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The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.

A focus on cell biology may accelerate progress in disease prevention and cures

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (∼10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability. Omura et al. screened for neuronal growth on myelin and find CAST/Ei inbred mice are uniquely able to regenerate axons in the injured CNS through Activin signaling. Enhancing Activin signaling confers a CNS-regenerative capacity in normally non-regenerative mouse strains.

The amyloid β (Aβ)-protein and microtubule-associated protein, tau, are the major components of the amyloid plaques and neurofibrillary tangles that typify Alzheimer's disease (AD) pathology. As such both Aβ and tau have long been proposed as therapeutic targets. Immunotherapy, particularly targeting Aβ, is currently the most advanced clinical strategy for treating AD. However, several Aβ-directed clinical trials have failed, and there is concern that targeting this protein may not be useful. In contrast, there is a growing optimism that tau immunotherapy may prove more efficacious. Here, for the first time, we studied the effects of chronic administration of an anti-tau monoclonal antibody (5E2) in amyloid precursor protein transgenic mice. For our animal model, we chose the J20 mouse line because prior studies had shown that the cognitive deficits in these mice require expression of tau. Despite the fact that 5E2 was present and active in the brains of immunized mice and that this antibody appeared to engage with extracellular tau, 5E2-treatment did not recover age-dependent spatial reference memory deficits. These results indicate that the memory impairment evident in J20 mice is unlikely to be mediated by a form of extracellular tau recognized by 5E2. In addition to the lack of positive effect of anti-tau immunotherapy, we also documented a significant increase in mortality among J20 mice that received 5E2. Because both the J20 mice used here and tau transgenic mice used in prior tau immunotherapy trials are imperfect models of AD our results recommend extensive preclinical testing of anti-tau antibody-based therapies using multiple mouse models and a variety of different anti-tau antibodies.

Background: Dendritic spines serve as key computational structures in brain plasticity. Much remains to be learned about their spatial and temporal distribution among neurons. Our aim in this study was to perform exploratory analyses based on the population distributions of dendritic spines with regard to their morphological characteristics and period of growth in dissociated hippocampal neurons. We fit a log-linear model to the contingency table of spine features such as spine type and distance from the soma to first determine which features were important in modeling the spines, as well as the relationships between such features. A multinomial logistic regression was then used to predict the spine types using the features suggested by the log-linear model, along with neighboring spine information. Finally, an important variant of Ripley's K-function applicable to linear networks was used to study the spatial distribution of spines along dendrites.Results: Our study indicated that in the culture system, (i) dendritic spine densities were "completely spatially random", (ii) spine type and distance from the soma were independent quantities, and most importantly, (iii) spines had a tendency to cluster with other spines of the same type.Conclusions: Although these results may vary with other systems, our primary contribution is the set of statistical tools for morphological modeling of spines which can be used to assess neuronal cultures following gene manipulation such as RNAi, and to study induced pluripotent stem cells differentiated to neurons. © 2013 Jammalamadaka et al.; licensee BioMed Central Ltd.

Epigenetic regulation of gene expression plays an important role in learning and memory, mediating the influence of experience on critical mechanisms of plasticity. Speakers in the opening session of the Summit reviewed research on epigenetic contributions to age-related cognitive decline and discussed strategies for the development of interventions targeting epigenetic mechanisms. The presentations focused on experience-dependent DNA methylation, the regulatory role of microRNAs, histone deacetylases as potential therapeutic targets, and strategies for exploring epigenetic contributions to the aging of brain and cognition. This session established useful mileposts for gaging progress in this rapidly advancing area of research. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are essential post-transcriptional regulators that determine cell identity and fate. Aberrant expression of miRNAs can lead to diseases, including cancer. Expression of many miRNAs in the de-differentiated brain tumor cancer stem cells resembles that of neural stem cells. In this issue of BMC Medicine, Silber et al provide evidence of the expression of such miRNAs and their potential to mediate differentiation in both stem cell populations. In this commentary, we discuss the known functions of miRNAs in cancer and stem cells, their therapeutic potential and how the findings of Silber et al provide insight into the role of miR-124/miR-137 dysregulation in glioblastomas. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers., Methods: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups., Results: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18-75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group., Conclusions: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD., (© 2024. The Author(s).)

Introduction: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD)., Methods: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination., Results: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter., Discussion: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials., Highlights: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aβ pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging., (© 2024. The Author(s).)

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R 2 =0.37, F 2 =0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging., Competing Interests: Additional Declarations: There is NO Competing Interest. Competing Interest Statement None of the authors have competing financial or non-financial interests as defined by Nature Portfolio.

Rapid advances in human brain organoid technologies have prompted the question of their consciousness. Although brain organoids resemble many facets of the brain, their shortcomings strongly suggest that they do not fit any of the operational definitions of consciousness. As organoids gain internal processing systems through statistical learning and closed loop algorithms, interact with the external world, and become embodied through fusion with other organ systems, questions of biosynthetic consciousness will arise., Competing Interests: K.S.K. is an employee and holds appointments as the Harriman Professor in Neuroscience and co-director of the Neuroscience Research Institute at University of California, Santa Barbara; is a member of the Alzheimer’s Disease Cooperative Study Epstein Family Research Scientific Advisory Board at University of California, San Diego; is a co-founder and director of the Tau Consortium at the Rainwater Charitable Foundation; has equity in and is a board member of Minerva Therapeutics; and receives consultancy fees from Expansion Therapeutics., (© 2024 The Author(s).)

Background: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant ( APOE3 Ch ). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent., Methods: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants., Results: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18 F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18 F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant., Conclusions: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials., Competing Interests: Declaration of interests K.S.K. consults for ADRx and Expansion Therapeutics and is a member of the Tau Consortium board of directors. F.L. consults for Biogen and Viewmind and has grants from the NIH, Red-Lat, Alzheimer’s Association, Biogen, DIAN-TU, DIAN-Obs, Large PD, and Enroll-HD. J.A.-U .is a consultant for the pharmaceutical company Tecnoquimicas (Colombia)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The question of what generates conscious experience has mesmerized thinkers since the dawn of humanity, yet its origins remain a mystery. The topic of consciousness has gained traction in recent years, thanks to the development of large language models that now arguably pass the Turing test, an operational test for intelligence. However, intelligence and consciousness are not related in obvious ways, as anyone who suffers from a bad toothache can attest-pain generates intense feelings and absorbs all our conscious awareness, yet nothing particularly intelligent is going on. In the hard sciences, this topic is frequently met with skepticism because, to date, no protocol to measure the content or intensity of conscious experiences in an observer-independent manner has been agreed upon. Here, we present a novel proposal: Conscious experience arises whenever a quantum mechanical superposition forms. Our proposal has several implications: First, it suggests that the structure of the superposition determines the qualia of the experience. Second, quantum entanglement naturally solves the binding problem, ensuring the unity of phenomenal experience. Finally, a moment of agency may coincide with the formation of a superposition state. We outline a research program to experimentally test our conjecture via a sequence of quantum biology experiments. Applying these ideas opens up the possibility of expanding human conscious experience through brain-quantum computer interfaces.

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau-ten times the length of the peptide-and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions., Competing Interests: Competing interests statement:K.S.K. consults for ADRx and Expansion Therapeutics and is a member of the Tau Consortium Board of Directors.

Neurodegenerative diseases, like Alzheimer's, are associated with the presence of neurofibrillary lesions formed by tau protein filaments in the cerebral cortex. While it is known that different morphologies of tau filaments characterize different neurodegenerative diseases, there are few metrics of global and local structure complexity that enable to quantify their structural diversity rigorously. In this manuscript, we employ for the first time mathematical topology and geometry to classify neurodegenerative diseases by using cryo-electron microscopy structures of tau filaments that are available in the Protein Data Bank. By employing mathematical topology metrics (Gauss linking integral, writhe and second Vassiliev measure) we achieve a consistent, but more refined classification of tauopathies, than what was previously observed through visual inspection. Our results reveal a hierarchy of classification from global to local topology and geometry characteristics. In particular, we find that tauopathies can be classified with respect to the handedness of their global conformations and the handedness of the relative orientations of their repeats. Progressive supranuclear palsy is identified as an outlier, with a more complex structure than the rest, reflected by a small, but observable knotoid structure (a diagrammatic structure representing non-trivial topology). This topological characteristic can be attributed to a pattern in the beginning of the R3 repeat that is present in all tauopathies but at different extent. Moreover, by comparing single filament to paired filament structures within tauopathies we find a consistent change in the side-chain orientations with respect to the alpha carbon atoms at the area of interaction., (© 2024. The Author(s).)

Understanding metabolic heterogeneity is the key to uncovering the underlying mechanisms of metabolic-related diseases. Current metabolic imaging studies suffer from limitations including low resolution and specificity, and the model systems utilized often lack human relevance. Here, we present a single-cell metabolic imaging platform to enable direct imaging of lipid metabolism with high specificity in various human-derived 2D and 3D culture systems. Through the incorporation of an azide-tagged infrared probe, selective detection of newly synthesized lipids in cells and tissue became possible, while simultaneous fluorescence imaging enabled cell-type identification in complex tissues. In proof-of-concept experiments, newly synthesized lipids were directly visualized in human-relevant model systems among different cell types, mutation status, differentiation stages, and over time. We identified upregulated lipid metabolism in progranulin-knockdown human induced pluripotent stem cells and in their differentiated microglia cells. Furthermore, we observed that neurons in brain organoids exhibited a significantly lower lipid metabolism compared to astrocytes., (© 2024. The Author(s).)

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Tau has attracted the attention of fundamental cell biologists for its control over microtubules and Alzheimer biologists for its tendency to form pathological inclusions. While an extensive and insightful literature exists on the tauopathies and vulnerable cell populations, we should acknowledge that a core problem remains-how the individually variable experience of dementia is embodied, how it is felt., (© 2023 The Authors. Cytoskeleton published by Wiley Periodicals LLC.)

Large families with autosomal dominant mutations leading to Alzheimer's disease and related conditions can show putative protective gene variants; however, no systematic search strategy exists to find these genes. Described here are the unique demographic circumstances and genetic setting in which the discovery of protective variants is likely. The identification of these genes may reveal pathways with therapeutic implications. ANN NEUROL 2023;94:613-617., (© 2023 The Author. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The triggering receptor expressed on myeloid cell 2 (TREM2) is a major regulator of neuroinflammatory processes in neurodegeneration. To date, the p.H157Y variant of TREM2 has been reported only in patients with Alzheimer's disease. Here, we report three patients with frontotemporal dementia (FTD) from three unrelated families with heterozygous p.H157Y variant of TREM2 : two patients from Colombian families (study 1) and a third Mexican origin case from the USA (study 2)., Methods: To determine if the p.H157Y variant might be associated with a specific FTD presentation, we compared in each study the cases with age-matched, sex-matched and education-matched groups-a healthy control group (HC) and a group with FTD with neither TREM2 mutations nor family antecedents (Ng-FTD and Ng-FTD-MND)., Results: The two Colombian cases presented with early behavioural changes, greater impairments in general cognition and executive function compared with both HC and Ng-FTD groups. These patients also exhibited brain atrophy in areas characteristic of FTD. Furthermore, TREM2 cases showed increased atrophy compared with Ng-FTD in frontal, temporal, parietal, precuneus, basal ganglia, parahippocampal/hippocampal and cerebellar regions. The Mexican case presented with FTD and motor neuron disease (MND), showing grey matter reduction in basal ganglia and thalamus, and extensive TDP-43 type B pathology., Conclusion: In all TREM2 cases, multiple atrophy peaks overlapped with the maximum peaks of TREM2 gene expression in crucial brain regions including frontal, temporal, thalamic and basal ganglia areas. These results provide the first report of an FTD presentation potentially associated with the p.H157Y variant with exacerbated neurocognitive impairments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations., Methods: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies., Results: 13 variants had p<1×10 -7 or p<1×10 -5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14., Discussion: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role., (© 2023 Alzheimer's Association.)

Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors., (© 2023. Springer Nature Limited.)