Remy Genthon

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

During the past decade, a conceptual shift occurred in the field of Alzheimers disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Preclinical Alzheimer's disease: A systematic review of the cohorts underlying the concept

Preclinical Alzheimers disease (AD) is a relatively recent concept describing an entity characterized by the presence of a pathophysiological biomarker signature characteristic for AD in the absence of specific clinical symptoms. There is rising interest in the scientific community to define such an early target population mainly because of failures of all recent clinical trials despite evidence of biological effects on brain amyloidosis for some compounds. A conceptual framework has recently been proposed for this preclinical phase of AD. However, few data exist on this silent stage of AD. We performed a systematic review to investigate how the concept is defined across studies. The review highlights the substantial heterogeneity concerning the three main determinants of preclinical AD: “normal cognition,” “cognitive decline,” and “AD pathophysiological signature.” We emphasize the need for a harmonized nomenclature of the preclinical AD concept and standardized population‐based and case‐control studies using unified operationalized criteria.

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

BACKGROUNDnImproved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimers disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimers disease.nnnMETHODSnThe 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 β 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 β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimers disease was defined as an amnestic syndrome of the hippocampal type.nnnFINDINGSnFrom 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 β deposition and the remainder did not. The amyloid β 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 β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42 to amyloid β1-40 (r=-0·61, p<0·0001), and identified amyloid β 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 β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimers disease. They were older than other participants positive for amyloid β 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]).nnnINTERPRETATIONnBrain β-amyloidosis alone did not predict progression to prodromal Alzheimers disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.nnnFUNDINGnInstitut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

Precision pharmacology for Alzheimer’s disease

The complex multifactorial nature of polygenic Alzheimers disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive omics-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.

Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1-42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40

The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide [i.e., Aβ1–42], total tau [t‐tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL‐40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimers disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10‐fold cross‐validation.

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

BACKGROUNDnSubjective cognitive decline (SCD) may result from many conditions, including Alzheimers disease (AD).nnnOBJECTIVEnIn this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD.nnnMETHODSnCognitively normal older adults (Nu200a=u200a318) 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.nnnRESULTSnScores 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 (nu200a=u200a19) and high (nu200a=u200a86) 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.nnnCONCLUSIONnThis 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.

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints.

Observational multimodal neuroimaging studies indicate sex differences in Alzheimers disease pathophysiological markers.

INNOVATIVE BIOMARKER-GUIDED DIAGNOSTIC SYSTEM FROM PRECLINICAL TO ALZHEIMER’S DISEASE DEMENTIA

it is not clear whether this relationship is the same for older people with mental health problems. Mental health problems are also associated with poor cognitive function and difficulties in social relationships. Therefore, we aimed to explore social relationships and cognitive function in older people with mental health problems. Methods: Baseline and two year follow-up data were analysed from the Cognitive Function and Ageing Study–Wales (CFASWales). ANCOVAs were conducted to compare differences in social isolation, loneliness, social contact, cognitive function, and cognitive reserve at baseline amongst older peoplewith and without mental health problems (N 1⁄4 2,135). Linear regression modelling was used to assess the relationship between social isolation and cognition in a subgroup of older people with mental health problems (N1⁄4 186) andmoderation analysis was used to test the moderating effect of cognitive reserve. Results:Older people with mental health problems perceived themselves as more isolated and lonely than those without mental health problems, despite having an equivalent level of social contact with friends and family. In people with mental health problems, social isolation was associated with poor cognitive function at baseline, but not with cognitive change at two year follow-up. Cognitive reserve did not moderate this association. 57% of the people whowere experiencing clinically relevant symptoms of depression or anxiety at baseline were no longer experiencing these symptoms at two year follow-up. Conclusions: Social isolation may be associated with poor cognitive function in people with mental health problems at baseline. The observation that cognitive function does not decrease over two years may be attributed to the improvement in symptoms associated with mental health over the two year follow-up period. This has important implications for interventions aiming to enhancemental health and social contact in later life.

INCREASED PLASMA BACE1 CONCENTRATIONS IN WOMEN WITH SUBJECTIVE MEMORY COMPLAINTS: CORRELATION WITH PLASMA NFL

analysis, logistic regression analysis, and then a Receiver Operation Characteristic curve. Association analysis between cfssDNA and AD analytes will be performed. Results: Pair T test combined analysis demonstrated that cfssDNA concentration in AD samples is significantly lower than non-demented control samples. (2 tail pvalue 0.0007). Logistic regression analysis shows that cfssDNA concentration can predict AD status and the power of prediction increases when age included in the model (p-value<0.0001). Finally, ROC curve has a score of 0.82 in all three datasets. Association analysis between cfssDNA and analytes for AD will be reported at the conference. Conclusions: cfssDNA concentration in CSF is significantly lower in AD cases than non-demented controls. Due to this finding cfss DNA can be added as a possible biomarker to monitor the development of AD.

CORRELATION AND LONGITUDINAL DYNAMICS OF PLASMA NFL AND TAU CONCENTRATIONS IN AMYLOID-PET NEGATIVE INDIVIDUALS WITH SUBJECTIVE MEMORY COMPLAINTS

Fig 1. P-Tau(T AD patients an BIOMARKERS FOR ALZHEIMER’S DISEASE IN THE BALTIMORE LONGITUDINAL STUDY OFAGING Maja Mustapic, Erez Eitan, Sean T. Berkowitz, Thomas C. Diehl, Seema Gulyani, Yang An, Mark P. Mattson, Susan M. Resnick, Edward J. Goetzl, Luigi Ferrucci, Dimitrios Kapogiannis, National Institute on Aging/National Institutes of Health (NIA/NIH), Baltimore, MD, USA; University of California San Francisco (UCSF), San Francisco, CA, USA. Contact e-mail: maja.mustapic@nih.gov