memory of objects48,77,78 or short term memory for conjunctions of features.79–81 Even though controlled episodic memory tests and category fluency tasks emerge as the most discriminant measures that allow pointing at future AD patients, most studies found actually that the predementia stage of AD can involve subtle deficits in a broad range of neuropsychological tests. Indeed, a combination of cognitive measures often provides greater predictive accuracy © 2014 Macmillan Publishers Limited Cognitive markers of Alzheimer’s disease C Bastin and E Salmon 5 Table 2. Predictive accuracy of cognitive measures, neuroimaging or CSF biomarkers and combination of markers for detecting progression to AD in longitudinal studies of MCI patients. N Study Follow-up duration Measures 27 (9) 3 years 20 (9) 3 years Borroni et al.95 Devanand et al.82 31 (18) 148 (39) 2 years 3 years Gomar et al.96 Venneri et al.97 Schmand et al.47 320 (116) 25 (11) 175 (81) 2 years 3 years 1.6 years —Episodic memory —MRI —Neuropsychology+MRI —Visuospatial ability —FDG-PET —Neuropsychology+FDG-PET Neuropsychology battery+SPECT —Neuropsychology battery —MRI —Neuropsychology+MRI Neuropsychology battery+MRI —Neuropsychology battery+MRI —Neuropsychology battery —MRI —CSF —FDG-PET —Neuropsychology+MRI+CSF —Neuropsychology+MRI+CSF+FDG-PET —Neuropsychology battery —MRI —Neuropsychology+MRI —Neuropsychology battery —FDG-PET —Neuropsychology+FDG-PET Visser et al. 85 Arnaiz et al.75 Peters et al.86 40 (18) 2 years Segovia et al.87 46 (26) 3 years Classification accuracy 88% 77% 96% 65% 75% 90% 77.8% 89.6% 80.5% 92.5% 71.9% Sensitivity 91% 64% 66% 63% 57% 70% 65% 82.5% 75% 87.5% 85% 74% 89% Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairment. N, Number of MCI patients (number of patients who progressed to AD); MRI, magnetic resonance imaging, measure of cerebral grey matter volume or cortical thickness; FDG-PET, fluorodeoxyglucose positron emission tomography, measure of cerebral glucose metabolism; SPECT, single-photon emission computed tomography, measure of cerebral perfusion; CSF, measure of tau and Aβ1-42 levels in CSF. than a single score.15,26,28,38,49,50,82 Thus, in the face of the variety of measures that was found to be sensitive and specific to early AD, future search for the best predictors should probably consider combination of tasks assessing episodic memory, semantic memory, executive functioning, visuospatial processing and abstract reasoning. COMBINING NEUROPSYCHOLOGY AND NEUROIMAGING FOR PREDICTION OF DEMENTIA Current research criteria for MCI due to AD83 and the recent recommendations for defining preclinical AD84 incorporated biomarkers like cerebrospinal fluid measures of amyloid and tau pathology, medial temporal atrophy on magnetic resonance images and reduction of glucose metabolism in the temporoparietal and medial posterior cortices or cerebral accumulation of amyloid on positron emission tomography scans. In this context, it seems advisable to combine several markers of AD as this may improve prediction accuracy. Actually, several studies have reported good predictive power for classifying MCI patients as future AD versus stable MCI when using combination of neuropsychological measures and biomarkers (medial temporal atrophy, temporoparietal glucose metabolism, cerebrospinal fluid amyloid, cortical thickness) (see Table 2). Some argued that combining neuroimaging and neuropsychological markers improved discrimination accuracy compared with each kind of predictor alone. This was in fact based on mere inspection of classification accuracies. For instance, Visser et al.85 used logistic regression analyses to assess the predictive power of a memory measure and the manually drawn volume of the medial temporal lobe to classify subjects with MCI as a function of whether they developed dementia or not in a 3-year follow-up period. They observed that the highest classification accuracy was obtained by combining the memory score and the medial temporal lobe volume (96%). Memory or cerebral atrophy alone © 2014 Macmillan Publishers Limited correctly classified, respectively, 88% and 77% of the patients. In the same vein, in Schmand et al.,47 combining a verbal episodic memory score, hippocampal volume and cerebrospinal fluid amyloid measure correctly predicted progression from MCI to AD with an accuracy of 70%, whereas classification accuracy was below 70% for each individual measure. Similarly, Peters et al.86 indicated that cortical thickness of the anterior cingulate gyrus combined to specific memory measures yielded a classification accuracy of 87.5% in the discrimination between stable MCI versus MCI who developed AD. These were considered more accurate predictions than those based on neuroimaging (75%) or cognitive measures (82.5%) alone. In an attempt to provide support to this observation, we recently assessed the statistical significance of the improvement in predictive accuracy from individual predictors to combined markers.87 As hypothesized, combining well-known neuropsychological markers of AD (RI48 and verbal fluency scores) and measures of cerebral glucose metabolism fluorodeoxyglucose positron emission tomography allowed to discriminate stable and progressor MCI patients significantly better (89%) than using neuroimaging data alone (74%) (permutation test, P o 0.001). CONCLUSIONS Individuals who will develop AD present with specific cognitive difficulties several years before any clinical sign of pathology is detected. When they exhibit MCI, it is possible to predict whether they have a high risk of progressing to the typical form of AD (amnesic presentation) based on performance in some neuropsychological tests. Prediction of AD achieves high sensitivity and specificity for a measure of verbal cued recall following controlled encoding (Free and Cued Selective Reminding test, RI48). This measure is thought to be particularly sensitive to early hippocampal neuropathological changes in AD and their cognitive consequence, namely a specific deficit of memory encoding and European Journal of Clinical Nutrition (2014) 1 – 8 Cognitive markers of Alzheimer’s disease C Bastin and E Salmon 6 consolidation, as opposed to a deficit in elaborative encoding and retrieval strategies like in normal aging and other forms of dementia. Future AD onset is also well predicted by category verbal fluency scores. These neuropsychological measures significantly improve predictive accuracy when they are added to neuroimaging biomarkers. This finding has been incorporated in recent revisions of diagnostic criteria for the prodromal phase of AD.63,83 Thus, specific neuropsychological deficits involving encoding of new information into episodic memory and word retrieval into semantic memory, combined with neuroimaging biomarkers, may allow to point at older individuals with greater risk to develop AD in coming years. Importantly, these markers alert about an increased probability of dementia, but should not be taken as definitive sign of future dementia. As stressed in the revised diagnostic criteria, the combination of neuropsychological profile and biomarkers should be used for research purposes rather than for the sake of clinical diagnosis. Indeed, one of the main goals of detecting at-risk individuals is the identification of targets for testing therapeutic interventions that have the potential of attenuating the rate of cognitive decline, such as individualized cognitive rehabilitation programs or modification of lifestyle, including nutritional interventions. CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGEMENTS CB is a Research Associate at the F.R.S-FNRS. Research conducted at the Cyclotron Research Centre is supported by ULg, FRS-FNRS, IUAP 7/11, ARC n° 12/17-01 REST, and SAO/FRA. REFERENCES 1 McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 263–269. 2 Jack Jr CR, Holtzman DM. Biomarker modeling of Alzheimer's disease. 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