Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort.

BACKGROUND: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer's disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). OBJECTIVE: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. METHODS: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aß42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. RESULTS: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-. CONCLUSION: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

Task-based functional connectivity reveals aberrance with the salience network during emotional interference in late-life depression.

OBJECTIVES: Late-life depression (LLD) is a common and debilitating disorder. Previously, resting-state studies have revealed abnormal functional connectivity (FC) of brain networks in LLD. Since LLD is associated with emotional-cognitive control deficits, the aim of this study was to compare FC of large-scale brain networks in older adults with and without a history of LLD during a cognitive control task with emotional stimuli. METHODS: Cross-sectional case-control study. Twenty participants diagnosed with LLD and 37 never-depressed adults 60-88 years of age underwent functional magnetic resonance imaging during an emotional Stroop task. Network-region-to-region FC was assessed with seed regions in the default mode, the frontoparietal, the dorsal attention, and the salience networks. RESULTS: FC between salience and sensorimotor network regions and between salience and dorsal attention network regions were reduced in LLD patients compared to controls during the processing of incongruent emotional stimuli. The normally positive FC between these networks were negative in LLD patients and inversely correlated with vascular risk and white matter hyperintensities. CONCLUSIONS: Emotional-cognitive control in LLD is associated with aberrant functional coupling between salience and other networks. This expands on the network-based LLD model and proposes the salience network as a target for future interventions.

Brain pathology and cognitive scores prior to onset of late-life depression.

OBJECTIVES: Understanding the biological changes that occur prior to onset of late-life depression (LLD) is key to its prevention. To investigate potential predictors of LLD, we assessed cognitive scores and neurodegenerative and vascular biomarkers in healthy older adults who later developed depression. METHODS: Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative of 241 cognitively unimpaired and non-depressed older adults aged 56-90 at baseline with at least 4 years of follow-up were included. Participants were classified based on whether they developed an incident depression (n = 96) or not (n = 145). Cognitive measures of memory, executive functioning, and language, and biomarkers proposed to be related to LLD: hippocampal volume, white matter hyperintensity volume (WMH), and cortical and cerebrospinal fluid (CSF) amyloid beta levels, were compared between the incident depression and the never-depressed groups at four time points: at baseline, the visit prior to onset, at onset, and after the onset of depression. RESULTS: In the incident depression group, there was a mild decline in cognitive scores from baseline to the visit before depression onset compared with the never-depressed group. The cognitive differences between the groups became more marked after depression onset. Baseline cortical amyloid burden, CSF amyloid beta levels, and WMH were significant predictors of incident depression. Compared to the non-depressed group, hippocampal volume was not reduced before onset, but was reduced following depression. CONCLUSIONS: Amyloid pathology and WMH can predict future development of LLD in cognitively unimpaired individuals and may be involved in precipitating vulnerability for depression in older adults.

Inhibition of emotions in healthy aging: age-related differences in brain network connectivity.

INTRODUCTION: Successful inhibition of distracting emotions is important for preserving well-being and daily functioning. There is conflicting evidence regarding the impact of healthy aging on emotional inhibition, and possible age-related alterations in the neuronal underpinnings of emotional interference processing are unexplored. METHODS: Thirty younger (mean age 26 years; 15 women) and 30 older (mean age 71 years; 13 women) healthy adults performed a face-word emotional Stroop task while undergoing functional magnetic resonance imaging of the brain. A resting-state scan was acquired for calculating the amplitude of low-frequency fluctuations as an estimate of vascular reactivity. Comparisons of brain activation during the task were assessed in a whole-brain, voxel-wise analysis, contrasting congruent, and incongruent conditions. The canonical regions of the frontoparietal, salience, dorsal attention, and default mode networks were used as seed regions for assessing functional connectivity within and between large-scale brain networks. Task performance was evaluated using response accuracy and response time. RESULTS: The older adults had longer response times and lower task accuracy than the younger adults, but the emotional interference effect was not significantly different between the groups. Whole-brain analysis revealed no significant age-related differences in brain activation patterns. Rescaling the data for estimated variability in vascular reactivity did not affect the results. In older adults, there was relatively stronger functional connectivity with the default mode network, the sensorimotor network, and the dorsal attention network for the frontoparietal and salience network seeds during the task. Conversely, younger adults had relatively stronger connections within and between the frontoparietal and salience networks. CONCLUSION: In this first fMRI study of emotional Stroop interference in older and younger adults, we found that the emotional interference effect was unchanged in healthy aging and replicated the finding from non-emotional task studies that older adults have greater between-network and less within-network connectivity compared to younger adults.

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aß1-42 pathology (Aß+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aß+ compared with Aß- controls. In MCI-Aß+ compared with Aß- controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aß+ and MCI-Aß+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.

Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10-8). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10-6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

A large fraction of genetic risk factors for Alzheimer's Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer's Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10-6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.

Prevalence of the apolipoprotein E ε4 allele in amyloid ß positive subjects across the spectrum of Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid ß (Aß) pathology. METHODS: We included 3451 Aß+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aß+ cognitively normal and Aß+ mild cognitive impairment (P < .05) but not in Aß+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aß pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.

Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.

We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer's Disease.

Introduction: Amyloid beta 1-43 (Aß43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (Aß42). Cerebrospinal fluid (CSF) Aß43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF Aß43 and established imaging biomarkers of Alzheimer's disease has never been assessed. Materials and Methods: In this observational study, CSF Aß43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid Aß43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aß43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aß43 and Aß42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aß43 average rho -0.73, Aß42 -0.74. Both CSF Aß peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aß42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aß43/42 and imaging biomarkers were significantly different for the two Aß peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid Aß43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aß42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aß43 performs better than the classical CSF biomarker Aß42 for distinguishing SCD and MCI.

Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF). METHODS: We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50). RESULTS: We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid-ß1-42 (Aß42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aß42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aß42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46). CONCLUSIONS: sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aß42, T-tau or P-tau.

Hippocampal complex atrophy in poststroke and mild cognitive impairment.

To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-ß concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-ß concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

IMPORTANCE: Cerebral amyloid-ß aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.