Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.

INTRODUCTION: We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. METHODS: We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. RESULTS: Cerebrospinal fluid (CSF) amyloid beta (Aß)42/40 was associated with Aß aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aß42/40 and Aß-PET, and CSF YKL-40 partly explained the association between Aß-PET, p-tau181 , and NfL. DISCUSSION: Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aß, CSF YKL-40 mediates the latter association between Aß and downstream Aß-induced tau pathology and tau-induced neuronal injury. HIGHLIGHTS: Lower CSF Aß42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aß and insoluble Aß. CSF YKL-40 mediated Aß-induced tau phosphorylation and tau-induced neuronal injury.

Is the association between blood pressure and cognition in the oldest-old modified by physical, vascular or brain pathology markers? The EMIF-AD 90 + Study.

BACKGROUND: Prior studies suggest a changing association between blood pressure (BP) and cognition with aging, however work in the oldest-old has yielded ambiguous results. Potentially, these mixed results can be explained by modifying factors. The aim of this study was to establish whether physical, vascular or brain pathology markers that describe a state of increased vulnerability, affect the association between BP and cognition in the oldest-old. Results may influence clinicians' decisions regarding the use of antihypertensives in this age group. METHODS: We included 122 individuals (84 without cognitive impairment and 38 with cognitive impairment) from the EMIF-AD 90 + Study (mean age 92.4 years). First, we tested cross-sectional associations of systolic and diastolic BP with a cognitive composite score. Second, we tested whether these associations were modified by physical markers (waist circumference, muscle mass, gait speed and handgrip strength), vascular markers (history of cardiac disease, carotid intima media thickness as a proxy for atherosclerosis and carotid distensibility coefficient as a proxy for arterial stiffness) or brain pathology markers (white matter hyperintensities and cortical thickness). RESULTS: In the total sample, there was no association between BP and cognition, however, waist circumference modified this association (p-value for interaction with systolic BP: 0.03, with diastolic BP: 0.01). In individuals with a high waist circumference, higher systolic and diastolic BP tended to be associated with worse cognition, while in individuals with a low waist circumference, higher systolic BP was associated with better cognition. The others physical, vascular and brain pathology markers did not modify the association between BP and cognition. CONCLUSIONS: When examining various markers for physical, vascular and brain vulnerability, only waist circumference affected the association between BP and cognition. This warrants further research to evaluate whether waist circumference may be a marker in clinical practice influencing the use of antihypertensives in the oldest-old.

Distinct disease mechanisms may underlie cognitive decline related to hearing loss in different age groups.

BACKGROUND: Hearing loss in older adults is associated with increased dementia risk. Underlying mechanisms that connect hearing loss with dementia remain largely unclear. METHODS: We studied the association of hearing loss and biomarkers for dementia risk in two age groups with normal cognition: 65 participants from the European Medical Information Framework (EMIF)-Alzheimer's disease (AD) 90+ study (oldest-old; mean age 92.7 years, 56.9% female) and 60 participants from the EMIF-AD PreclinAD study (younger-old; mean age 74.4, 43.3% female). Hearing function was tested by the 'digits-in-noise test' and cognition by repeated neuropsychological evaluation. Regressions and generalised estimating equations were used to test the association of hearing function and PET-derived amyloid burden, and linear mixed models were used to test the association of hearing function and cognitive decline. In the oldest-old group, mediation analyses were performed to study whether cognitive decline is mediated through regional brain atrophy. RESULTS: In oldest-old individuals, hearing function was not associated with amyloid pathology (p=0.7), whereas in the younger-old individuals hearing loss was associated with higher amyloid burden (p=0.0034). In oldest-old individuals, poorer hearing was associated with a steeper decline in memory, global cognition and language, and in the younger-old with steeper decline in language only. The hippocampus and nucleus accumbens mediated the effects of hearing loss on memory and global cognition in the oldest-old individuals. CONCLUSIONS: Hearing loss was associated with amyloid binding in younger-old individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.

Impact of the FindMyApps program on people with mild cognitive impairment or dementia and their caregivers; an exploratory pilot randomised controlled trial.

PURPOSE: FindMyApps is a web-based selection-tool and errorless learning training program to help people with mild dementia/Mild Cognitive Impairment (MCI) and caregivers find user-friendly apps. In preparation of a definitive trial, the impact and feasibility of the FindMyApps intervention on self-management and engagement in meaningful activities, including social participation, was explored. MATERIALS AND METHODS: An exploratory pilot randomised controlled trial (trial registration approval number: NL7210) with pre/post measurements was conducted with community-dwelling people with mild dementia/MCI and their caregivers (n = 59) in the Netherlands. Dyads in the experimental group (n = 28) received training to use the tablet and FindMyApps, and the errorless learning method was taught to their caregivers. Control group dyads (n = 31) received a tablet (without FindMyApps), instructions on tablet-use and links to dementia-friendly apps. Validated instruments were used to assess person with dementia's self-management, meaningful activities and social participation, caregiver's sense of competence and both their quality of life. RESULTS AND CONCLUSIONS: No statistical significant group differences on the outcomes were found. Small to moderate effect-sizes in favour of the FindMyApps group were found for self-management and social participation. Caregivers tended to have more positive care experiences. Subgroup analyses showed that people older than 70 benefitted more from FindMyApps regarding self-management and higher educated people benefitted more regarding social participation. FindMyApps is feasible for the target group and may have potential to improve self-management and social participation. For a future definitive effectiveness trial a larger sample size is recommended, as well as taking into account the possible impact of education and age.IMPLICATIONS FOR REHABILITATIONThe FindMyApps program is feasible for people with dementia/MCI and may have potential to improve their self-management and social participation.Informal caregivers may develop a more positive care experience when utilizing FindMyApps to find suitable apps for self-management and social participation for the person with dementia/MCI.

Grey matter network markers identify individuals with prodromal Alzheimer's disease who will show rapid clinical decline.

Individuals with prodromal Alzheimer's disease show considerable variability in rates of cognitive decline, which hampers the ability to detect potential treatment effects in clinical trials. Prognostic markers to select those individuals who will decline rapidly within a trial time frame are needed. Brain network measures based on grey matter covariance patterns have been associated with future cognitive decline in Alzheimer's disease. In this longitudinal cohort study, we investigated whether cut-offs for grey matter networks could be derived to detect fast disease progression at an individual level. We further tested whether detection was improved by adding other biomarkers known to be associated with future cognitive decline [i.e. CSF tau phosphorylated at threonine 181 (p-tau181) levels and hippocampal volume]. We selected individuals with mild cognitive impairment and abnormal CSF amyloid ß1-42 levels from the Amsterdam Dementia Cohort and the Alzheimer's Disease Neuroimaging Initiative, when they had available baseline structural MRI and clinical follow-up. The outcome was progression to dementia within 2 years. We determined prognostic cut-offs for grey matter network properties (gamma, lambda and small-world coefficient) using time-dependent receiver operating characteristic analysis in the Amsterdam Dementia Cohort. We tested the generalization of cut-offs in the Alzheimer's Disease Neuroimaging Initiative, using logistic regression analysis and classification statistics. We further tested whether combining these with CSF p-tau181 and hippocampal volume improved the detection of fast decliners. We observed that within 2 years, 24.6% (Amsterdam Dementia Cohort, n = 244) and 34.0% (Alzheimer's Disease Neuroimaging Initiative, n = 247) of prodromal Alzheimer's disease patients progressed to dementia. Using the grey matter network cut-offs for progression, we could detect fast progressors with 65% accuracy in the Alzheimer's Disease Neuroimaging Initiative. Combining grey matter network measures with CSF p-tau and hippocampal volume resulted in the best model fit for classification of rapid decliners, increasing detecting accuracy to 72%. These data suggest that single-subject grey matter connectivity networks indicative of a more random network organization can contribute to identifying prodromal Alzheimer's disease individuals who will show rapid disease progression. Moreover, we found that combined with p-tau and hippocampal volume this resulted in the highest accuracy. This could facilitate clinical trials by increasing chances to detect effects on clinical outcome measures.

The Impact of Amyloid PET Disclosure on Quality of Life in Patients With Young Onset Dementia.

INTRODUCTION: The impact of amyloid positron emission tomography (PET) imaging on patient health outcomes for individuals with dementia is unknown. In the present study, we explored the association between diagnostic outcome and clinician's level of certainty with quality of life (QoL) after [18F]flutemetamol PET results were disclosed in young onset dementia patients in a memory clinic cohort. METHODS: In 154 patients suspected of dementia, QoL was measured before and after [18F]flutemetamol PET results were disclosed. Multiple regression analyses were conducted with (changed) general and disease-specific QoL measures as dependent factors [QoL-Alzheimer disease (AD) and EQ-5D Dutch tariff] and etiological diagnosis and clinician's certainty as independent factors. RESULTS: (Change in) diagnosis of AD was associated to QOL in 2 of the 4 analyses (utility-based QoL ß=0.15, P=0.010; disease-specific QoL ß=2.0, P=0.037). Diagnostic certainty was associated to QOL in 1 of the 4 analyses (generic QoL ß=0.002, P=0.028). DISCUSSION: The diverse results in this explorative analysis do not reflect a univocal association between diagnosis, certainty, and QoL. Nevertheless, this result could be interpreted as a possible potential for advanced diagnostic technologies for AD, which requires confirmation in future research.

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline.

BACKGROUND AND OBJECTIVES: Multiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). We used the following N biomarkers: CSF total tau (t-tau), medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL), and serum glial fibrillary acidic protein (GFAP). We determined correlations between biomarkers. We assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression) and Mini-Mental State Examination (MMSE) over time (linear mixed models). Models included age, sex, CSF ß-amyloid (Aß) (A), and CSF p-tau (T) as covariates, in addition to the N biomarker. RESULT: We included 401 individuals (61±9 years, 42% female, MMSE 28 ± 2, vascular comorbidities 8%-19%). N biomarkers were modestly to moderately correlated (range r -0.28 - 0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL, and GFAP added predictive value beyond Aß and p-tau (hazard ratio 1.52 [95% CI 1.11-2.09]; 1.51 [1.05-2.17]; 1.50 [1.04-2.15]). T-tau, HV, and GFAP individually predicted MMSE slope (range ß -0.17 to -0.11, p < 0.05), but only HV remained associated beyond Aß and p-tau (ß -0.13 [SE 0.04]; p < 0.05). DISCUSSION: In cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as a measure for N. HV, NfL, and GFAP predicted clinical progression beyond A and T. Our results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that HV, NfL, and GFAP predicted clinical progression beyond A and T in individuals with SCD.

Tau-related grey matter network breakdown across the Alzheimer's disease continuum.

BACKGROUND: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-ß (Aß) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. METHODS: We included 533 individuals (178 Aß-negative cognitively unimpaired (CU) subjects, 105 Aß-positive CU subjects, 122 Aß-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. RESULTS: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aß-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. CONCLUSIONS: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.

Amyloid-ß, cortical thickness, and subsequent cognitive decline in cognitively normal oldest-old.

OBJECTIVE: To investigate the relationship between amyloid-ß (Aß) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aß status determined by [18 F]-flutemetamol PET (normal = Aß - vs. abnormal = Aß+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aß on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aß+. Compared to Aß-, Aß+ individuals showed steeper decline on memory (ß ± SE = -0.26 ± 0.09), and processing speed (ß ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aß+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aß abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aß pathology.

Applying the ATN scheme in a memory clinic population: The ABIDE project.

OBJECTIVE: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features. METHODS: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time. RESULTS: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ (p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia. CONCLUSIONS: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.

Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort: The ABIDE project.

INTRODUCTION: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. METHODS: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post-positron emission tomography diagnosis and management change between "AUC-consistent" and "AUC-inconsistent" patients. RESULTS: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post-positron emission tomography diagnosis (28%-21%) and management (32%-17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). DISCUSSION: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.

Development and Usability of ADappt: Web-Based Tool to Support Clinicians, Patients, and Caregivers in the Diagnosis of Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. OBJECTIVE: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. METHODS: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. RESULTS: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. CONCLUSIONS: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

Gray matter T1-w/T2-w ratios are higher in Alzheimer's disease.

Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1-weighted by T2-weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1-w/T2-w ratio value). We selected structural T1-w and T2-w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1-w/T2-w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1-w/T2-w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1-w/T2-w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = -.16 to -.21). These higher T1-w/T2-w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1-w/T2-w values.

Association of Amyloid Positron Emission Tomography With Changes in Diagnosis and Patient Treatment in an Unselected Memory Clinic Cohort: The ABIDE Project.

Importance: Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. Objective: To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort. Design, Setting, and Participants: Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned. Main Outcomes and Measures: Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment. Results: Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy. Conclusions and Relevance: This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.