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Background and objectivesIncreasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment.MethodsAmong 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5.ResultsAmong all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers.DiscussionSOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.

BACKGROUND AND OBJECTIVES: To develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for identifying at-risk individuals who are candidates for early intervention with amyloid targeted treatments. METHODS: We used data from 4,134 cognitively normal individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimers (A4) Study. The sample was divided into training and test sets. A modified version of AutoScore, a machine learning-based software tool, was used to develop a scoring system using the training set. Three risk scores were developed using candidate predictors in various combinations from the following categories: demographics (age, sex, education, race, family history, body mass index, marital status, and ethnicity), subjective measures (Alzheimers Disease Cooperative Study Activities of Daily Living-Prevention Instrument, Geriatric Depression Scale, and Memory Complaint Questionnaire), objective measures (free recall, Mini-Mental State Examination, immediate recall, digit symbol substitution, and delayed logical memory scores), and APOE4 status. Performance of the risk scores was evaluated in the independent test set. RESULTS: PARS model 1 included age, body mass index (BMI), and family history and had an area under the curve (AUC) of 0.60 (95% CI 0.57-0.64). PARS model 2 included free recall in addition to the PARS model 1 variables and had an AUC of 0.61 (0.58-0.64). PARS model 3, which consisted of age, BMI, and APOE4 information, had an AUC of 0.73 (0.70-0.76). PARS model 3 showed the highest, but still moderate, performance metrics in comparison with other models with sensitivity of 72.0% (67.6%-76.4%), specificity of 62.1% (58.8%-65.4%), accuracy of 65.3% (62.7%-68.0%), and positive predictive value of 48.1% (44.1%-52.1%). DISCUSSION: PARS models are a set of simple and practical risk scores that may improve our ability to identify individuals more likely to be amyloid positive. The models can potentially be used to enrich trials and serve as a screening step in research settings. This approach can be followed by the use of additional variables for the development of improved risk scores. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in cognitively unimpaired individuals PARS models predict Aβ positivity with moderate accuracy.

ObjectivesAlzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.MethodsWe mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.ResultsWM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains.ConclusionsThe negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.

ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.ResultsWe found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.ConclusionsOur results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

ObjectiveTo identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).MethodsWe stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.ResultsIndividuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.ConclusionsThe magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.

Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.

ObjectiveTo estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.MethodsIn 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.ResultsRates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.ConclusionsA considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.

ObjectiveTo examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages.MethodsThe sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.ResultsAcross groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).ConclusionWomen showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.

ObjectiveTo investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral β-amyloid (Aβ) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study.MethodsThe burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Aβ, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.ResultsIncreased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Aβ (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Aβ. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Aβ levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.ConclusionsIncreased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified.

ObjectiveA randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).MethodsParticipants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.ResultsResveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.ConclusionsResveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.Classification of evidenceThis study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

ObjectiveWe studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group.MethodsWe studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants.ResultsUsing a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively.ConclusionsOur results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment.

ObjectiveDiverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.MethodsBlood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.ResultsMean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003).ConclusionsLevels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

ObjectiveTo examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline.MethodsFrom the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders.ResultsSDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01).ConclusionsConsistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

ObjectiveThe objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.MethodsThis was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).ResultsLower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.ConclusionsChanges in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.

BackgroundThe goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.MethodsWe developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.ResultsThe CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.ConclusionsAutomated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidenceThis study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

ObjectivesThe aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).MethodsWe measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [(18)F]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.ResultsThe proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).ConclusionsOur findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

ObjectiveTo determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.MethodsPatients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.ResultspRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.ConclusionPresence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.

ObjectiveTo identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.MethodsA 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.ResultsWe detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.ConclusionsOur findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

ObjectiveTo investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers.MethodsThe Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden × time) or time-varying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden.ResultsCardiovascular risk profiles were not predictive of progression in CSF β₄₂-amyloid, [¹⁸F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4.ConclusionIncreased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway.

ObjectiveRecent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.MethodsWe measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.ResultsCLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).ConclusionsCLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Objective:To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).Methods:The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.Results:CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.Conclusion:The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.