Andrea Tales, Frank Jessen, Christopher Butler, Gordon Wilcock, Judith Phillips, Tony Bayer
Subjective Cognitive Decline
Jon Stone, Suvankar Pal, Daniel Blackburn, Markus Reuber, Parvez Thekkumpurath, Alan Carson
Functional (Psychogenic) Cognitive Disorders: A Perspective from the Neurology Clinic
Abstract: Cognitive symptoms such as poor memory and concentration represent a common cause of morbidity among patients presenting to general practitioners and may result in referral for a neurological opinion. In many cases, these symptoms do not relate to an underlying neurological disease or dementia. In this article we present a personal perspective on the differential diagnosis of cognitive symptoms in the neurology clinic, especially as this applies to patients who seek advice about memory problems but have no neurological disease process. These overlapping categories include the following ‘functional’ categories: 1) cognitive symptoms as part of anxiety or depression; 2) “normal” cognitive symptoms that become the focus of attention; 3) isolated functional cognitive disorder in which symptoms are outwith 'normal' but not explained by anxiety; 4) health anxiety about dementia; 5) cognitive symptoms as part of another functional disorder; and 6) retrograde dissociative (psychogenic) amnesia. Other ‘non-dementia’ diagnoses to consider in addition are 1) cognitive symptoms secondary to prescribed medication or substance misuse; 2) diseases other than dementia causing cognitive disorders; 3) patients who appear to have functional cognitive symptoms but then go on to develop dementia/another neurological disease; and finally 4) exaggeration/malingering. We discuss previous attempts to classify the problem of functional cognitive symptoms, the importance of making a positive diagnosis for the patient, and the need for large cohort studies to better define and manage this large group of patients.
Catherine Pennington, Amrit Hayre, Margaret Newson Elizabeth Coulthard
Functional Cognitive Disorder: A Common Cause of Subjective Cognitive Symptoms
Abstract: Patients frequently present to the memory clinic with self-reported cognitive symptoms that cannot be attributed to structural, toxic, or metabolic causes, and are out of keeping with their performance on neuropsychological assessment. This can be considered to be Functional (psychosomatic) Cognitive Disorder, which results in significant patient distress and often has a major impact on social functioning and employment. We performed a retrospective analysis of the Bristol ReMemBr group cognitive clinic database to ascertain the prevalence of Functional Cognitive Disorder, review the patient characteristics, and develop new guidelines for diagnosis and management. 196 patients were screened of whom 23 were diagnosed with Functional Cognitive Disorder; the oldest patient with this diagnosis was aged 60 years at symptom onset. When considering only those presenting below the age of 60 years (total no. held on database = 69), a third were diagnosed with Functional Cognitive Disorder. On neuropsychological testing, 47% had an atypical (invalid) pattern of results, or failed tests of performance validity. Of those with valid neuropsychological results, 80% scored in the normal range. Depression and anxiety were common but did not appear to be the primary cause of cognitive symptoms. Particular characteristics seen were excessively low self-rating of memory ability, and discrepancies between perceived and actual cognitive performance. The rate of unemployment was high, often due to the cognitive symptomatology. This is an important disorder to address, being common in working adults, and carrying a risk of misdiagnosis as early neurodegeneration, with subsequent inappropriate treatment and inclusion in clinical trials.
Amy Jenkins, Andrea Tales, Jeremy Tree, Antony Bayer
Are We Ready? The Construct of Subjective Cognitive Impairment and its Utilization in Clinical Practice: A Preliminary UK-Based Service Evaluation
Abstract: Extensive research on the concept of mild cognitive impairment (MCI) as a potential prodromal stage of dementia has highlighted the likelihood that abnormalities in information processing occur at even earlier stages in the disease process with research increasingly focused on the relatively new concept of subjective cognitive impairment (SCI). An individual with SCI will experience cognitive impairment solely on a subjective level, which is in contrast to an individual with MCI who will also experience cognitive impairment at an objective level. SCI is believed to be a risk factor for development of MCI. This qualitative service evaluation aimed to determine how much is known about SCI and how it is currently managed in specialist clinical practice in the UK. An email-based questionnaire containing a vignette of an individual presenting with SCI was distributed to 112 memory clinics requesting information on their most likely approach to such an individual. The 21% response rate evinces potential time pressure within clinical services that may preclude research participation and/or a lack of issue salience at present. However, the data from those who responded provide an important insight into ‘where we are now’ in relation to this issue. Analysis revealed main themes associated with SCI, namely the factors that influence what action is taken when an individual presents and what further investigations are performed, the multiplicity of potential outcomes experienced, and the barriers clinicians may face. The findings highlight the need for a coherent and consistent framework in relation to the management of SCI.
Tobias Luck, Susanne Röhr, Frank Jessen, Arno Villringer, Matthias C. Angermeyer, Steffi G. Riedel-Heller
Mortality in Individuals with Subjective Cognitive Decline: Results of the Leipzig Longitudinal Study of the Aged (LEILA75+)
Abstract: Background: Studies have shown that dementia and cognitive impairment can increase mortality, but less is known about the association between subjectively perceived cognitive deficits (subjective cognitive decline, SCD) and mortality risk. Objective: In this study, we analyzed mortality in non-demented individuals with SCD in a general population sample aged 75+ years. Method: Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate survival times of individuals with and without SCD and multivariable Cox proportional hazards regression to assess the association between SCD and mortality risk, controlled for covariates. Results: Out of 953 non-demented individuals at baseline, 117 (12.3%) expressed SCD. Participants with SCD showed a significantly higher case-fatality rate per 1,000 person-years (114.8, 95% CI=90.5-145.7 versus 71.7, 95% CI=64.6-79.5) and a significantly shorter mean survival time than those without (5.4 versus 6.9 years, p<0.001). The association between SCD and mortality remained significant in the Cox analysis; SCD increased mortality risk by about 50% (adjusted Hazard Ratio=1.51) during the study period. Besides SCD, older age, male gender, diabetes mellitus, stroke, and lower global cognitive functioning were also significantly associated with increased mortality. Conclusion: Our findings suggest an increased mortality risk in non-demented older individuals with SCD. Even though further studies are required to analyze potential underlying mechanisms, subjective reports on cognitive deficits may be taken seriously in clinical practice not only for an increased risk of developing dementia and AD but also for a broader range of possible adverse health outcomes.
Caroline Tandetnik, Meagan T. Farrell, Mark S. Cary, Sarah Cines, Sheina Emrani, Jason Karlawish, Stephanie Cosentino
Ascertaining Subjective Cognitive Decline: A Comparison of Approaches and Evidence for Using an Age-Anchored Reference Group Abstract: Background: Subjective cognitive decline (SCD) is increasingly considered promising to detect preclinical Alzheimer’s disease. How SCD is ascertained is critical for determining its potential utility in identifying at-risk individuals, yet SCD measures differ along several dimensions. Objective: We aimed to examine the extent to which reports of SCD in healthy elderly may be influenced by the characteristics of the SCD measures. We investigated variations in rates of SCD endorsement across different measures, including an open-ended question. We also examined the association of responses across measures, and the degree to which specific SCD items were associated with objective memory performance. Methods: 99 healthy elderly completed a series of questionnaires from which 10 items examining SCD for memory and other aspects of cognition were drawn. We applied Cochran’s Q tests to assess differences in rates of SCD, correlation analyses to examine association of SCD responses, and regression models to determine the association between SCD items and delayed verbal memory. Results: Rates of SCD varied as a function of the assessment format, ranging from 1 to 7% for memory and 5 to 20% for concentration. SCD was lower for memory versus non-memory domains. SCD items were associated both within and across domains. The most accurate predictor of memory was memory-related SCD in comparison to others the same age. Conclusion: Characteristics of SCD items influence rates of endorsement. Querying SCD using an “age-anchored” question may provide the most accurate reflection of actual cognitive performance.
Gianfranco Dalla Barba, Valentina La Corte, Bruno Dubois
For a Cognitive Model of Subjective Memory Awareness
Abstract: The clinical challenge in subjective memory decline (SMD) is to identify which individuals will present memory deficits. Since its early description from Babinsky, who coined the term ‘anosognosia’ (i.e., the lack of awareness of deficit), the awareness of cognitive impairment is crucial in clinical neuropsychology. We propose a cognitive model in which SMD and anosognosia can be considered two opposite forms of distorted awareness of cognitive performance and can be accounted for within a model in which consciousness of memory performance can vary in a continuum from normal awareness of performance (preserved or impaired) to anosognosia through a disorder of consciousness related to SMD that we call “cognitive dysgnosia”, i.e., awareness of normal performance as impaired. This model suggests that the neuropsychological assessment of memory performance should always be coupled with a deep evaluation of awareness of the subject’s memory profile, which allow to better identify the disorder of consciousness with or without cognitive impairment. In this line, it seems necessary to develop more sensitive neuropsychological tools in order to discriminate, within the SMD, individuals who are likely to develop clinical Alzheimer’s disease from those whose memory decline complaint is not associated with an underlying neurodegenerative pathology.
Laura A. Rabin, Colette M. Smart, Paul K. Crane, Rebecca E. Amariglio, Lorin M. Berman, Mercè Boada, Rachel F. Buckley, Gaël Chételat, Bruno Dubois, Kathryn A. Ellis, Katherine A. Gifford, Angela L. Jefferson, Frank Jessen, Mindy J. Katz, Richard B. Lipton, Tobias Luck, Paul Maruff, Michelle M. Mielke, José Luis Molinuevo, Farnia Naeem, Audrey Perrotin, Ronald C. Petersen, Lorena Rami, Barry Reisberg, Dorene M. Rentz, Steffi G. Riedel-Heller, Shannon L. Risacher, Octavio Rodriguez, Perminder S. Sachdev, Andrew J. Saykin, Melissa J. Slavin, Beth E. Snitz, Reisa A. Sperling, Caroline Tandetnik, Wiesje M. van der Flier, Michael Wagner, Steffen Wolfsgruber, the Alzheimer’s Disease Neuroimaging Initiative, Sietske A.M. Sikkes, and the Subjective Cognitive Decline Initiative (SCD-I) Working Group
Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures used Across 19 International Research Studies
Abstract: Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures—approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes.
Natalia Valech, María A. Mollica, Jaume Olives, Adrià Tort, Juan Fortea, Alberto Lleo, Belén Sánchez-Saudinós, José Luis Molinuevo, Lorena Rami
Informants’ Perception of Subjective Cognitive Decline Helps to Discriminate Preclinical Alzheimer’s Disease from Normal Aging
Abstract: Background: Self-reported and informant-reported subjective cognitive decline (SCD) may be useful in the detection of preclinical Alzheimer’s disease (Pre-AD) and cognitive impairment related to abnormal amyloid-β (Aβ42) levels. Objectives: a) To compare the Subjective Cognitive Decline Questionnaire (SCD-Q) ratings between Pre-AD subjects and cognitively healthy controls, b) to study the association of SCD-Q scores with levels of AD biomarkers in cognitively healthy and cognitively impaired subjects, and c) to compare SCD-Q ratings in cognitively impaired subjects with or without abnormal Aβ42. Methods: Two hundred and seventeen participants (111 subjects; 106 informants) answered the SCD-Q. All subjects underwent a lumbar puncture to determine levels of Aβ42 and tau, and an extensive neuropsychological battery. Healthy subjects were classified as Controls (CTR) or Pre-AD according to the absence or the presence of abnormal Aβ42, and those with cognitive impairment (CI) into Non-amyloid (NonAB-CI) or Amyloid (AB-CI) impairment. Results: Informants’ SCD-Q scores were significantly higher in the Pre-AD group than in the CTR group (F=6-75; p=0.01). No significant differences were found in self-ratings. In the cognitively impaired groups, there were no significant differences in the SCD-Q ratings. In the whole sample, informants’ ratings of SCD-Q correlated with Aβ42 (r=-0.21; p=0.02) and tau levels (r= 0.28; p=0.00). Conclusions: Higher informants’ ratings of SCD-Q differentiated Pre-AD subjects from CTR. Informants’ ratings of SCD-Q correlated weakly with cerebrospinal fluid AD biomarkers.
Octavio Rodríguez-Gómez, Carla Abdelnour, Frank Jessen, Sergi Valero, Merçé Boada
Influence of Sampling and Recruitment Methods in Studies of Subjective Cognitive Decline
Abstract: Subjective cognitive decline (SCD) has been proposed as a marker of neurodegeneration in cognitively normal elderly. This idea is supported by the growing evidence that SCD is associated with Alzheimer’s disease (AD) biomarkers and increases the risk of future cognitive impairment. Nevertheless, this evidence is not complete, since other studies have not found these associations. This discrepancy could have a methodological basis. It is well known that across the broad spectrum of degenerative disease from healthy controls to dementia, the research setting affects key characteristics of the sample such as age, educational level, or family history of dementia. However, virtually no studies have specifically tested the influence of sampling and recruitment methods in SCD research. Population-based samples are less biased and therefore they probably are more suitable for the study of memory complaints as a symptom at the population level. On the other hand, the memory clinic setting could introduce a set of biases that make these patients more likely to develop cognitive impairment. Thus, memory clinic would be the most cost-effective context in which to study the phenomenology of SCD due to AD and eventually recruit patients for secondary prevention trials. However, this general hypothesis needs to be tested. Studies that compare samples of patients with SCD from different settings are necessary. Sometimes it is difficult for patients with subtle forms of cognitive impairment to access specialized diagnostic centers. Based in our experience we state that Open House type initiatives may be useful for attracting these individuals to memory clinics.
Hilary Anne Archer, Margaret Anne Newson, Elizabeth Jane Coulthard
Subjective Memory Complaints: Symptoms and Outcome in Different Research Settings
Abstract: Subjective memory complaints (SMC) are important and may, in certain individuals, herald the onset of neurodegenerative diseases such Alzheimer’s disease. However, they are very common and in some individuals will result from mood disorders/personality factors or systemic illnesses. Research has been hampered by the wide variety of criteria and neuropsychological tests used to define this disorder. Different terminology has also hindered the ability to generate generalizable results. We evaluate how subjects with SMC are defined within different research settings (community, primary care, and memory clinic), their rates of progression to mild cognitive impairment and dementia, and how individuals within these contexts differ in terms of complaints, personal characteristics, and help-seeking behavior.
Jennifer A. Yates, Linda Clare, Robert T. Woods, Fiona E. Matthews and the Cognitive Function and Ageing Study Wales
Subjective Memory Complaints are Involved in the Relationship between Mood and Mild Cognitive Impairment
Abstract: Subjective memory complaints (SMC) are a criterion in many definitions of mild cognitive impairment (MCI). However, there is controversy over whether this is useful and appropriate, as previous research has suggested that SMC may be a function of mood problems such as anxiety and depression. This paper aimed to establish the relationship between MCI and mood in older people and to investigate the role that SMC play in the relationship. Structured interviews were conducted with community dwelling older people in Wales to collect information regarding cognitive functioning, mood, and well-being. A widely-used algorithm was used to categorize 3,173 participants into three groups: not cognitively impaired, MCI including SMC (MCI), and MCI without SMC (MCIW). The odds of experiencing anxiety or depression were calculated for each cognitive group. Participants with MCI had increased odds of experiencing symptoms of both anxiety and depression, but the odds were not changed for participants in the not cognitively impaired or MCIW categories. A mediation analysis was performed on the whole sample using cognition as a dichotomous variable, grouped using an age-, education-, and gender-adjusted median cut off point. This showed that SMC partially mediated the relationship between anxiety and cognition, and depression and cognition. Mood problems may be related to SMC rather than objective cognitive impairment, as only participants with MCI that included SMC showed increased odds of experiencing anxiety and depression. SMC are likely to play a mediating role in the relationship between mood and cognitive functioning.
Rachel F. Buckley, Michael M. Saling, Ingo Frommann, Steffen Wolfsgruber, Michael Wagner
Subjective Cognitive Decline from a Phenomenological Perspective: A Review of the Qualitative Literature
Abstract: Background: Subjective cognitive decline is related to greater risk of dementia and biological markers of Alzheimer’s disease (AD), but researchers are yet to characterize the phenomenological perspective of cognitive decline in those with and without a diagnosis of AD. Objective: To collate and synthesize studies measuring the subjective experience of cognitive change or decline in healthy older adults and those with mild cognitive impairment and AD. Methods: We reviewed 58 peer-reviewed articles that were found to directly or indirectly refer to the subjective experience of cognitive decline. Results: We extracted eight central themes, dealing with cognitive changes experienced by each diagnostic group, and also related to issues of changing self-identity, the causal attribution of cognitive decline, the anxiety and concern related to perceived decline, the negative perceptions attached to a diagnosis of dementia, changing levels of insight, and perception of well-being in aging. Conclusion: This review is the first step toward characterizing phenomenological profiles of cognitive change in both non-demented and demented older adults. Developing a clearer understanding of subjective cognitive decline, particularly at the earliest stages of AD, will augment the sensitivity of detection of individuals at greater risk of future dementia.
Audrey Perrotin, Robin de Flores, Franck Lamberton, Géraldine Poisnel, Renaud La Joie, Vincent de la Sayette, Florence Mézenge, Clémence Tomadesso, Brigitte Landeau, Béatrice Desgranges, Gaël Chételat
Hippocampal Subfield Volumetry and 3D Surface Mapping in Subjective Cognitive Decline
Abstract: Background. Subjective cognitive decline (SCD) may be the first clinical sign of Alzheimer’s disease (AD). SCD individuals with normal cognition may already have significant hippocampal atrophy, a well-known feature of AD. Objective. To test the hypothesis that SCD, compared to healthy individuals without SCD, have a pattern of hippocampal subfield atrophy similar to that measured in the AD pathology. Methods. 17 SCD, 21 AD, and 40 matched controls underwent a standard T1-weighted MRI and a dedicated high-resolution MRI proton-density hippocampal sequence. For each participant, three hippocampal regions-of-interest were manually delineated on the proton-density hippocampal sequence corresponding to the CA1, subiculum, and other (including CA2-3-4 and dentate gyrus) subfields. Total intracranial volume (TIV)-normalized subfield volumes were compared between-group. Voxelwise group comparisons assessed from the standard T1 MRI were also projected on 3D hippocampal surface views. Results. Both patient groups showed significant TIV-normalized volume decrease in hippocampus global volume and in CA1 and subiculum subfields as well as in the other subfield in AD compared to controls. Significant differences were observed between SCD and AD in hippocampus global TIV-normalized volume. Atrophy maps on hippocampal surface showed major involvement of the lateral part (CA1) in both SCD and AD, with larger overlap of other regions in AD. Conclusion. The findings indicate topographically similar hippocampal subfield changes in SCD individuals as those found in AD. This further highlights the relevance of SCD recruited from a memory clinic in assessing predementia AD stages.
Beth E. Snitz, Oscar L. Lopez, Eric McDade, James T. Becker, Ann D. Cohen, Julie C. Price, Chester A. Mathis, William E. Klunk
Amyloid-β Imaging in Older Adults Presenting to a Memory Clinic with Subjective Cognitive Decline: A Pilot Study
Abstract: Background: Subjective cognitive decline (SCD) in otherwise normal aging may be identified via symptom inventories in a research setting (‘questionnaire-discovered complaints’) or via patients seeking evaluation/services in a clinical setting (‘presenting complainers’). Most studies of SCD and amyloid-β (Aβ) imaging to date have used the former approach, with inconsistent results. Objective: To test whether ‘presenting SCD’ participants in an academic memory clinic setting show increased brain Aβ deposition on imaging. Methods: Fourteen patients (mean age 68.1, SD 4.0 years) diagnosed with subjective cognitive complaints with normal neuropsychological testing were recruited into a Pittsburgh compound B (PiB)-PET study. Detailed self-report inventories and additional cognitive tests were administered. Results were compared to a reference cohort of cognitively normal volunteers (NC) from an independent neuroimaging study (mean age 73.6, SD 5.8 years). Results: 57% (8/14) of SCD participants were PiB-positive by a sensitive, regionally-based definition, compared to 31% (26/84) of the NC cohort. SCD participants had significantly higher PiB retention (SUVR) than NC in three of six regions of interest: frontal cortex (p=0.02), lateral temporal cortex (p=0.02), and parietal cortex (p=0.04). SCD participants showed measurable deviations on questionnaires reflecting high negative affect (i.e., depressive symptoms and neuroticism). Findings were suggestive that deficits on verbal associative binding may be specific to Aβ-positive versus Aβ-negative SCD. Conclusion: Older participants with SCD presenting to a memory clinic in this pilot study sample have higher brain Aβ deposition compared to normal aging study volunteers unselected on complaints. Further study of presenting SCD are warranted to determine the prognostic significance of Aβ deposition in this context.
Alexander Koppara, Ingo Frommann, Alexandra Polcher, Mario A. Parra, Wolfgang Maier, Frank Jessen, Thomas Klockgether, Michael Wagner
Feature Binding Deficits in Subjective Cognitive Decline and in Mild Cognitive Impairment
Abstract: Background: Feature binding is a sensitive and specific cognitive marker for Alzheimer's disease (AD). Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are clinical categories associated with an increased risk for AD. Objective: To investigate whether the SCD and MCI group are impaired with regard to feature binding. Methods: The feature binding test was administered to memory clinic patients with either SCD (n=19, mean MMSE: 29.2) or with MCI (n=23, mean MMSE: 26.5), and to a group of healthy controls (HC, n=23, mean MMSE: 29.0). Participants were assessed with the CERAD Plus neuropsychological test battery. Cognitive performance of the three groups was compared by ANCOVA with age, gender and education as covariates and planned contrasts. Results: Groups differed in the binding condition. Planned contrasts showed significant differences in adjusted means between HC and SCD (p=0.003), as well as between HC and MCI (p<0.0001). Discussion: The feature binding task detects subtle cognitive impairments in participants with SCD, who are unimpaired in traditional neuropsychological testing. This corroborates the use of feature binding tests in preclinical AD studies and suggests that specific cognitive deficits can be found in SCD. Future studies incorporating AD biomarkers and longitudinal follow-up are needed to further establish the clinical utility of feature binding.
Simone Lista, Jose L. Molinuevo, Enrica Cavedo, Lorena Rami, Philippe Amouyel, Stefan J. Teipel, Francesco Garaci, Nicola Toschi, Marie-Odile Habert, Kaj Blennow, Henrik Zetterberg, Sid E. O’Bryant, Leigh Johnson, Samantha Galluzzi, Arun L.W. Bokde, Karl Broich, Karl Herholz, Hovagim Bakardjian, Bruno Dubois, Frank Jessen, Maria C. Carrillo, Paul S. Aisen, Harald Hampel
Evolving Evidence for the Value of Neuroimaging Methods and Biological Markers in Subjects Categorized with Subjective Cognitive Decline
Abstract: There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer’s disease (AD), may denote very early, subtle cognitive decline that cannot be identified using established standardized tests of cognitive performance. The substantial heterogeneity of existing SCD-related research data has led the Subjective Cognitive Decline Initiative (SCD-I) to accomplish an international consensus on the definition of a conceptual research framework on SCD in preclinical AD. In the area of biological markers, the cerebrospinal fluid signature of AD has been reported to be more prevalent in subjects with SCD compared to healthy controls; moreover, there is a pronounced atrophy, as demonstrated by magnetic resonance imaging, and an increased hypometabolism, as revealed by positron emission tomography, in characteristic brain regions affected by AD. In addition, SCD individuals carrying an apolipoprotein ε4 allele are more likely to display AD-phenotypic alterations. The urgent requirement to detect and diagnose AD as early as possible has led to the critical examination of the diagnostic power of biological markers, neurophysiology, and neuroimaging methods for AD-related risk and clinical progression in individuals defined with SCD. Observational studies on the predictive value of SCD for developing AD may potentially be of practical value, and an evidence-based, validated, qualified, and fully operationalized concept may inform clinical diagnostic practice and guide earlier designs in future therapy trials.