Abstract Background In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging. Methods We used data from the Berlin Aging Study II (BASE-II, 60–80 years of age at baseline, average follow-up 7.4 ± 1.5 years, range 3.9–10.4, n = 1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: physiological (insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15)), inflammatory (high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6)), functional (muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty phenotype (FP), cognitive health, blood pressure), and epigenetic (epigenetic clock, DunedinPACE). Cox proportional hazard regression analyses were performed to investigate their role in prediction of all-cause as well as cause-specific mortality. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. Results In adjusted models of all-cause mortality, HGS, IL-6, standing balance, cognitive health, and the epigenetic clock (DunedinPACE) statistically significantly predicted mortality, with the epigenetic clock (DunedinPACE) emerging as the strongest predictor. CRP, gait speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FP and TUG were not associated with mortality in this study. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set consisting of muscle mass, standing balance, and epigenetic clock (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65). Conclusion Among the fourteen investigated biomarkers of aging, DunedinPACE emerged with the strongest and most consistent association with mortality.

Metabolic dysfunction-associated steatotic liver disease (MASLD, introduced in 2023), formerly termed non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide and is closely linked to obesity, insulin resistance, and cardiometabolic dysfunction. Exercise is widely recommended as a cornerstone of MASLD management; however, the magnitude of its hepatic and metabolic benefits and the underlying molecular mechanisms remain incompletely defined. We aim to synthesize evidence from randomized controlled trials assessing how structured exercise interventions influence hepatic steatosis and metabolic dysfunction in adults with MASLD. A targeted search of PubMed from database inception to February 2025 identified eligible trials, of which eleven were included in the qualitative synthesis. Across studies, aerobic and resistance exercise interventions were consistently associated with reductions in hepatic fat content, improvements in plasma lipid profiles and liver enzyme concentrations, and enhanced indices of insulin sensitivity, frequently occurring independently of substantial weight loss. Mechanistically, exercise-induced activation of pathways related to mitochondrial function, lipid oxidation, inflammation modulation, and insulin signaling likely contributes to these benefits. Despite heterogeneity in intervention design, duration, and outcome assessment, the collective evidence supports structured exercise as an effective non-pharmacological strategy for improving hepatic steatosis and metabolic dysfunction in MASLD. Future studies integrating molecular biomarkers with clinical endpoints are warranted to refine exercise prescriptions and elucidate mechanisms of therapeutic response.

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu) in 26 men, ProtAgeGap decreased by the equivalent of 10 months. While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk. Clinical trial number: clinicaltrials.gov: NCT01803568 registered 2013-02-26.

Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.

UbiA prenyltransferase domain containing 1 (Ubiad1) has the potential to affect cholesterol and phospholipid levels in different cell types. We previously identified Ubiad1 as a candidate gene for regulating subcutaneous fat pad weight in a mouse genome-wide association study. Here we evaluated the relationship between Ubiad1 and obesity-related traits in cohorts of humans and mice, and in Ubiad1+/− mice fed a high-fat diet. In both humans and mice, adipose tissue Ubiad1 mRNA expression correlated negatively with adiposity and positively with mitochondria-related genes. To determine the role of Ubiad1 in high-fat diet-induced obesity, we disrupted the Ubiad1 gene in mice. Deletion of Ubiad1 was embryonically lethal in C57BL/6 N mice, preventing analysis of adult Ubiad1−/− mice. Thus, male and female Ubiad1+/+ and Ubiad1+/− mice were fed high-fat diet for 10 weeks, with no difference in weight gain and adipose tissue organ weights observed between the genotypes. Analysis of liver mRNA expression revealed that Ubiad1 heterozygosis (Ubiad1+/−) altered several pathways involved in lipid metabolism. Detailed lipid quantification with HPLC-qTOF/MS showed increased levels of hepatic ceramides in female Ubiad1+/− mice, whereas phosphatidylglycerols, phosohatidylinositol and lysophosphatidylethanolamines were reduced in male Ubiad1+/− mice. Our findings reveal sex-specific effects of Ubiad1 expression on hepatic lipid metabolism.

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes.

Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes. Funding: South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes’ legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123). Clinical trial number: clinicaltrials.gov: NCT01803568 .

Many aging men experience reduced energy and libido related to non-optimal testosterone levels. We conducted a randomized double-blind trial with TrigozimR fenugreek extract to assess impact on plasma and saliva testosterone, and some subjective effects. 95 men (40-80y) completed a 12-week intervention, taking 3 tablets daily with 0 mg (placebo; n = 22), 600 mg (n = 21), 1200 mg (n = 25) and1800 mg (n = 27) fenugreek extract and essential nutrients. Samples were collected at weeks 0, 2, 6, and 12. Participants answered a pre- and post-intervention questionnaire on lifestyle and libido. We measured total testosterone (HPLC-MS/MS) and sex hormone binding globulin (ELISA), calculated free testosterone index (FTI), and measured saliva testosterone. Plasma total testosterone and FTI increased after any dose of TrigozimR vs. baseline (13.0%, p = 1.0x10-4 and 16.3%, p = 6.2x10-6), but not vs. placebo (9.0%, p = 0.122 and 11.3% p = 0.059). 1800 mg TrigozimR resulted in 12.2% increased FTI (p = 0.025). Saliva testosterone concentration increased after any dose of TrigozimR vs. baseline (31.1%, p = 2.3x10-4) and vs. placebo (37.2%, p = 0.042). 1800 mg TrigozimR for 12 weeks resulted in 19.6% (p = 0.006) increased saliva testosterone. Compliance was confirmed by enhanced plasma concentration of 25-hydroxy vitamin D3. We observed no subjective effects or side-effects of TrigozimR. TrigozimR increased saliva and plasma testosterone concentration during intervention but only for saliva vs. placebo. Saliva may be preferred for measuring free testosterone due to no protein-bound testosterone.

Although there are some epigenome-wide association studies (EWAS) of insulin resistance, for most of them authors did not replicate their findings, and most are focused on populations of European ancestry, limiting the generalizability. In the Epigenetics in Pregnancy (EPIPREG; n = 294 Europeans and 162 South Asians) study, we conducted an EWAS of insulin resistance in maternal peripheral blood leukocytes, with replication in the Born in Bradford (n = 879; n = 430 Europeans and 449 South Asians), Methyl Epigenome Network Association (MENA) (n = 320), and Botnia (n = 56) cohorts. In EPIPREG, we identified six CpG sites inversely associated with insulin resistance across ancestry, of which five were replicated in independent cohorts (cg02988288, cg19693031, and cg26974062 in TXNIP; cg06690548 in SLC7A11; and cg04861640 in ZSCAN26). From methylation quantitative trait loci analysis in EPIPREG, we identified gene variants related to all five replicated cross-ancestry CpG sites, which were associated with several cardiometabolic phenotypes. Mediation analyses suggested that the gene variants regulate insulin resistance through DNA methylation. To conclude, our cross-ancestry EWAS identified five CpG sites related to lower insulin resistance.

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration-which is shorter than current recommendations.

IntroductionStakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain-organized in a separate work package-included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. MethodsStakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. ResultsConsortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. ConclusionStakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public ContributionPatient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

Context The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity. Objective We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites. Methods In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts. Results SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB. Conclusion Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.

Brief summary: This pooled study, including five cross-sectional or intervention studies (n=24–823) and using publicly available data from genome-wide association studies (GWAS) to perform Mendelian randomization, investigated the influence of glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity on serum soluble leptin receptor (sOb-R) levels. The authors showed that insulin and BMI were associated with decreased serum sOb-R levels, whereas physical activity and food intake acutely increased sOb-R levels, suggesting an involvement in the short-term regulation of leptin signalling.

Background: The capacity of an individual to respond to changes in food intake so that postprandial metabolic perturbations are resolved, and metabolism returns to its pre-prandial state, is called phenotypic flexibility. This ability may be a more important indicator of current health status than metabolic markers in a fasting state.Aim: In this parallel randomized controlled trial study, an energy-restricted healthy diet and 2 dietary challenges were used to assess the effect of weight loss on phenotypic flexibility.Methods: Seventy-two volunteers with overweight and obesity underwent a 12-wk dietary intervention. The participants were randomized to a weight loss group (WLG) with 20% less energy intake or a weight-maintenance group (WMG). At weeks 1 and 12, participants were assessed for body composition by MRI. Concurrently, markers of metabolism and insulin sensitivity were obtained from the analysis of plasma metabolome during 2 different dietary challenges-an oral glucose tolerance test (OGTT) and a mixed-meal tolerance test.Results: Intended weight loss was achieved in the WLG (-5.6 kg, P < 0.0001) and induced a significant reduction in total and regional adipose tissue as well as ectopic fat in the liver. Amino acid-based markers of insulin action and resistance such as leucine and glutamate were reduced in the postprandial phase of the OGTT in the WLG by 11.5% and 28%, respectively, after body weight reduction. Weight loss correlated with the magnitude of changes in metabolic responses to dietary challenges. Large interindividual variation in metabolic responses to weight loss was observed.Conclusion: Application of dietary challenges increased sensitivity to detect metabolic response to weight loss intervention. Large interindividual variation was observed across a wide range of measurements allowing the identification of distinct responses to the weight loss intervention and mechanistic insight into the metabolic response to weight loss.

Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.

Purpose of Review To summarize the key factors contributing to the onset and progress of nonalcoholic fatty liver disease (NAFLD) and put them in a system genetics context. We particularly focus on how genetic regulation of hepatic lipids contributes to NAFLD. Recent Findings NAFLD is characterized by excessive accumulation of fat in the liver. This can progress to steatohepatitis (inflammation and hepatocyte injury) and eventually, cirrhosis. The severity of NAFLD is determined by a combination of factors including obesity, insulin resistance, and lipotoxic lipids, along with genetic susceptibility. Numerous studies have been conducted on large human cohorts and mouse panels, to identify key determinants in the genome, transcriptome, proteome, lipidome, microbiome and different environmental conditions contributing to NAFLD. Summary We review common factors contributing to NAFLD and put them in a systems genetics context. In particular, we describe how genetic regulation of liver lipids contributes to NAFLD. The combination of an unhealthy lifestyle and genetic predisposition increases the likelihood of accumulating lipotoxic specie lipids that may be one of the driving forces behind developing severe forms of NAFLD.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20–89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems ( n = 1742) and participants sleeping the recommended 7–8 h ( n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.