Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters.

BACKGROUND: Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters. METHODS: We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression. RESULTS: At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction. LIMITATIONS: CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders. CONCLUSIONS: The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma.

Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes.

White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based Study of Health in Pomerania (SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified hsa-miR-425-5p as directly associated with WMLs. In subsequent analyses, hsa-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the SH3PXD2A gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced hsa-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Detrimental Effects of ApoE ε4 on Blood-Brain Barrier Integrity and Their Potential Implications on the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood-brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.

The interplay between micro RNAs and genetic liability to Alzheimer's Disease on memory trajectories in the general population.

Deficits in cognitive function and memory are common early symptoms of neurodegenerative disorders, such as Alzheimer's Disease (AD). Several studies have discussed micro RNAs (miRNAs) as potential epigenetic early detection biomarkers. In a longitudinal general population sample (n = 548) from the Study of Health in Pomerania, we analyzed the associations between 167 baseline miRNA levels and changes in verbal memory scores with a mean follow-up time of 7.4 years. We additionally assessed the impact of an individual's genetic liability for AD on verbal memory scores in n = 2,334 subjects and a possible interactions between epigenetic and genetic markers. Results revealed two miRNAs associated with changes in immediate verbal memory over time. In interaction analyses between miRNAs and a polygenic risk score for AD, five miRNAs showed a significant interaction effect on changes in verbal memory. All of these miRNAs have previously been identified in the context of AD, neurodegeneration or cognition. Our study provides candidate miRNAs for a decline in verbal memory as an early symptom of neurodegeneration and AD. Further experimental studies are needed to verify the diagnostic value of these miRNA markers in the prodromal stage of AD.

Deciphering the Effect of Different Genetic Variants on Hippocampal Subfield Volumes in the General Population.

The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases.

Association of spermidine plasma levels with brain aging in a population-based study.

INTRODUCTION: Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). METHODS: Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). RESULTS: Higher spermidine levels were significantly associated with lower hippocampal volume (ß = -0.076; 95% confidence interval [CI]: -0.13 to -0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = -0.104; 95% CI: -0.17 to -0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. DISCUSSION: Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

A sound mind in a sound body: a novel concept unravelling heterogeneity of depression.

Depression is a highly prevalent and debilitating condition, yet we still lack both in-depth knowledge concerning its etiopathology and sufficiently efficacious treatment options. With approximately one third of patients resistant to currently available antidepressants there is a pressing need for a better understanding of depression, identifying subgroups within the highly heterogeneous illness category and to understand the divergent underlying biology of such subtypes, to help develop and personalise treatments. The TRAJECTOME project aims to address such challenges by (1) identifying depression-related multimorbidity subgroups and shared molecular pathways based on temporal disease profiles from healthcare systems and biobank data using machine learning approaches, and by (2) characterising these subgroups from multiple aspects including genetic variants, metabolic processes, lifestyle and environmental factors. Following the identification of multimorbidity trajectories, a disease burden score related to depression and adjusted for multimorbidity was established summarising the current state of the patient to weigh the molecular mechanisms associated with depression. In addition, the role of genetic and environmental factors, and also their interactions were identified for all subgroups. The project also attempted to identify potential metabolomic markers for the early diagnostics of these multimorbidity conditions. Finally, we prioritized molecular drug candidates matching the multimorbidity pathways indicated for the individual subgroups which would potentially offer personalised treatment simultaneously for the observable multimorbid conditions yet minimising polypharmacy and related side effects. The present paper overviews the TRAJECTOME project including its aims, tasks, procedures and accomplishments. (Neuropsychopharmacol Hung 2023; 25(4): 183-193)

TREML2 Gene Expression and Its Missense Variant rs3747742 Associate with White Matter Hyperintensity Volume and Alzheimer's Disease-Related Brain Atrophy in the General Population.

Although the common pathology of Alzheimer's disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant's AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2's role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.

Vitamin D deficit is associated with accelerated brain aging in the general population.

Vitamin D deficiency has been associated with reduced neurocognitive functioning and the neurodegenerative processes. However, existing evidence on brain structural correlates of vitamin D deficiency is controversial. We sought to investigate associations of vitamin D levels with imaging patterns of brain aging. In addition, we investigated whether low vitamin D levels were associated with gray matter volumes, whole brain volumes and hippocampus volumes. Structural MRI data and vitamin D levels were obtained in 1,865 subjects from the general population. Linear regressions were applied to investigate the association of vitamin D levels and vitamin D deficiency with imaging derived brain age, total brain, gray matter and hippocampal volumes. Different sets of covariates were included. Vitamin D deficiency was significantly associated with increased brain age. Also, linear vitamin D levels were significantly associated with total brain and gray matter volumes, while no significant association with hippocampal volume was found. Further interaction analyses showed that this association was only significant for male subjects. Our results support previous findings suggesting that vitamin D-deficient individuals have an accelerated brain aging. In addition, associations between vitamin D levels and total brain/ gray matter volumes suggest neuroprotective effects of vitamin D on the brain.

Genome-wide gene-gene interaction of the 5-HTTLPR promoter polymorphism emphasizes the important role of neuroplasticity in depression.

Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms affecting depressive disorders. GWAS results support the heterogeneity of depression as a disorder affected by a large number of genetic variants with mainly small effect sizes. However, not much is known about the interplay of different genetic risk factors. Moreover, recent studies are questioning the role of common candidate genes in the development of depressive disorders. One such candidate variant is the serotonin-transporter-promoter-polymorphism 5-HTTLPR in the SLC6A4 gene. We hypothesize that 5-HTTLPR exerts its effect on depressive disorders in interaction with other genetic variants. In the present study we test this hypothesis using a genome-wide gene-gene interaction approach on a large sample from the UK Biobank (N = 127,558). We identified a region in the DPF1 gene that displayed a genome-wide significant (p = 3.31 × 10-7) interaction effect with the biallelic version of 5-HTTLPR on lifetime depression. DPF1 has not previously been described as risk factor for depressive disorders but is exclusively expressed in the brain as a major regulator of neuronal development and neuroplasticity. This study stresses the need for further analyses that take into consideration the fact that genetic variants do operate in biological networks.

APOE ε4 in Depression-Associated Memory Impairment-Evidence from Genetic and MicroRNA Analyses.

(1) Background: The aim of this study was to replicate a reported interaction between APOE ε4 status and depression on memory function in two independent, nondemented samples from the general population and to examine the potential role of circulating plasma miRNAs. (2) Methods: The impact of the APOE ε4 allele on verbal memory and the interaction with depression is investigated in two large general-population cohorts from the Study of Health in Pomerania (SHIP, total n = 6286). Additionally, biological insights are gained by examining the potential role of circulating plasma miRNAs as potential epigenetic regulators. Analyses are performed using linear regression models adjusted for relevant biological and environmental covariates. (3) Results: Current depression as well as carrying the APOE ε4 allele were associated with impaired memory performance, with increasing effect for subjects with both risk factors. In a subcohort with available miRNA data subjects with current depressive symptoms and carrying APOE e4 revealed reduced levels of hsa-miR-107, a prominent risk marker for early Alzheimer's Disease. (4) Conclusions: Our results confirm the effect of depressive symptoms and APOE ε4 status on memory performance. Additionally, miRNA analysis identified hsa-miR-107 as a possible biological link between APOE ε4, depressive symptoms, and cognitive impairment.

The interplay between genetic variation and gene expression of the glucocorticoid receptor gene NR3C1 and blood cortisol levels on verbal memory and hippocampal volumes.

The hypothalamus-pituitary-adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.

Effects of Apolipoprotein E polymorphism on carotid intima-media thickness, incident myocardial infarction and incident stroke.

The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20-79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (ß: - 0.02 [95% CI - 0.04, - 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.

Plasma circulating micro-RNAs associated with alexithymia reflect a high overlap on neuropsychiatric outcomes.

BACKGROUND: Alexithymia ("no word for feelings") is a personality feature that is common in patients with psychiatric disorders. However, little is known about biological causes and mechanism behind. Research so far focusses on genetic risk variants primary associated with depression, but analyses on epigenetic mechanisms are still missing. METHODS: In a sample of n = 813 subjects from the "Study of Health in Pomerania" we analyzed the association between alexithymia and plasma circulating micro RNAs (miRNA). Significant miRNAs were compared to associations regarding depression and pathway analyses were performed. RESULTS: Two miRNAs were significantly associated with at least one of the alexithymia scores (hsa-miR-324-3p, hsa-miR-33a-5p) and three miRNAs additionally revealed a strong association pattern to alexithymia (hsa-miR-106b-5p, hsa-miR-484, hsa-miR-25-3p). None of these miRNAs was significantly associated with depressive symptoms in our sample. Literature research showed that all of the miRNAs have been found in association with several neuropsychiatric phenotypes. LIMITATIONS: Main limitations are the lack of a replication sample as well as the limited number of miRNAs analyzed. CONCLUSIONS: This is the first analysis investigating the association between miRNAs and alexithymia. Results indicate that miRNAs are not specific for one psychiatric disorder but may influence biological mechanisms that are involved in various psychiatric conditions which might be relevant for future treatment options and improve the biological understanding of psychiatric conditions.

The Impact of Resilience, Alexithymia and Subjectively Perceived Helplessness of Myocardial Infarction on the Risk of Posttraumatic Stress.

The aim of this study was to investigate the impact of resilience, alexithymia and the subjectively perceived severity (fear of death, pain intensity, helplessness) of myocardial infarction (MI) on posttraumatic symptom severity (PTSS) after MI. Patients were assessed with the Posttraumatic Diagnostic Scale (PDS), Resilience Scale (RS-11) and Toronto Alexithymia Scale (TAS-20). Subjectively perceived severity of MI was measured with three items on a 10-point Likert scale. To test our hypothesis, we applied Pearson correlations as well as multiple hierarchical linear regression analyses. A higher resilience score was significantly associated with lower (r = - .39, p < .001) PTSS. Higher scores of alexithymia (r = .38, p < .01) and subjectively perceived helplessness (r = .42, p < .001) were associated with higher PTSS. Multiple hierarchical linear regression analyses revealed that resilience, the TAS-20 subscale difficulty identifying feelings (DIF) and especially subjectively perceived helplessness were independent significant predictors for the PTSS, adjusted R2 = .29, F(5, 102) = 9.57, p < .001. Our results suggest that resilience reduces the PTSS whereas alexithymia and subjectively perceived helplessness increase the risk. Especially the subjectively perceived helplessness explains a high degree of variance of PTSS and should be assessed to hindering further mental health burden.

Longitudinal association of Apolipoprotein E polymorphism with lipid profile, type 2 diabetes and metabolic syndrome: Results from a 15 year follow-up study.

AIMS: To examine the association of different APOE alleles with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) as well as the influence of high-sensitive C-reactive protein (hs-CRP) on these associations. METHODS: We analyzed data from 3917 participants aged 20-81 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 10.8 years. Linear and logistic mixed models were performed to test the association of APOE alleles with T2DM and MetS. RESULTS: We observed 393 T2DM and 1411 MetS events at baseline, and 576 T2DM and 1342 MetS events over the follow-up. The E4 carriers had a lower odds of developing T2DM (OR: 0.47 [0.24, 0.94]) than E3 homozygotes even after adjustment for potential confounders. The E2 carriers showed no associations. The inverse association between E4 alleles and T2DM moderately attenuated after adjustment for hs-CRP levels. The lower odds of developing T2DM in E4 carriers was more pronounced in participants without obesity, hypertension or MetS. However, both E2 and E4 carriers had higher odds of developing MetS (E2 OR: 1.45 [1.03, 2.03]; E4 OR: 1.56 [1.17, 2.09]) than E3 homozygotes. CONCLUSIONS: While the presence of APOE E4 allele might increase the chance of MetS through its major action on lipids, E4 allele might offer a protection towards T2DM through its influence on inflammation.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Effect of periodontal treatment on preclinical Alzheimer's disease-Results of a trial emulation approach.

INTRODUCTION: We investigated the relationship between periodontal treatment and pre-clinical Alzheimer's disease (AD). METHODS: In this quasi-experimental design, 177 periodontally treated patients from the "Greifswald Approach to Individualized Medicine" cohort, which used the same protocols as the population-based Study of Health in Pomerania TREND (SHIP-TREND), and 409 untreated subjects from SHIP-TREND were analyzed. Subjects were younger than 60 years at the magnetic resonance imaging examination, with a median observation period of 7.3 years. Imaging markers for brain atrophy in late-onset AD and brain aging were used as the outcomes. RESULTS: Robust to sensitivity analyses, periodontal treatment had a favorable effect on AD-related brain atrophy (-0.41; 95% confidence interval: -0.70 to -0.12; P = .0051), which corresponds to a shift from the 50th to the 37th percentile of the outcome distribution. For brain aging, the treatment effect was uncertain. CONCLUSION: Periodontitis is related to pre-clinical AD in our population.