Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

BACKGROUND AND OBJECTIVES: Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. METHODS: We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of ß-amyloid (Aß) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. RESULTS: A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: ßMMSE = -0.055, 95% CI -0.067 to -0.043, ßFCSRT = -0.034, 95% CI -0.043 to -0.025, ßfluency = -0.029, 95% CI -0.038 to -0.020, ßSPPB = -0.040, 95% CI -0.057 to -0.022, and ß4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: ßMMSE = -0.039, 95% CI -0.053 to -0.025, ßFCSRT = -0.022, 95% CI -0.032 to -0.012, ßfluency = -0.014, 95% CI -0.024 to -0.004, and ß4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aß42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: ß = 0.011, 95% CI 0.002-0.020, and ß = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. DISCUSSION: In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in mild cognitive impairment.

Introduction: Both the loss of awareness for cognitive decline (a. k.a anosognosia) and neuropsychiatric symptoms (NPS) are common in patients with Alzheimer's disease (AD) dementia, even in prodromal stages, and may exacerbate functional impairment and negatively impact caregiver burden. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross-sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI). Methods: We included 237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with a baseline clinical diagnosis of MCI. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study-partners at baseline and annually over a mean of 4.29 years [standard deviation (SD) = 2.72]. Anosognosia was defined as the study-partner having an ECog score ≥2.5/4 and the participant having an ECog score < 2.5/4 on their baseline measure and their last observation without more than two consecutive deviating observations during the follow-up period. The 12-item study-partner-rated Neuropsychiatric Inventory determined the presence or absence of specific NPS. Survival analyses were performed to analyze the frequency and temporal onset of NPS over time in individuals with and without anosognosia. Results: Thirty-eight out of 237 participants displayed anosognosia. Groups had similar lengths of follow-up at baseline (p > 0.9), though participants with anosognosia had lower MMSE scores (p = 0.049) and a higher proportion of amyloid-positivity using PET (p < 0.001. At baseline, the frequencies of agitation (p = 0.029) and disinhibition (p < 0.001) were higher in the anosognosia group compared to the non-anosognosia group. Survival analyses showed earlier onset of seven of the 12 NPS in the anosognosia group (p's < 0.001). Discussion: Loss of awareness for cognitive decline is associated with greater frequency and earlier onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process for anosognosia and NPS, a finding that needs to be addressed in future studies.

Understanding factors associated with the trajectory of subjective cognitive complaints in groups with similar objective cognitive trajectories.

BACKGROUND: Cognitive complaints are often regarded as an early sign of Alzheimer's disease (AD) but may also occur in several other conditions and contexts. This study examines the correlates of cognitive complaint trajectories over a 5-year period in individuals who shared similar objective cognitive trajectories. METHODS: We analyzed a subsample (n = 1748) of the MEMENTO cohort, consisting of individuals with subjective cognitive decline or mild cognitive impairment at baseline. Participants were stratified based on their latent MMSE trajectory over a 5-year period: "high and increasing," "subtle decline," and "steep decline." Within each of the three strata, we used a latent-class longitudinal approach to identify distinct trajectories of cognitive complaints. We then used multiple logistic regressions to examine the association between these complaint trajectories and several factors, including AD biomarkers (blood pTau/Aß42 ratio, cortical thickness, APOE genotype), anxiety, depression, social relationships, a comorbidity-polypharmacy score, and demographic characteristics. RESULTS: Among participants with high and increasing MMSE scores, greater baseline comorbidity-polypharmacy scores (odds ratio (OR) = 1.30, adjusted p = 0.03) were associated with higher odds of moderate and increasing cognitive complaints (as opposed to mild and decreasing complaints). Baseline depression and social relationships also showed significant associations with the complaint pattern but did not survive correction for multiple comparisons. Among participants with subtle decline in MMSE scores, greater baseline depression (OR = 1.76, adjusted p = 0.02) was associated with higher odds of moderate and increasing cognitive complaints (versus mild and decreasing). Similarly, baseline comorbidity-polypharmacy scores and pTau/Aß42 ratio exhibited significant associations, but they did not survive correction. Among participants with a steep decline in MMSE scores, greater baseline comorbidity-polypharmacy scores increased the odds of moderate complaints (versus mild, OR = 1.38, unadjusted p = 0.03, adjusted p = 0.32), but this effect did not survive correction for multiple comparisons. CONCLUSIONS: Despite similar objective cognitive trajectory, there is heterogeneity in the subjective perception of these cognitive changes. This perception was explained by both AD-related and, more robustly, non-AD-related factors. These findings deepen our understanding of the multifaceted nature of subjective cognitive complaints in individuals at risk for dementia and underscore the importance of considering a range of factors when interpreting cognitive complaints.

The temporal lobe in typical and atypical Alzheimer disease.

Alzheimer disease (AD) is defined neuropathologically by abnormal extra-cellular ß-amyloid plaques combined with intraneuronal tau aggregation. Patients sharing the same neuropathological features but presenting different clinical manifestations and evolutions have led to the notion of AD spectrum. This spectrum encompasses typical and atypical forms of AD. For all of them, specific parts of the temporal lobes, as well as their structural and functional connections with other brain regions, are affected. In typical amnestic late-onset Alzheimer's disease (>65 years old; LOAD), tau pathology gradually spreads to the brain from the medial temporal lobe (MTL). MTL is an inhomogeneous structure consisting of several subregions densely connected to each other and to other cortical and subcortical brain regions. These regions play a crucial role in the storage of information in episodic memory. In less common early-onset AD (<65 years old; EOAD), a large proportion of patients presents atypical clinical manifestations, in which memory impairment is not inaugural and predominant. Instead, these patients have predominant and/or isolated deficits in language, visuospatial, motor, or executive/behavioral functions. In atypical variants, brain damage is mainly centered on the posterior regions, with relative sparing of the MTL. However, the temporal lobe also appears to be variably and specifically damaged in some subtypes of EOAD. For example, the left superior temporal gyrus is the core of brain damage in the language variant, as well as the ventral regions of the temporal lobe play an important role in the clinic of the visual variant.

Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimer's Disease Spectrum.

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer's disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum. Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups. Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed. Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer's disease. The presence of an informant also seems necessary given its accuracy as a source of information.

Subtle postoperative cognitive disorder in preclinical Alzheimer's disease.

BACKGROUND: We examined the association between preclinical Alzheimer's disease (AD) and undergoing anesthesia and surgery ("surgery" henceforth) in a cohort of elderly individuals with a subjective cognitive decline (SCD). METHODS: Individuals with SCD (N = 268) were enrolled in a longitudinal follow-up study. Participants underwent comprehensive yearly cognitive evaluation for a period of 4 years. Brain amyloid load and glucose metabolism were studied by 18F-Florbetapir and Fluorodeoxyglucose positron emission tomography (PET) at baseline and after two years of follow-up. Exposure to surgery was systematically assessed during the first two years of follow-up. The association between surgery, cognition and AD markers was evaluated using generalized linear mixed models for cognition and linear models for neuroimaging markers. RESULTS: Sixty-five participants (24.25%) underwent surgery during the first year of follow-up, and 43 (16.04%) during the second year. Undergoing surgery had no overall impact on cognition over 4 years of follow-up nor on amyloid load and brain metabolism at two years of follow-up. However, a second step analysis revealed a small but significant association between undergoing surgery and a subtle decline in executive functions such as mental flexibility and divided attention (TMT B-A), in participants with greater amyloid load at baseline (Cohen's f2 = 0.01, multiple comparison corrected p < 0.001). Highly educated participants with surgery had significantly decreased metabolism over two years, when compared to low educated participants (Cohen's f2 = 0.04, p = 0.031). CONCLUSIONS: Our results suggest that surgery is associated with an increased risk of subtle cognitive decline after surgery, in the cognitively healthy elderly at risk for AD.

Awareness of Cognitive Decline in Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Background: Identifying a poor degree of awareness of cognitive decline (ACD) could represent an early indicator of Alzheimer's disease (AD). Objectives: (1) to understand whether there is evidence of poor ACD in the pre-dementia stages of AD; (2) to summarize the main findings obtained investigating ACD in AD; (3) to propose a conceptual framework. Data Sources: We searched Scopus, Pubmed, and the reference lists for studies published up to August 2020. Original research articles must report a measure of ACD and included individuals with AD dementia, or prodromal AD (or MCI), or being at risk for AD. Data Synthesis: All studies covering preclinical, prodromal, and AD dementia were systematically reviewed. We intended to perform a meta-analysis of empirical studies on preclinical AD or prodromal AD (or MCI), to compare ACD between clinical groups. Due to the paucity of literature on preclinical AD, meta-analysis was only possible for prodromal AD (or MCI) studies. Results: We systematically reviewed 283 articles, and conducted a meta-analysis of 18 articles on prodromal AD (or MCI), showing that ACD was not significantly different between patients with amnestic and non-amnestic MCI (SMD = 0.09, p = 0.574); ACD was significantly poorer in amnestic MCI (SMD = -0.56, p = 0.001) and mild AD (SMD = -1.39, p < 0.001) than in controls; ACD was also significantly poorer in mild AD than in amnestic MCI (SMD = -0.75, p < 0.001), as well as poorer than in non-amnestic MCI (SMD = -1.00, p < 0.001). We also discuss key findings on ACD in AD, such as its neural and cognitive correlates. Conclusions and Implications: We propose that patients may be complaining of their initial subtle cognitive changes, but ACD would soon start to decrease. The individual would show mild anosognosia in the MCI stage, and severe anosognosia in dementia. The evaluation of ACD (comparing self-report to cognitive scores or to informant-report) could be useful to guide the clinician toward a timely diagnosis, and in trials targeting early-stage AD.

Understanding the Variability in Graph Data Sets through Statistical Modeling on the Stiefel Manifold.

Network analysis provides a rich framework to model complex phenomena, such as human brain connectivity. It has proven efficient to understand their natural properties and design predictive models. In this paper, we study the variability within groups of networks, i.e., the structure of connection similarities and differences across a set of networks. We propose a statistical framework to model these variations based on manifold-valued latent factors. Each network adjacency matrix is decomposed as a weighted sum of matrix patterns with rank one. Each pattern is described as a random perturbation of a dictionary element. As a hierarchical statistical model, it enables the analysis of heterogeneous populations of adjacency matrices using mixtures. Our framework can also be used to infer the weight of missing edges. We estimate the parameters of the model using an Expectation-Maximization-based algorithm. Experimenting on synthetic data, we show that the algorithm is able to accurately estimate the latent structure in both low and high dimensions. We apply our model on a large data set of functional brain connectivity matrices from the UK Biobank. Our results suggest that the proposed model accurately describes the complex variability in the data set with a small number of degrees of freedom.

Awareness of cognitive decline trajectories in asymptomatic individuals at risk for AD.

BACKGROUND: Lack of awareness of cognitive decline (ACD) is common in late-stage Alzheimer's disease (AD). Recent studies showed that ACD can also be reduced in the early stages. METHODS: We described different trends of evolution of ACD over 3 years in a cohort of memory-complainers and their association to amyloid burden and brain metabolism. We studied the impact of ACD at baseline on cognitive scores' evolution and the association between longitudinal changes in ACD and in cognitive score. RESULTS: 76.8% of subjects constantly had an accurate ACD (reference class). 18.95% showed a steadily heightened ACD and were comparable to those with accurate ACD in terms of demographic characteristics and AD biomarkers. 4.25% constantly showed low ACD, had significantly higher amyloid burden than the reference class, and were mostly men. We found no overall effect of baseline ACD on cognitive scores' evolution and no association between longitudinal changes in ACD and in cognitive scores. CONCLUSIONS: ACD begins to decrease during the preclinical phase in a group of individuals, who are of great interest and need to be further characterized. TRIAL REGISTRATION: The present study was conducted as part of the INSIGHT-PreAD study. The identification number of INSIGHT-PreAD study (ID-RCB) is 2012-A01731-42.

The meta-memory ratio: a new cohort-independent way to measure cognitive awareness in asymptomatic individuals at risk for Alzheimer's disease.

BACKGROUND: Lack of awareness of cognitive decline (ACD) has been described at the preclinical and prodromal stages of Alzheimer's disease (AD). In this study, we introduced a meta-memory ratio (MMR) and explored how it is associated with neuroimaging AD biomarkers in asymptomatic individuals at risk for AD. METHOD: Four hundred forty-eight cognitively healthy participants from two cohorts of subjective memory complainers (INSIGHT-PreAD and ADNI) were included. Regression models were used to assess the impact of AD biomarkers on the MMR. RESULT: In both cohorts, there was a significant quadratic effect of cerebral amyloidosis on the MMR value. In particular, participants had a high ACD up to the amyloid positivity threshold, above which a decrease of ACD was eventually observed as the amyloid load increased. CONCLUSION: This nonlinear evolution of ACD in very early AD must be taken into account in clinical care and for trial enrollment as well.

Latent class analysis identifies functional decline with Amsterdam IADL in preclinical Alzheimer's disease.

INTRODUCTION: Trials in Alzheimer's disease (AD) now include participants at the earliest stages to prevent further decline. However, the lack of tools sensitive to subtle functional changes in early-stage AD hinders the development of new therapies as it is difficult to prove their clinical relevance. METHODS: We assessed functional changes over three years in 289 elderly memory complainers from the Investigation of Alzheimer's Predictors in subjective memory complainers cohort using the Amsterdam Instrumental-Activities-of-Daily-Living questionnaire (A-IADL-Q). RESULTS: No overall functional decline related to AD imaging markers was evidenced. However, five distinct classes of A-IADL-Q trajectories were identified. The largest class (212 [73.4%]) had stable A-IADL-Q scores over 3 years. A second group (23 [8.0%]) showed a persistent functional decline, higher amyloid load (P = .0005), and lower education (P = .0392). DISCUSSION: The A-IADL-Q identified a subtle functional decline in asymptomatic at-risk AD individuals. This could have important implications in the field of early intervention in AD.

Cognitive and neuroimaging features and brain ß-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

BACKGROUND: Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain ß-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease. METHODS: The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid ß deposition on 18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18F-FDG and 18F-florbetapir PET every 24 months. We assessed associations of amyloid ß deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type. FINDINGS: From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid ß deposition and the remainder did not. The amyloid ß subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid ß deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid ß1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid ß1-42 to amyloid ß1-40 (r=-0·61, p<0·0001), and identified amyloid ß deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid ß. Four participants (all positive for amyloid ß deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid ß deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater 18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]). INTERPRETATION: Brain ß-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent. FUNDING: Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

Evidence of practice effect in CANTAB spatial working memory test in a cohort of patients with mild cognitive impairment.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a system of neuropsychological tests frequently used to track the progression of cognitive deficits in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We investigated test-retest reliability in seven CANTAB tests. Twenty-five MCI patients, with either AD-like or conflicting/normal cerebrospinal fluid profiles underwent three testing sessions at 6-month intervals, including the following tests: Reaction Time and Rapid Visual Information Processing (assessing attention and reaction times); Delayed Matching-to-Sample, Paired Associates Learning, Spatial Recognition Memory and Pattern Recognition Memory (assessing memory); Spatial Working Memory (assessing executive functions). No significant difference was found when comparing the two groups. Many CANTAB measures obtained low or marginal test-retest coefficients. We observed a marked improvement in Spatial Working Memory (SWM) in both groups when comparing the baseline performance with the 6-month follow-up, but no difference in performance between 6- and 12-month follow-ups. A similar trend was documented in Paired Associates Learning (PAL), but the effect size was small. Such improvement may result from a practice effect, likely due to the learning of an effective strategy. Our evidence raised an important issue concerning the need for methodological caution when interpreting the results of longitudinal studies using SWM and PAL.

Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease.

BACKGROUND: Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD). OBJECTIVE: In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. METHODS: Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. RESULTS: Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group. CONCLUSION: This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.