Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles.

Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes.

Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms in vivo , measuring 5,543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n=490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n=487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders, we performed a metabolome-wide association study (MWAS), identifying 40 associations between CSF metabolites and brain traits. Similarly, over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. METHODS: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). RESULTS: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (ß = -0.52, CI -0.74 to -0.30, p < 0.001) and participants with AD (ß = -0.30, CI -0.58 to -0.02, p = 0.04). DISCUSSION: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline.

Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-ß pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-ß and tau in an independent manner instead of there being a causal relationship between amyloid-ß and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-ß PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-ß)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-ß, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-ß were strongly associated with within-pair differences in tau (ß = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (ß = -0.37, P = 0.03) and memory functioning (ß = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (ß = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (ß = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-ß on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-ß to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-ß, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-ß on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.

Plasma biomarkers predict amyloid pathology in cognitively normal monozygotic twins after 10 years.

Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-ß1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein to detect early Alzheimer's disease pathology, accounting for confounding by genetic and early environmental factors. Participants were 200 monozygotic twins, aged ≥60 years with normal cognition from the european medical information framework for Alzheimer's disease study. All twins had amyloid-ß status and plasma samples available at study enrolment. For 80 twins, additional plasma samples were available that had been collected approximately 10 years prior to amyloid-ß status assessment. Single-molecule array assays were applied to measure amyloid-ß1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein. Predictive value of and longitudinal change in these biomarkers were assessed using receiver operating characteristic curve analysis and linear mixed models. Amyloid pathology could be predicted using blood-based biomarkers obtained at the time of amyloid status assessment (amyloid-ß1-42/1-40: area under the curve = 0.65, P = 0.01; phosphorylated-tau181: area under the curve = 0.84, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.74, P < 0.001), as well as using those obtained 10 years prior to amyloid status assessment (amyloid-ß1-42/1-40: area under the curve = 0.69, P = 0.03; phosphorylated-tau181: area under the curve = 0.92, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.84, P < 0.001). Longitudinally, amyloid-ß1-42/1-40 levels decreased [ß (SE) = -0.12 (0.01), P < 0.001] and phosphorylated-tau181 levels increased [ß (SE) = 0.02 (0.01), P = 0.004]. Amyloid-ß-positive individuals showed a steeper increase in phosphorylated-tau181 compared with amyloid-ß-negative individuals [ß (SE) = 0.06 (0.02), P = 0.004]. Also amyloid-ß-positive individuals tended to show a steeper increase in glial fibrillary acidic protein [ß (SE) = 0.04 (0.02), P = 0.07]. Within monozygotic twin pairs, those with higher plasma phosphorylated-tau181 and lower amyloid-ß1-42/1-40 levels were more likely to be amyloid-ß positive [ß (SE) = 0.95 (0.26), P < 0.001; ß (SE) = -0.28 (0.14), P < 0.05] indicating minimal contribution of confounding by genetic and early environmental factors. Our data support the use of amyloid-ß1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein as screening tools for Alzheimer's disease pathology in the normal aging population, which is of importance for enrolment of high-risk subjects in secondary, or even primary, prevention trials. Furthermore, these markers show potential as low-invasive monitoring tool of disease progression and possibly treatment effects in clinical trials.

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.

Amyloid-ß and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score.

BACKGROUND: What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-ß pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. METHODS: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-ß status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-ß status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-ß status, and their interaction on changes in cognitive functioning over time. RESULTS: Fifty-two participants (19%) had abnormal amyloid-ß, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-ß status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-ß status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-ß×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE ß(SE)=-0.05(0.02); AD-PRS ß(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-ß status and AD-PRS predicted a steeper decline in memory functioning (amyloid-ß ß(SE)=-0.07(0.04); AD-PRS ß(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-ß status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-ß abnormal individuals only (ß(SE)=-0.13(0.06); ß(SE)=-0.22(0.07), respectively). CONCLUSION: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-ß only. Furthermore, independent of amyloid-ß status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

Abnormal cerebrospinal fluid levels of amyloid and tau are associated with cognitive decline over time in cognitively normal older adults: A monozygotic twin study.

Introduction: The contribution of genetic and environmental factors to the relation between cerebrospinal fluid (CSF) biomarkers and cognitive decline in preclinical Alzheimer's disease remains unclear. We studied this in initially cognitively normal monozygotic twins. Methods: We included 122 cognitively normal monozygotic twins (51 pairs) with a follow-up of 4.3 ± 0.4 years. We first tested associations of baseline CSF Aß1-42/1-40 ratio, total tau (t-tau), and 181-phosphorylated-tau (p-tau) status with subsequent cognitive decline using linear mixed models, and then performed twin specific analyses. Results: Baseline abnormal amyloid-ß and tau CSF markers predicted steeper decline on memory (p ≤ .003) and language (p ≤ 0.04). Amyloid-ß and p-tau markers in one twin predicted decline in memory in the co-twin and tau markers in one twin predicted decline in language in the co-twin (r range -0.26,0.39; p's ≤ .02). Discussion: These results suggest that memory and language decline are early features of AD that are in part determined by the same genetic factors that influence amyloid-ß and tau regulation.

Regional associations of white matter hyperintensities and early cortical amyloid pathology.

White matter hyperintensities (WMHs) have a heterogeneous aetiology, associated with both vascular risk factors and amyloidosis due to Alzheimer's disease. While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored. We included 662 non-demented participants from three Amyloid Imaging to Prevent Alzheimer's disease (AMYPAD)-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD PreclinAD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early accumulating regions (medial orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection. Global associations between WMH, amyloid, and cardiovascular risk scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language). While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal-precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory. In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology.

The heritability of vocal tract structures estimated from structural MRI in a large cohort of Dutch twins.

While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity of the 7000 or so currently spoken languages, but relatively little is known about its genetic bases, especially in what concerns normal variation. Here, we capitalize on five cohorts totaling 632 Dutch twins with structural magnetic resonance imaging (MRI) data. Two raters placed clearly defined (semi)landmarks on each MRI scan, from which we derived 146 measures capturing the dimensions and shape of various vocal tract structures, but also aspects of the head and face. We used Genetic Covariance Structure Modeling to estimate the additive genetic, common environmental or non-additive genetic, and unique environmental components, while controlling for various confounds and for any systematic differences between the two raters. We found high heritability, h2, for aspects of the skull and face, the mandible, the anteroposterior (horizontal) dimension of the vocal tract, and the position of the hyoid bone. These findings extend the existing literature, and open new perspectives for understanding the complex interplay between genetics, environment, and culture that shape our vocal tracts, and which may help explain cross-linguistic differences in phonetics and phonology.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Genetically identical twins show comparable tau PET load and spatial distribution.

Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-ß pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < ß < 0.56), physical activity (-0.41 < ß < -0.42) and social activity (-0.32 < ß < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Amyloid-driven disruption of default mode network connectivity in cognitively healthy individuals.

Cortical accumulation of amyloid beta is one of the first events of Alzheimer's disease pathophysiology, and has been suggested to follow a consistent spatiotemporal ordering, starting in the posterior cingulate cortex, precuneus and medio-orbitofrontal cortex. These regions overlap with those of the default mode network, a brain network also involved in memory functions. Aberrant default mode network functional connectivity and higher network sparsity have been reported in prodromal and clinical Alzheimer's disease. We investigated the association between amyloid burden and default mode network connectivity in the preclinical stage of Alzheimer's disease and its association with longitudinal memory decline. We included 173 participants, in which amyloid burden was assessed both in CSF by the amyloid beta 42/40 ratio, capturing the soluble part of amyloid pathology, and in dynamic PET scans calculating the non-displaceable binding potential in early-stage regions. The default mode network was identified with resting-state functional MRI. Then, we calculated functional connectivity in the default mode network, derived from independent component analysis, and eigenvector centrality, a graph measure recursively defining important nodes on the base of their connection with other important nodes. Memory was tested at baseline, 2- and 4-year follow-up. We demonstrated that higher amyloid burden as measured by both CSF amyloid beta 42/40 ratio and non-displaceable binding potential in the posterior cingulate cortex was associated with lower functional connectivity in the default mode network. The association between amyloid burden (CSF and non-displaceable binding potential in the posterior cingulate cortex) and aberrant default mode network connectivity was confirmed at the voxel level with both functional connectivity and eigenvector centrality measures, and it was driven by voxel clusters localized in the precuneus, cingulate, angular and left middle temporal gyri. Moreover, we demonstrated that functional connectivity in the default mode network predicts longitudinal memory decline synergistically with regional amyloid burden, as measured by non-displaceable binding potential in the posterior cingulate cortex. Taken together, these results suggest that early amyloid beta deposition is associated with aberrant default mode network connectivity in cognitively healthy individuals and that default mode network connectivity markers can be used to identify subjects at risk of memory decline.

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

BACKGROUND: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease. METHODS: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. RESULTS: Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. CONCLUSIONS: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

Onset of Preclinical Alzheimer Disease in Monozygotic Twins.

OBJECTIVE: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aß) aggregation as measured by the Aß1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aß production (beta-secretase 1, Aß1-40, and Aß1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aß production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aß aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aß1-38 in one twin correlated with Aß1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aß production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aß production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aß and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987-1000.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Longitudinal retinal layer changes in preclinical Alzheimer's disease.

PURPOSE: Several studies found reduced retinal thickness on optical coherence tomography (OCT) in Alzheimer's disease (AD), even in preclinical stages, labelling this technique of interest as biomarker. In this study, we examine retinal thickness changes in preclinical AD, as defined by cognitively normal individuals with amyloid-beta (Aß) on positron emission tomography (PET). METHODS: For this monocentre study, 145 cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the EMIF-AD PreclinAD study. At baseline, participants underwent [18 F] flutemetamol PET that was visually rated for cortical Aß. Binding potential was calculated as continuous measure for Aß. Optical coherence tomography (OCT) was performed at baseline and after 22 months to assess changes in total and individual inner retinal layer thickness in the macular region (ETDRS circles) and peripapillary retinal nerve fibre layer thickness. Differences in rate of change between amyloid-beta positive and negative individuals and associations between binding potential and change in retinal thickness were evaluated. RESULTS: Sixteen participants (11%) were positive for Aß. Change in retinal thickness did not differ in any region between Aß+ and Aß- individuals. A positive association between binding potential and change in inner plexiform layer thickness was observed in the inner macular ring (beta = 1.708, CI = 0.575 to 2.841, p = 0.003). CONCLUSION: Aß+ individuals did not differ in rate of change of any retinal layer compared to controls, but higher binding potential at baseline was associated with less IPL thinning over time. Optical coherence tomography (OCT) as a longitudinal screening tool for preclinical AD seems limited, but IPL changes offer leads for further research.

Ocular biomarkers for cognitive impairment in nonagenarians; a prospective cross-sectional study.

BACKGROUND: Ocular imaging receives much attention as a source of potential biomarkers for dementia. In the present study, we analyze these ocular biomarkers in cognitively impaired and healthy participants in a population aged over 90 years (= nonagenarian), and elucidate the effects of age on these biomarkers. METHODS: For this prospective cross-sectional study, we included individuals from the EMIF-AD 90+ study, consisting of a cognitively healthy (N = 67) and cognitively impaired group (N = 33), and the EMIF-AD PreclinAD study, consisting of cognitively healthy controls aged ≥60 (N = 198). Participants underwent Optical Coherence Tomography (OCT) and fundus photography of both eyes. OCT was used to asses total and individual inner retinal layer thickness in the macular region (Early Treatment Diabetic Retinopathy Study circles) as well as peripapillary retinal nerve fiber layer thickness, fundus images were analyzed with Singapore I Vessel Assessment to obtain 7 retinal vascular parameters. Values for both eyes were averaged. Differences in ocular biomarkers between the 2 nonagenarian groups were analyzed using linear regression, differences between the individual nonagenarian groups and controls were analyzed using generalized estimating equations. RESULTS: Ocular biomarkers did not differ between the healthy and cognitively impaired nonagenarian groups. 19 out of 22 ocular biomarkers assessed in this study differed between either nonagenarian group and the younger controls. CONCLUSION: The ocular biomarkers assessed in this study were not associated with cognitive impairment in nonagenarians, making their use as a screening tool for dementing disorders in this group limited. However, ocular biomarkers were significantly associated with chronological age, which were very similar to those ascribed to occur in Alzheimer's Disease.