Autosomal Dominant Alzheimer Research Articles

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease.

Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.

CSF proteomics in autosomal dominant Alzheimer's disease highlights parallels with sporadic disease.

Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, 1 decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. Of the 66 differentially expressed proteins, 36 had been measured previously in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, P < 0.001). Twenty-nine of the 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.

Decreased functional integration in higher‐order association areas in individuals with autosomal‐dominant Alzheimer’s disease: Findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundThe disruption of brain functional connections has been linked to cognitive impairment in Alzheimer’s disease. The functional architecture of the brain can be modeled using graph theory, which provides metrics to describe both local and global network properties. Autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to study brain changes in preclinical AD since carriers of ADAD mutations are destined to develop dementia at young age and have a well‐characterized disease trajectory. Here, we applied a graph theory approach to examine the functional network topology in Presenilin‐1 (PSEN1) E280A carriers and non‐carriers.MethodsA total of 43 cognitively‐unimpaired individuals (18 PSEN1 carriers, 25 non‐carriers; mean age = 36.6±5.2) from the Colombia‐Boston biomarker study were included. Participants underwent resting‐state fMRI in a 3T scanner, and a comprehensive multi‐domain neuropsychological battery. fMRI data were preprocessed using C‐PAC. Global functional connectivity (FC) was derived from the nodal strength of the Pearson correlation matrix between time‐series of 400 ROIs [Shaeffer‐2016] within 6 different functional networks [Yeo‐2011]. The strength of within‐ (z) and between‐network (h) functional integration was derived from a consensus modularity analysis [Dwyer‐2014]. Differences in cognitive variables were evaluated using Mann‐Whitney tests. Differences in FC were assessed using permutation methods: global FC using FSL‐randomize and integration parameters were based on a consensus analysis applied to random controlled matrices. Both methods were repeated 1000 times, with a p&lt;0.05 significance threshold.ResultsThere were no group differences in cognitive variables. Compared to non‐carriers, carriers exhibited decreased local FC in higher‐order association areas, and increased connectivity in somatosensory areas. There were no group differences in the within‐network integration. Carriers showed decreased between‐network integration, especially in higher‐order association networks, mainly the default mode network (Fig.1).ConclusionsFindings support the hypothesis that alterations of functional network topology are evident in preclinical ADAD, primarily in the higher‐order cognitive networks. Early identification of abnormalities within these networks may be useful in understanding how FC changes may lead to subsequent cognitive decline in individuals at increased risk for AD. Future work with larger samples should investigate the relationships between FC changes and the neurobiological factors underlying AD.

Plasma metabolomics indexes time to clinical dementia in autosomal dominant Alzheimer’s disease mutation carriers

AbstractBackgroundMetabolic dysregulation has been implicated in the pathobiology of Alzheimer’s disease (AD), including familial autosomal dominant AD (ADAD). Recent metabolic neuroimaging of preclinical ADAD mutation carriers has suggested that levels of the reactive glial marker myo‐inositol increase with proximity to expected age at dementia onset. It remains unclear, however, if similar metabolic change related to anticipated phenoconversion can be observed at network‐scale in the peripheral plasma metabolome of ADAD mutation carriers.MethodWe collected peripheral blood plasma from ADAD mutation carriers with and without objective cognitive decline (ncarrier = 55) who participated in a longitudinal kindred study. We used untargeted liquid chromatography‐ mass spectrometry (LC‐MS) metabolomics to infer putative metabolic pathway and protein disruptions associated with impending dementia diagnosis at whole‐genome scale. Spearman 𝝆 correlation coefficients were determined for each identified mass feature in relation to clinical, family‐wise estimated years to diagnosis prior to the submission of these summary statistics to metabolomic modeling.ResultA total of 91 LC‐MS mass features were significantly correlated with estimated years to dementia onset, nominal p’s &lt; .05. Pathway‐based, genome‐scale metabolomic modeling analysis revealed a de novo plasma metabolomic activity network composed of interconnected lipid and small, polar metabolite hubs. These same correlations were also submitted to gene‐inferring, whole‐genome metabolomic modeling using PIUmet. Intriguingly, mRNA expression of prioritized genes was not limited to the brain and involved multiple peripheral tissues. In the CNS itself, however, genes prioritized by PIUMet metabolomic modeling frequently demonstrated expression in glia.ConclusionConsistent with prior metabolic findings in ADAD mutation carriers, network alterations to the peripheral plasma metabolome correspond with increasing proximity to expected age of dementia onset. Because neuroinflammation has been previously described as an immunometabolic process in pathological aging, emerging metabolic network disintegrity in ADAD may index reactive glial pathobiology previously suggested by prior metabolic investigations of this population. These perturbed networks inferred from participant blood plasma suggest targetable CNS‐peripheral metabolic dyshomeostases which otherwise precipitate pathobiological “failures of compensation” and concomitant cognitive decline in carriers of Mendelian ADAD mutations.

Tracking reactive astrocytes in autosomal dominant Alzheimer disease with plasma GFAP and multi‐modal PET imaging

AbstractBackgroundWe have proposed astrogliosis as a “first wave” of response to AD pathology with diverging longitudinal changes of reactive astrocytes and amyloid‐β positron emission tomography (PET) retention in pre‐symptomatic autosomal dominant AD (ADAD). It has been suggested that plasma glial fibrillary acidic protein (GFAP) could be a marker of neuroinflammation in AD brain, although this hypothesis remains unproven. We therefore compared plasma GFAP levels with 11C‐deprenyl (DED) with a multi‐modal PET design in ADAD mutation carriers (MC) and non‐carriers (NC).MethodTwenty‐three individuals from families with known ADAD mutations were included (MC = 9; NC = 14). All individuals underwent PET imaging with 11C‐DED, 11C‐PIB and 18F‐FDG, for assessing monoamine oxidase B as a marker of reactive astrocytes, amyloid‐beta deposition, and glucose metabolism, respectively. Plasma sampling was performed after a median of 3 (interquartile range 1.5‐5.5) months. GFAP levels were measured using single molecule array technology. Eleven individuals had follow‐up imaging investigations and plasma sampling after a median of 2.7 (interquartile range 2.5‐2.9) years.ResultPlasma GFAP levels and 11C‐PIB binding increased significantly from pre‐symptomatic to symptomatic stage while 11C‐DED binding and 18F‐FDG uptake significantly decreased towards estimated onset of clinical symptoms in MC. Cross‐sectionally, plasma GFAP showed negative correlations with [18F]FDG uptake in widespread cortical areas, in contrast to no correlations with 11C‐DED or 11C‐PIB binding. 11C‐DED binding showed a positive correlation with 18F‐FDG uptake. Across the follow‐up interval, plasma GFAP levels showed a four‐fold greater intraindividual variation relative to 11C‐DED binding variation (longitudinal Δ variance = 1.67 vs 0.39 z‐scores, respectively). When averaging plasma GFAP values and tracer binding across consecutive time points for the same individual, strong negative correlations were found between plasma GFAP and 11C‐DED binding and 18F‐FDG uptake, but no significant correlation was found between plasma GFAP levels and 11C‐PIB binding in MC.ConclusionDivergent plasma GFAP levels and PET 11C‐DED brain binding in pre‐symptomatic ADAD carriers may reflect different but associated underlying processes, including different types of reactive astrocytes. However, the levels of plasma GFAP show large intraindividual variation over time and the assessment of reactive astrocytes based solely on cross‐sectional plasma GFAP levels poses great challenges and warrants further investigations.

Long‐term memory over 1‐week and markers of brain pathology in cognitively unimpaired individuals from a Colombian cohort with autosomal dominant Alzheimer’s disease

AbstractBackgroundLong‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.MethodsA total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.ResultsLearning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p&lt;0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).ConclusionsOur preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.

Prevalence and pathological correlates of unawareness of memory impairment in non‐demented individuals with autosomal dominant Alzheimer’s disease: an item‐level investigation of the Memory Complaints Scale

AbstractBackgroundAwareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A mutation for autosomal dominant Alzheimer’s disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members.MethodA total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and &lt;0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher’s exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers.ResultMutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p&lt;0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid.ConclusionOur results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia.

Increased white matter hyperintensity burden on MRI in autosomal dominant familial compared to young onset sporadic Alzheimer’s disease.

AbstractBackgroundWhite matter hyperintensities (WMH) on MRI may be observed in familial and sporadic AD. However, studies comparing WMH burden between these two groups are lacking. We conducted this study to evaluate the load and distribution of WMH in individuals with autosomal dominant familial Alzheimer’s disease (FAD) and young onset sporadic AD (SAD), their relationship to grey matter volumes and to neuropsychological test scores (NPT).MethodIn this cross‐sectional study, we evaluated global and local differences in WMH severity on MRI in 19 individuals with symptomatic FAD due to Presenilin 1 mutations, 20 individuals with young onset SAD and 19 healthy control subjects, controlling for age, cerebrovascular risk (CVR) and APOEε4 carrier status. Relationships between WMH, grey matter (GM) volumes and NPT were also investigated.ResultThe FAD group had higher WMH load in all the areas considered apart from juxta‐cortical and periventricular layers when compared to the SAD group. The two groups were well matched for disease duration and severity of cognitive impairment as assessed by the MMSE. APOEε4 genotype and cardiovascular risk factors acted as negative confounders in the identified differences in WMH volumes. There was no association between WMH and GM volumes or NPT in either AD group.ConclusionDespite their young age and minimal CVR, the FAD group in this study had a higher load of WMH compared to the SAD group, suggesting that WMH may reflect aspects of AD pathology that are particularly prominent in FAD. Our analysis suggests that APOEε4 genotype and cardiovascular risk factors may have a greater influence on WMH burden in SAD than in FAD. Furthermore, we did not identify a correlation between WMH load and GM volumes in either group, suggesting that WMH are not merely correlates of GM pathology in AD but may represent independent features of the disease.

Electrocardiogram differences in cognitively unimpaired PSEN1‐E280A carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal‐Dominant Alzheimer’s Disease Colombia Trial

AbstractBackgroundSome but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid‐β pathology itself, in persons with late‐onset Alzheimer’s Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described in the electrocardiogram (ECG), but those are not consistent between studies. We explored differences in several ECG measures in cognitively unimpaired (CU) Presenilin 1 (PSEN1)‐E280A carriers and non‐carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841).MethodThe trial enrolled 252 CU 30–60‐year‐old participants. We included participants (144 PSEN1‐E280A mutation carriers and 71 non‐carriers) in these analyses who were enrolled in the trial during their first screening attempt. Baseline cardiovascular data and medical history were obtained by medical assessment and blood sample. Interval durations, QRS voltages of all leads, and the diagnosis were taken from baseline ECG. T‐test, chi‐square, correlation, and effect size were used in the data analysis. The p values in this are exploratory.ResultMean age (years) for carriers was 36 and 43 for non‐carriers. Years of education, sex, and clinical variables like body mass index, cholesterol, hemoglobin A1c, TSH, and previous cardiovascular disorders were similar between groups. There were no differences in the heart rate, PR, QRS, or corrected QT interval duration. Voltages in AVL and DI leads were lower in carriers than non‐carriers with a low size of effect (0.42 vs. 0.50, p = 0.03; 0.64 vs. 0.71, p = 0.04, respectively), while the other ten leads and low voltage in any of the 12 derivates did not show any difference. There was also a negative and small correlation between voltage and age for DII, V6, and AVR (‐0.146, ‐0.144, ‐0.137; p = 0.03,0.03,0.04; respectively).ConclusionOur findings suggest no clinically significant difference in ECG parameters between PSEN1‐E280A mutation carriers compared to non‐carriers. Since intramyocardial deposits of amyloid‐β are age‐dependent, it is likely that there are low levels of these deposits in young CU individuals. Longitudinal studies with larger samples that include CU patients might identify ECG‐related changes associated with amyloid‐β cardiac deposits.

Matrix disequilibrium in Alzheimer's disease and conditions that increase Alzheimer's disease risk.

Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

Tau accumulation in autosomal dominant Alzheimer’s disease: a longitudinal [18F]flortaucipir study

Cortical tau accumulation is a key pathological event that partly defines Alzheimer’s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging.

A biomarker-validated time scale in years of disease progression has identified early- and late-onset subgroups in sporadic Alzheimer’s disease

BackgroundIt is possible to calculate the number of years to the expected clinical onset (YECO) of autosomal-dominant Alzheimer’s disease (adAD). A similar time scale is lacking for sporadic Alzheimer’s disease (sAD). The purpose was to design and validate a time scale in YECO for patients with sAD in relation to CSF and PET biomarkers.MethodsPatients diagnosed with Alzheimer’s disease (AD, n = 48) or mild cognitive impairment (MCI, n = 46) participated in the study. They underwent a standardized clinical examination at the Memory clinic, Karolinska University Hospital, Stockholm, Sweden, which included present and previous medical history, laboratory screening, cognitive assessment, CSF biomarkers (Aβ42, total-tau, and p-tau), and an MRI of the brain. They were also assessed with two PET tracers, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose. Assuming concordance of cognitive decline in sAD and adAD, YECO for these patients was calculated using equations for the relationship between cognitive performance, YECO, and years of education in adAD (Almkvist et al. J Int Neuropsychol Soc 23:195-203, 2017).ResultsThe mean current point of disease progression was 3.2 years after the estimated clinical onset in patients with sAD and 3.4 years prior to the estimated clinical onset in patients with MCI, as indicated by the median YECO from five cognitive tests. The associations between YECO and biomarkers were significant, while those between chronological age and biomarkers were nonsignificant. The estimated disease onset (chronological age minus YECO) followed a bimodal distribution with frequency maxima before (early-onset) and after (late-onset) 65 years of age. The early- and late-onset subgroups differed significantly in biomarkers and cognition, but after control for YECO, this difference disappeared for all except the APOE e4 gene (more frequent in early- than in late-onset).ConclusionsA novel time scale in years of disease progression based on cognition was designed and validated in patients with AD using CSF and PET biomarkers. Two early- and late-disease onset subgroups were identified differing with respect to APOE e4.

Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man

We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Retinotopic degeneration of the retina and optic tracts in autosomal dominant Alzheimer's disease.

We investigated the correlation between retinal thickness and optic tract integrity in subjects with autosomal dominant Alzheimer's disease (ADAD) causing mutations. Retinal thicknesses and diffusion tensor images (DTI) were obtained using optical coherence tomography and magnetic resonance imaging, respectively. The association between retinal thickness and DTI measures was adjusted for age, sex, retinotopy, and correlation between eyes. Optic tract mean diffusivity and axial diffusivity were negatively correlated with retinotopically defined ganglion cell inner plexiform thickness (GCIPL). Fractional anisotropy was negatively correlated with retinotopically defined retinal nerve fiber layer thickness. There was no correlation between outer nuclear layer (ONL) thickness and any DTI measure. In ADAD, GCIPL thickness is significantly associated with retinotopic optic tract DTI measures even in minimally symptomatic subjects. Similar associations were not present with ONL thickness or when ignoring retinotopy. We provide in vivo evidence for optic tract changes resulting from ganglion cell pathology in ADAD.

Associations of category fluency clustering performance with in vivo brain pathology in autosomal dominant Alzheimer's disease.

Alzheimer's disease (AD) is known to impact semantic access, which is frequently evaluated using the Category Fluency (Animals) test. Recent studies have suggested that in addition to overall category fluency scores (total number of words produced over time), poor clustering could signal AD-related cognitive difficulties. In this study, we examined the association between category fluency clustering performance (i.e., stating words sequentially that are all contained within a subcategory, such as domestic animals) and brain pathology in individuals with autosomal dominant Alzheimer's disease (ADAD). A total of 29 non-demented carriers of the Presenilin1 E280A ADAD mutation and 32 noncarrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate in vivo amyloid-beta in the neocortex and tau in medial temporal lobe regions. Differences between carriers and noncarriers on cognitive tests were assessed with Mann-Whitney tests; associations between cognitive test performance and brain pathology were assessed with Spearman correlations. Animal fluency scores did not differ between carriers and noncarriers. Carriers, however, showed a stronger association between animal fluency clustering and in vivo AD brain pathology (neocortical amyloid and entorhinal tau) relative to noncarriers. This study indicates that using category fluency clustering, but not total score, is related to AD pathophysiology in the preclinical and early stages of the disease.

Effects of APOE4 and education on the clinical onset of autosomal dominant Alzheimer’s disease due to the PSEN1 E280A mutation (S39.004)

<h3>Objective:</h3> Determine the impact of APOE4 genotype and education on the clinical onset of autosomal dominant Alzheimer’s disease. <h3>Background:</h3> Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests it may be influenced by additional genetic and environmental risk factors. Although the e4 allele of the apolipoprotein E (APOE4) gene and education level both influence clinical onset of dementia in sporadic Alzheimer’s disease (AD), it is unclear whether APOE4 affects onset of ADAD. Here, we investigated the effects of APOE4 and education on the clinical onset of ADAD. <h3>Design/Methods:</h3> We analyzed retrospective data from 675 presenilin-1 (<i>PSEN1</i>) E280A mutation carriers (141 APOE4 carriers, 534 APOE4 non-carriers) and 594 <i>PSEN1</i> non-carriers (148 APOE4 carriers, 446 APOE4 non-carriers) from a Colombian kindred with ADAD. We used the Mini-Mental State Examination (MMSE) as a proxy for clinical impairment. Model parameters in both <i>PSEN1</i> carriers and non-carriers were estimated using a Hamiltonian Markov chain Monte Carlo method. The age-related trajectories of APOE4 carriers versus non-carriers were compared in both <i>PSEN1</i> carriers and non-carriers. <h3>Results:</h3> In <i>PSEN1</i> carriers, lower MMSE scores began to significantly differentiate APOE4 carriers from non-carriers at age 45, the average age of mild cognitive impairment onset in this kindred. Years of education moderated the effect of APOE such that APOE4 carriers with lower educational levels had lower average MMSE scores in comparison to APOE4 non-carriers. <h3>Conclusions:</h3> Our findings suggest 1) age-related changes in global cognitive function may be accelerated in ADAD mutation carriers who are APOE4 carriers, compared to APOE4 non-carriers; and 2) higher educational levels may have a protective effect against cognitive impairment, even in the presence of genetic risk factors. Further longitudinal studies are necessary to clarify the impact of both education and APOE4 genotype on ADAD clinical progression. <b>Disclosure:</b> Mr. Barksdale has nothing to disclose. The institution of Dr. Langella has received research support from Alzheimer’s Association. Dr. Vasquez has nothing to disclose. David Fernando Aguillon, Sr. has nothing to disclose. Yinghua Chen has nothing to disclose. Dr. Su has nothing to disclose. Dr. ACOSTA-BAENA has nothing to disclose. Juliana Acosta Uribe has nothing to disclose. Ana Baena has nothing to disclose. Gloria Garcia-Ospina has nothing to disclose. Margarita Giraldo-Chica has nothing to disclose. Victoria Tirado has nothing to disclose. Mrs. Munoz has nothing to disclose. Miss Guzman Martinez has nothing to disclose. Dr. Rios Romenets has nothing to disclose. Mr. Oliveira has nothing to disclose. Dr. Yang has received personal compensation in the range of $500-$4,999 for serving as a invited speaker with Genentech, Inc.. The institution of Clara Vila-Castelar has received research support from Alzheimer’s Association. The institution of Clara Vila-Castelar has received research support from NIA . The institution of Dr. Pruzin has received research support from Alzheimer’s Association. Dr. Ghisays has received personal compensation for serving as an employee of Banner Alzheimer’s Institute. Joseph Arboleda-Velasquez has nothing to disclose. Dr. Kosik has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Rainwater Foundation. The institution of Dr. Kosik has received research support from National Institute of Health. The institution of Dr. Kosik has received research support from Hillblom Foundation. The institution of Dr. Kosik has received research support from Adelson Medical Foundation. The institution of Dr. Kosik has received research support from Alzheimer Association/Rainwater Foundation. The institution of Dr. Kosik has received research support from Thome Memorial FOundation. Dr. Reiman has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Denali, Green Valley, Zinfandel, and Takeda. Dr. Reiman has received stock or an ownership interest from Alkahest, Alzheon, Aural Analytics, Denali, and United Neuroscience.. Dr. Reiman has received intellectual property interests from a discovery or technology relating to health care. Dr. Reiman has received personal compensation in the range of $500-$4,999 for serving as a Member, National Advisory Council on Aging (NACA) with NIA. Francisco Lopera has nothing to disclose. Dr. Quiroz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Quiroz has received intellectual property interests from a discovery or technology relating to health care.

Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser (http://web.hararilab.org/SNARE/).

A peptide-centric quantitative proteomics dataset for the phenotypic assessment of Alzheimer’s disease

Alzheimer’s disease (AD) is a looming public health disaster with limited interventions. Alzheimer’s is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing.