Citations

AbstractBackgroundBrain glucose hypometabolism is among the earliest pathogenic changes in Alzheimer’s disease (AD). This metabolic dysfunction points to the personal bioenergetic capacity, defined as the ability to maintain energy homeostasis under all circumstances including deregulated glucose uptake, as a potential source of resilience to the disease. Fasting blood acylcarnitine profiles are a central readout for this capacity in the absence of dietary glucose and capture the activity and efficiency of glucose‐independent routes of mitochondrial energy metabolism.MethodWe used fasting serum acylcarnitine profiles of 1,531 participants (465 with normal cognition, 762 with mild cognitive impairment, and 304 with clinical AD) from the AD Neuroimaging Initiative to perform unsupervised subgroup identification using hierarchical clustering. Identified subgroups were investigated for differences in A/T/N biomarker profiles and cognitive status. The contributions of genetic and potentially modifiable factors defining the subgroups were quantified using analysis of explained variance. The influence of the strongest determining factors on longitudinal cognitive trajectories was estimated using linear mixed‐effects models and gene‐by‐environment interaction analysis.ResultWe found several bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. The strongest genetic contribution to this bioenergetic endophenotype seems to be specifically linked to succinylcarnitine metabolism and significantly modulates the rate of future cognitive decline. In contrast, potentially modifiable sustainment of beta‐oxidation efficiency seems to decelerate bioenergetic aging, thus creating a bioenergetic reserve that delays progression of cognitive decline. Using gene‐by‐environment interaction analysis, we demonstrate that this molecular framework identifies a subgroup of individuals that is likely to benefit significantly from personalized therapeutic, dietary or lifestyle interventions tailored to increase resilience against bioenergetic disturbances in AD.ConclusionOur study reports on a set of genetic and metabolic markers that define bioenergetically distinct subgroups with significant differences on the AD biomarker and cognitive level. Longitudinal data suggest that targeting the modifiable fraction of this endophenotype might be a promising strategy to slow down disease progression in individuals with specific allelic configurations.

Abstract Resilience, which relates to one's ability to respond to stressors, typically declines with age and the development of comorbid conditions in older organisms. Although progress has been made to improve our understanding of resilience in older adults, disciplines have employed different frameworks and definitions to study various aspects of older adults' response to acute or chronic stressors. “Overview of the Resilience World: State of the Science,” a bench‐to‐bedside conference on October 12–13, 2022, was sponsored by the American Geriatrics Society and National Institute on Aging. This conference, summarized in this report, explored commonalities and differences among the frameworks of resilience most commonly used in aging research in the three domains of resilience: physical, cognitive, and psychosocial. These three main domains are intertwined, and stressors in one domain can lead to effects in other domains. The themes of the conference sessions included underlying contributors to resilience, the dynamic nature of resilience throughout the life span, and the role of resilience in health equity. Although participants did not agree on a single definition of “resilience(s),” they identified common core elements of a definition that can be applied to all domains and noted unique features that are domain specific. The presentations and discussions led to recommendations for new longitudinal studies of the impact of exposures to stressors on resilience in older adults, the use of new and existing cohort study data, natural experiments (including the COVID‐19 pandemic), and preclinical models for resilience research, as well as translational research to bring findings on resilience to patient care.

AbstractObjectiveTo compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.MethodsGenotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers.ResultsPRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older.InterpretationPRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4.

Abstract Introduction Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD‐associated metabolic changes in the brain has been missing. Methods We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late‐life cognitive performance and AD neuropathology measures. Results We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD‐relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology. Discussion This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow‐up studies.

Abstract Introduction The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study (NIA‐LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). Methods Recruitment focused on families with two living affected siblings and a third first‐degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E ( APOE ) genotypes, genome‐wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results APOE genotype modified the age‐at‐onset in many large families. Novel variants and known variants associated with early‐ and late‐onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion The NIA‐LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age‐at‐onset provides opportunities to investigate the complexity of familial AD.

AbstractIntroductionA few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data.MethodsWe used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data.ResultsWe identified 3,012 rare AD‐specific CNVs whose residing genes are enriched for cellular glucuronidation and neuron projection pathways. Genes whose mRNA expressions are significantly correlated with common CNVs are involved in major histocompatibility complex class II receptor activity. Integration of CNVs, gene expression, and clinical and pathological traits further pinpoints a key CNV that potentially regulates immune response in AD.DiscussionWe identify CNVs as potential genetic regulators of immune response in AD. The identified CNVs and their downstream gene networks reveal novel pathways and targets for AD.

Background. Teratomas in the pediatric population are most commonly found in the sacrococcygeal region. Pediatric intraspinal teratomas, however, are an exceedingly rare central nervous system (CNS) neoplasm. The clinical presentation of these intraspinal neoplasms can vary significantly and thus can be difficult to identify in infants less than one year of age where verbal expression and motor development are still lacking. Case Description. A 7-month-old, previously healthy male presented with a thoracic scoliosis and an asymptomatic right midupper thoracic spinal prominence present since birth. MRI revealed an extensive heterogenous mass in the right epidural space from T5-T6 and the right paravertebral space, resulting in severe spinal stenosis. Outcome. Complete resection of the tumor, including a three-level neurotomy, was achieved by posterior decompression/laminectomy. The final tumor was consistent with a mature teratoma. The surgical resection was performed without any immediate complications. Conclusions. Extramedullary epidural teratomas are exceptionally rare tumors in the pediatric population. Clinical presentation can be ambiguous, particularly in an infant. MRI was useful in suggesting a teratoma as a potential diagnosis and for postoperative surveillance for recurrence. However, histopathological analysis remains the gold standard for definitive diagnosis. Surgical resection is the mainstay of treatment, especially in the setting of cord compression and progressive loss of motor function. Close follow-up is crucial to monitor for progressive spinal deformity or recurrence.

Abstract Not all apolipoprotein E ( APOE ) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4‐attenuating signals from methylome‐wide association analyses (N = 572, ε4+ and ε4–) of neurofibrillary tangles and neuritic plaques, we conducted a meta‐analysis for pathological AD within the ε4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA‐seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principal component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (odds ratio = 2.39, 95% confidence interval = [1.64,3.46], P = 7.08 × 10 –6 ). An epigenomic factor associated with a reduced proportion of activated microglia (epigenomic factor of activated microglia, EFAM) appears to attenuate the risk of ε4 on AD.