Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
Functional MRI (fMRI) studies have linked the posteromedial cortex to episodic learning (encoding) and remembering (retrieval) processes. The posteromedial cortex is considered part of the default network and tends to deactivate during encoding, but activate during retrieval, a pattern known as the encoding/retrieval flip. Yet, the exact relationship between the neural correlates of memory performance (hit/miss) and memory stage (encoding/retrieval) and the extent of overlap with intrinsic cortical networks remains to be elucidated. Using task-based fMRI, we isolated the pattern of activity associated with memory performance, memory stage and the interaction between both. Using resting-state fMRI, we identified which intrinsic large-scale functional networks overlapped with regions showing task-induced effects. Our results demonstrated an effect of successful memory performance in regions associated with the control network and an effect of unsuccessful memory performance in the ventral attention network. We found an effect of memory retrieval in brain regions that span the default and control networks. Finally, we found an interaction between memory performance and memory stage in brain regions associated with the default network, including the posteromedial cortex, posterior parietal cortex and parahippocampal cortex. We discuss these findings in relation to the encoding/retrieval flip. In general, the findings demonstrate that task-induced effects cut across intrinsic cortical networks. Furthermore, regions within the default network display functional dissociations and this may have implications for the neural underpinnings of age-related memory disorders.
Neuropsychiatric symptoms in Alzheimer’s disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3 year period in normal older control (NC), mild cognitive impairment (MCI), and mild AD dementia subjects.
Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer’s Disease Neuroimaging Initiative study underwent 3 years of cognitive and behavioral assessments.
Greater hallucinations, anxiety, and apathy were associated with greater global functional impairment at baseline, while baseline hallucinations and apathy were associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep, and appetite.
These results suggest that increased baseline hallucinations and apathy are associated with current and future disease progression in AD.
Alzheimer’s disease; anxiety; apathy; disease progression; hallucinations; MCI; Neuropsychiatric Symptoms
Alzheimer’s disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness?
Alzheimer’s disease (AD) remains one of the most feared consequences of aging, affecting more than one out of every ten individuals over the age of 65. With more than 10,000 baby boomers turning 65 every day in the United States alone, we are truly facing an AD epidemic. Over the past decade, a string of disappointing clinical trial results have raised concerns about our current strategy for development of AD-modifying therapies. Three hypotheses can explain these recent AD trial failures: (i) We are targeting the wrong pathophysiological mechanisms; (ii) The drugs do not engage the intended targets in patients; and (iii) The drugs are hitting the right targets, but are doing so at the wrong stage of the disease. Here, we address the third supposition and suggest that specific amyloid-based therapies be directed at much earlier stages of ADperhaps even prior to the emergence of clinical symptoms. Furthermore, we argue that the field has sufficient tools to begin “secondary prevention” trials in asymptomatic individuals whoare at high risk for progression to cognitive impairment and AD dementia.
Impairment in activities of daily living (ADL) accompanies cognitive and behavioral symptoms in Alzheimer’s disease (AD). Conventionally, ADL impairment has been relegated to the stage of dementia, but instrumental ADL impairment has been shown to occur earlier at the stage of mild cognitive impairment (MCI). There are many subjective and performance-based instrumental ADL scales, some of which are useful in distinguishing between MCI and AD dementia, and even between MCI and clinically normal elderly individuals. These scales have been associated with amyloid and neurodegeneration biomarkers of AD. Clinically normal elderly individuals who have a positive AD biomarker are thought to be at the preclinical stage of AD. Scales of more complex ADL are needed to better capture individuals with preclinical AD before they start to progress to MCI.
The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB–001), a humanized monoclonal antibody to amyloid β, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid β was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.
bapineuzumab; Alzheimer disease; humans; pharmacokinetics; monoclonal antibody
The neural networks supporting encoding of new information are thought to decline with age, although mnemonic techniques such as repetition may enhance performance in older individuals. Accumulation of amyloid-β, one hallmark pathology of Alzheimer’s disease (AD), may contribute to functional alterations in memory networks measured with functional magnetic resonance imaging (fMRI) prior to onset of cognitive impairment. We investigated the effects of age and amyloid burden on fMRI activity in the default network and hippocampus during repetitive encoding.
Older individuals, particularly those with high amyloid burden, demonstrated decreased task-induced deactivation in the posteromedial cortices during initial stimulus presentation and failed to modulate fMRI activity in response to repeated trials, whereas young subjects demonstrated a stepwise decrease in deactivation with repetition. The hippocampus demonstrated similar patterns across the groups, showing task-induced activity that decreased in response to repetition.
These findings demonstrate that age and amyloid have dissociable functional effects on specific nodes within a distributed memory network, and suggest that functional brain changes may begin far in advance of symptomatic AD.
episodic memory; functional MRI; hippocampus; amyloid; aging
The recently developed Face Name Associative Memory Exam (FNAME), a challenging paired associative learning task, shows promise in detecting the subtle cognitive changes characteristic of preclinical Alzheimer’s disease. In this study, we evaluated the validity and reliability of the FNAME in 210 cognitively normal older individuals (58-90 years of age). Construct validity of the measure was assessed by principal components analysis, which revealed two independent factors. Correlations between the FNAME subtests and another episodic memory test were significant. The results indicated strong test-retest reliability in a subsample (n = 41). Normative data stratified by age were also generated.
preclinical Alzheimer’s disease; aging; neuropsychology; instrument validation
The reduction of neural activity in response to repeated stimuli, repetition suppression, is one of the most robust experience-related cortical dynamics known to cognitive neuroscience. Functional magnetic resonance imaging (fMRI) studies during episodic memory encoding have demonstrated repetition suppression in the hippocampus and this reduction has been linked to successful memory formation. An emerging body of functional imaging evidence suggests that the posteromedial cortex, in addition to the medial temporal lobes, may have a pivotal role in successful episodic memory. This area typically deactivates during initial memory encoding, but its functional changes in response to repetitive encoding remain poorly specified. Here, we investigate the repetition-related changes in the posteromedial cortex as well as the hippocampus while the participants underwent an fMRI experiment involving repetitive encoding of face–name pairs. During the first encoding trial of face–name pairs, significant activation in the hippocampus was observed. The second and third encoding trials demonstrated a repetition suppression effect in the hippocampus, indicated by a stepwise decrease of activation. In contrast, the posteromedial cortex demonstrated significant deactivation during the initial encoding trial of face–name pairs. The second and third encoding trials demonstrated a stepwise decrease of deactivation, repetition enhancement, with activity at or above baseline levels in the final encoding trial. These findings demonstrate that hippocampus repetition suppression as well as posteromedial repetition enhancement is related to successful encoding processes and are discussed in relation to the default mode hypothesis as well as potential implications for understanding late-life amnestic disorders.
episodic memory; functional MRI; hippocampus; posteromedial cortex; repetition
There is an unmet medical need to identify neuroimaging biomarkers that is able to accurately diagnose and monitor Alzheimer's disease (AD) at very early stages and assess the response to AD-modifying therapies. To a certain extent, volumetric and functional magnetic resonance imaging (fMRI) studies can detect changes in structure, cerebral blood flow and blood oxygenation that are able to distinguish AD and mild cognitive impairment (MCI) subjects from normal controls. However, it has been challenging to use fully automated MRI analytic methods to identify potential AD neuroimaging biomarkers. We have thus proposed a method based on independent component analysis (ICA), for studying potential AD-related MR image features, coupled with the use of support vector machine (SVM) for classifying scans into categories of AD, MCI, and normal control (NC) subjects. The MRI data were selected from Open Access Series of Imaging Studies (OASIS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) databases. The experimental results showed that our ICA-based method can differentiate AD and MCI subjects from normal controls, although further methodological improvement in the analytic method and inclusion of additional variables may be required for optimal classification.
Alzheimer's disease; mild cognitive impairment; magnetic resonance imaging; independent component analysis; support vector machine; neuroimaging biomarker
Age-related changes in neural circuits, neural networks, and their plasticity are central to our understanding of age changes in cognition and brain structure and function. This paper summarizes selected findings on these topics presented at the Cognitive Aging Summit II. Specific areas discussed were synaptic vulnerability and plasticity, including the role of different types of synaptic spines, and hormonal effects in the dorsolateral prefrontal cortex of nonhuman primates, the impact of both compensatory processes and dedifferentiation on demand-dependent differences in prefrontal activation in relation to age and performance, the role of vascular disease, indexed by white matter signal abnormalities, on prefrontal activation during a functional magnetic resonance imaging-based cognitive control paradigm, and the influence of amyloid-β neuropathology on memory performance in older adults and the networks of brain activity underlying variability in performance. A greater understanding of age-related changes in brain plasticity and neural networks in healthy aging and in the presence of underlying vascular disease or amyloid pathology will be essential to identify new targets for intervention. Moreover, this understanding will assist in promoting the utilization of existing interventions, such as lifestyle and therapeutic modifiers of vascular disease.
cognitive changes; aging; Neural networks
An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities.
Amyloid burden and white matter hyperintensities (WMH) are two common markers of neurodegeneration present in advanced aging. Each represents a potential early indicator of an age-related neurological disorder that impacts cognition. The presence of amyloid is observed in a substantial subset of cognitively normal older adults, but the literature remains equivocal regarding whether amyloid in nondemented populations is deleterious to cognition. Similarly, WMH are detected in many nondemented older adults and there is a body of evidence indicating that WMH are associated with decreased executive function and other cognitive domains. The current study investigated amyloid burden and WMH in clinically normal older adult humans aged 65 to 86 (N=168) and examined each biomarker’s relation with cognitive domains of episodic memory, executive function, and speed of processing. Factors for each domain were derived from a neuropsychological battery on a theoretical basis without reference to the relation between cognition and the biomarkers. Amyloid burden and WMH were not correlated with one another. Age was associated with lower performance in all cognitive domains, while higher estimated verbal intelligence was associated with higher performance in all domains. Hypothesis-driven tests revealed that amyloid burden and WMH had distinct cognitive profiles, with amyloid burden having a specific influence on episodic memory and WMH being primarily associated with executive function but having broad (but lesser) effects on the other domains. These findings suggest that even prior to clinical impairment, amyloid burden and WMH likely represent neuropathological cascades with distinct etiologies and dissociable influences on cognition.
Previous studies have revealed that functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signal in specific brain regions correlates with cross-sectional performance on standardized clinical trial measures in Alzheimer's disease (AD); however, the relationship between longitudinal change in fMRI-BOLD signal and neuropsychological performance remains unknown. Objective: To identify changes in regional fMRI-BOLD activity that tracks change in neuropsychological performance in mild AD dementia over 6 months.
Twenty-four subjects (mean age 71.6) with mild AD dementia (mean Mini Mental State Examination 21.7, Global Clinical Dementia Rating 1.0) on stable donepezil dosing participated in two task-related fMRI sessions consisting of a face-name paired associative encoding memory paradigm 24 weeks apart during a randomized placebo-controlled pharmaco-fMRI drug study. Regression analysis was used to identify regions where the change in fMRI activity for Novel > Repeated stimulus contrast was associated with the change scores on postscan memory tests and the Free and Cued Selective Reminding Test (FCSRT).
Correlations between changes in postscan memory accuracy and changes in fMRI activity were observed in regions including the angular gyrus, parahippocampal gyrus, inferior frontal gyrus and cerebellum. Correlations between changes in FCSRT-free recall and changes in fMRI were observed in regions including the inferior parietal lobule, precuneus, hippocampus and parahippocampal gyrus.
Changes in encoding-related fMRI activity in regions implicated in mnemonic networks correlated with changes in psychometric measures of episodic memory retrieval performed outside the scanner. These exploratory results support the potential of fMRI activity to track cognitive change and detect signals of short-term pharmacologic effect in early-phase AD studies.
Functional MRI; Clinical trial; Episodic memory; Biomarker; Dementia
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
Functional MRI holds significant potential to aid in the development of early interventions to improve memory function, and to assess longitudinal change in memory systems in aging and early Alzheimer's disease. However, the test-retest reliability of hippocampal activation and of “beneficial” deactivation in the precuneus has yet to be fully established during memory encoding tasks in older subjects. Using a mixed block and event-related face-name associative encoding paradigm, the reliability of hippocampal activation and default network deactivation was assessed over a four-to-six week inter-scan interval in 27 older individuals who were cognitively normal (Clinical Dementia Rating Scale= 0; n=18) or very mildly impaired (CDR=0.5; n=9). Reliability was assessed in whole brain maps and regions-of-interest using both a full task paradigm of six functional runs as well as an abbreviated paradigm of the first two functional runs, which would be advantageous for use in clinical trials. We found reliable hippocampal signal response across both block and event-related designs in the right hippocampus. Comparable reliability in hippocampal activation was found in the full and the abbreviated paradigm. Similar reliability in hippocampal activation was observed across both CDR groups overall, but the CDR 0.5 group was more variable in left hippocampal activity. Task-related deactivation in the precuneus demonstrated much greater variability than hippocampal activation in all analyses. Overall, these results are encouraging for the utility of fMRI in “Proof of Concept” clinical trials investigating the efficacy of potentially therapeutic agents for treatment of age-related memory changes, cognitive impairment, and early Alzheimer's disease.
test-retest; hippocampus; precuneus; reliability; mild cognitive impairment; aging
Functional magnetic resonance imaging (fMRI) is a relative newcomer in the field of biomarkers for Alzheimer’s disease (AD). fMRI has several potential advantages, particularly for clinical trials, as it is a non-invasive imaging technique that does not require the injection of contrast agent or radiation exposure and thus can be repeated many times during a longitudinal study. fMRI has relatively high spatial and reasonable temporal resolution, and can be acquired in the same session as structural MRI. Perhaps most importantly, fMRI may provide useful information about the functional integrity of brain networks supporting memory and other cognitive domains, including the neural correlates of specific behavioral events, such as successful versus failed memory formation.
Alzheimer’s disease; biomarker; cognitive impairment; dementia; fMRI; functional magnetic resonance imaging
Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimer’s disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloid-β deposition using Positron Emission Tomography with Pittsburg Compound B (PiB-PET) in cognitively normal older individuals. One-hundred thirty one subjects (mean age 73.5 ± 6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment.
preclinical Alzheimer’s disease; early detection; amyloid imaging; subjective cognitive complaints
To elucidate the relationship between the two hallmark proteins of Alzheimer's disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals.
A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.
Research centers across the United States and Canada.
We examined one hundred seven participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.
Main Outcome Measures
Using linear mixed effects models, we investigated the relationship between CSF p-tau181p, CSF Aβ1-42 and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).
We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR-SB, and ADAS-cog in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from zero.
In cognitively normal older individuals, Aβ-associated clinical decline over a mean of three years may occur only in the presence of ongoing, “downstream” neurodegeneration.
Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention.
Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging.
A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R2 = 0.40; unstandardized partial regression coefficient, β = 5.8; p = 0.0002) and in MCI subjects only (R2 = 0.28; β = 6.1; p = 0.003), but not in NC subjects only.
These results suggest that daily functional impairment is related to greater amyloid burden in MCI.
Alzheimer's disease; Amyloid; Instrumental activities of daily living; Mild cognitive impairment; Pittsburgh compound B; Positron emission tomography
Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease. At the time of clinical manifestation of dementia, significant irreversible brain damage is already present, rendering the diagnosis of AD at early stages of the disease an urgent prerequisite for therapeutic treatment to halt, or at least slow, disease progression. In this Review, we discuss various neuroimaging measures that are proving to have potential value as biomarkers of AD pathology for the detection and prediction of AD before the onset of dementia. Recent studies that have identified AD-like structural and functional brain changes in elderly people who are cognitively within the normal range or who have mild cognitive impairment (MCI) are discussed. A dynamic sequence model of changes that occur in neuroimaging markers during the different disease stages is presented and the predictive value of multimodal neuroimaging for AD dementia is considered.