Objective: Semantic fluency is an essential part of the cognitive assessment of Alzheimer’s disease (AD), but the utility of the telephone-administered version in detecting impairment in its in-person counterpart, or the associations with AD biomarkers, is unclear. Methods: Participants without previously diagnosed dementia from the population-based TWINGEN study (n = 200) completed telephone-administered 1-minute animal naming and in person-administered Consortium to Establish a Registry for Alzheimer’s Disease – neuropsychological battery (CERAD-nb) and provided blood sample for determining plasma phosphorylated tau217 (p-tau217). Results: The two modalities showed a moderate-to-high correlation (r = .63), with a bias of 3.41 words favoring in-person administration. Older age and lower education, but not plasma p-tau217, were significantly associated with poorer semantic fluency in both modalities. Area under the receiver operating characteristics curve was .76 (95% CI: .65; .88) for impairment in in-person semantic fluency and .70 (95% CI: .56; .84) for CERAD-nb total score. Group differences for p-tau217 status were found using a three-range approach: most (60%) with low animal naming score had high p-tau217 whereas most (73%) with high score had low p-tau217 (χ2[2] = 9.41, p = .009). Conclusions: Telephone-administered animal naming can identify individuals with semantic fluency impairment with some caveats. Keywords: Dementia; Alzheimer disease; psychometrics; neuropsychological tests; neuropsychology; cognitive aging

Understanding the cortical architecture underlying individual differences in general cognitive ability (GCA) remains a central question in cognitive neuroscience. Prior work has established associations between global brain size and GCA, yet the regional effects and directionality of these relationships remain debated. Using a genetically informed cortical parcellation in 11,289 UK Biobank participants, we examined associations between cortical surface area (SA), cortical thickness (CT), and GCA measured via verbal-numerical reasoning. Total SA showed a robust positive association with GCA. At the regional level, dorsolateral prefrontal and superior temporal SA exhibited the strongest positive associations, which persisted after adjustment for global SA. In contrast, CT showed comparatively modest associations. Using Mendelian randomization (MR) with genome-wide significant genetic instruments, we observed evidence consistent with a bidirectional relationship between total SA and GCA. At the regional level, dorsolateral prefrontal and temporal SA demonstrated evidence of MR-inferred directional effects on GCA, while GCA showed evidence of MR-inferred directional effects on total SA and perisylvian thickness. These findings support a polyregional SA architecture underlying GCA, with prominent contributions from prefrontal and temporal association cortices. Our results refine global brain-GCA models and highlight the value of genetically informed parcellation for identifying regional cortical contributions.

Individuals with high self-esteem experience less social anxiety, fewer depressive symptoms, and exhibit lower neuroticism and higher extraversion. We aimed to explore the genetic and environmental influences behind these associations. Self-esteem, four mental health indicators, and five personality factors were assessed in 1,288 Finnish young adult twins, including 583 complete pairs. The mean age of the participants was 21.9 years (SD = 0.8). Classical twin modelling was used to estimate genetic and environmental correlations. Additionally, regression models were used to examine the association between self-esteem and polygenic scores (PGS) of several mental health traits. Among all participants, self-esteem associated positively with extraversion, agreeableness, and conscientiousness and negatively with depressive symptoms, alexithymia, schizotypal personality, overall mental health problems and neuroticism. These associations were explained by additive genetic factors (19–66

INTRODUCTION:Proteomic aging clocks detect disease-related systemic and organ-specific changes and are easily accessible by minimally invasive blood draws. However, their potential in Alzheimer's disease (AD) assessment remains unestablished. METHODS:We investigated associations of proteomic and epigenetic clocks with AD-related blood-based biomarkers and cognitive tests. Omics were generated from blood samples of 153 cognitively unimpaired individuals (average age 62 years); blood biomarkers and cognition were measured approximately nine years after. RESULTS:Proteomic clocks explained up to 23% of variance in cognitive and biomarker measures not explained by epigenetics. Accelerated systemic and brain-specific proteomic aging were linked to poorer cognition and higher levels of plasma neurofilament light chain. Exploratory interaction analyses suggested weaker proteomic aging-cognition associations in individuals with higher genetic liability for diabetes. DISCUSSION:Our study illustrates the potential of plasma proteomic clocks in detecting AD-related phenotypes. However, co-morbidities possibly constitute confounding factors, compromising the performance of proteomic aging models.

Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop petVAE , a 2D variational autoencoder model. The model accurately reconstructed Aβ PET scans without prior labeling or pre-selection based on scanner type or region of interest. Latent representations of scans extracted from the petVAE (11,648 latent features per scan) were used to visualize, analyze, and cluster the AD continuum. We identified the latent features most representative of the continuum, and clustering of PET scans using these features produced four clusters. Post-hoc characterization revealed that two clusters (Aβ-, Aβ-+) were predominantly Aβ negative and two (Aβ+, Aβ++) were predominantly Aβ positive. All clusters differed significantly in standardized uptake value ratio (p < 1.64×10 -8 ) and cerebrospinal fluid (CSF) Aβ (p < 0.02), demonstrating petVAE's ability to assign scans along the Aβ continuum. The clusters at the extremes of the continuum (Aβ-, Aβ++) resembled to the conventional Aβ negative and Aβ positive groups and differed significantly in cognitive performance, Apolipoprotein E ( APOE ) ε4 prevalence, and Aβ, tau and phosphorylated tau CSF biomarkers (p < 3×10 -6 ). The two intermediate clusters (Aβ-+, Aβ+) showed significantly higher odds of carrying at least one APOE ε4 allele compared with the Aβ-cluster (p < 0.026). Participants in Aβ+ or Aβ++ clusters exhibited a significantly faster rate of progression to AD compared to Aβ-group (Hazard ratio = 2.42 and 9.43 for groups Aβ+ and Aβ++, respectively, p < 1.17×10 -7 ). Thus, petVAE was capable of reconstructing PET scans while also extracting latent features that effectively represented the AD continuum and defined biologically meaningful clusters. By capturing subtle Aβ-related changes in brain PET scans, petVAE -based classification enables the detection of preclinical AD stages and offers a new data-driven framework for studying disease progression.

BackgroundAtrophy of the medial temporal lobes and deep gray matter, along with ventricular enlargement, are typical structural magnetic resonance imaging (MRI) findings in the brains of patients with Alzheimer's disease (AD). However, there are few twin studies on this subject.PurposeTo determine whether the visual rating method (VRM) and tensor-based morphometry (TBM) can detect the structural brain changes in monozygotic and dizygotic twin pairs discordant for memory performance.Material and MethodsA total of 12 monozygotic and 24 same-sex dizygotic twin pairs discordant for memory performance and 44 cognitively healthy non-twin volunteers were studied.ResultsSignificant within-twin pair differences in brain atrophy were detected in the medial temporal lobes and ventricular areas (both with VRM and TBM), and in deep gray matter structures (TBM only). When monozygotic and dizygotic twin pairs were analyzed separately, the differences were not statistically significant.ConclusionOur study yielded promising TBM results in distinguishing memory-discordant co-twins in temporal and deep gray matter atrophy. In addition, the findings confirm the assumption that AD affects twins in the same way, independent of genes. Studies with larger twin cohorts would better reveal possible differences between monozygotic and dizygotic twin pairs.

Alzheimer's disease-related plasma biomarker interrelationships and factors underlying these associations remain poorly understood. To address this, we studied the heritability of plasma biomarkers and their associations with cognition. This study included 696 twins, aged 65-85, without a diagnosis of Alzheimer's disease or related dementias. Plasma amyloid beta 42 and 40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified with Simoa HD-X, and cognition was assessed with cCOG. Heritability of plasma biomarkers was assessed with multivariate twin models and associations with cognition with linear mixed effect models. Phenotypic associations varied from 0.22 between p-tau181 and GFAP to 0.73 between p-tau181 and p-tau217, and the heritability estimates ranged from 0.39 (p-tau181) to 0.66 (GFAP). Genetic and environmental correlations were 0.32-0.67 and 0.06-0.78, with the strongest correlations observed between p-tau181 and p-tau217. P-tau181 and p-tau217 were associated with cognition (β = -0.12; 95% CI: -0.19--0.04 and β = -0.19; 95% CI: -0.26--0.12, respectively). The observed phenotypic and genetic associations highlight shared underlying mechanisms among plasma biomarkers. Despite p-tau181 and p-tau217 having the strongest genetic and environmental correlations, neither approached unity, implying unique genetic and environmental factors. Our results offer insight into the genetic architecture of diagnostic and progression markers of Alzheimer's disease and inform their use in future gene-finding studies.

Plasma phosphorylated tau217 has been suggested as a core biomarker for establishing a biological Alzheimer's disease diagnosis. This blood biomarker has not been studied together with scalable cognitive assessment tools in population-based samples. We investigated the prevalence of cognitive and Alzheimer's disease biomarker abnormalities and associations between plasma phosphorylated tau217 and remotely measured cognitive function in individuals without dementia. We used a population-based cross-sectional sample of 65-85-year-olds (n = 691, 57% females), excluding those with previously diagnosed Alzheimer's disease or other dementia-causing neurodegenerative disease. Cognition was measured with a telephone-administered word list recall task (episodic memory) and animal naming (semantic fluency). Plasma phosphorylated tau217 was determined with the ALZpath assay. The prevalence of individuals with abnormalities in tests measuring episodic memory, semantic fluency, and plasma phosphorylated tau217 was 10-13%. Higher plasma phosphorylated tau217 levels were associated with lower scores on telephone-administered cognitive tests. We found a substantial minority of a population-based sample of individuals without a clinical diagnosis of Alzheimer's disease to have cognitive and plasma phosphorylated tau217 profiles suggesting underlying Alzheimer's disease. Combining plasma phosphorylated tau217 with remote cognitive assessment could be a scalable, accessible, and cost-effective protocol for screening individuals with undiagnosed or at risk for Alzheimer's disease.

OBJECTIVES:In short follow-up studies, greater leisure-time physical activity (LTPA) has been associated with better cognition in old age, but more longitudinal studies are needed. Our aim was to identify long-term LTPA trajectories from midlife to late old age and examine whether these trajectories are associated with nonagenarians' cognition. METHODS:In total, 125 participants from the NONAGINTA-Memory and Health in Nonagenarians study were included. The participants responded to health surveys of the older Finnish Twin Cohort study, including LTPA at the mean ages of 45, 52, 59, and 91 years. Cognition was assessed at the mean age of 91 years (standard deviation 1.54) via telephone interview (global cognitive function, episodic memory, and semantic fluency). We identified LTPA trajectories with K-means clustering for longitudinal data, and we used generalized estimating equations models to investigate differences in cognition among the LTPA trajectories. Covariates included age, sex, and education. RESULTS:We found 3 LTPA trajectories from midlife to nonagenarian age. The largest proportion of participants belonged to the Constant low trajectory (52%), characterized by a stable low level of physical activity throughout the follow-up. Two other trajectories were Starting low and increasing (25%) and Starting high and decreasing (23%). Nonagenarians' cognitive measures did not differ among the LTPA trajectories. DISCUSSION:Longitudinal physical activity behavior may not preserve cognitive function in those who survive to nonagenarian age but larger studies are warranted.

We investigated longitudinal associations between adolescent attention-deficit/hyperactivity disorder (ADHD) symptoms and later antisocial behavior and tested 1) whether these associations are independent of familial factors shared by co-twins and 2) whether cognitive performance moderates the associations. In a population-based sample of Finnish twins (N = 602-1330, 53% female), we assessed ADHD symptoms with teacher assessments and a diagnostic interview in adolescence, symptoms of antisocial personality disorder with a diagnostic interview in young adulthood, and criminal behavior across the lifespan with self-reports in early midlife. Cognitive performance was assessed with commonly used test measures in young adulthood. Adolescent ADHD symptoms were consistently associated with an increased risk for antisocial symptoms (incidence rate ratio [IRR] = 1.18-1.27) and criminal behavior (IRR = 1.16-1.20) later in life. Within-pair and interaction analyses suggested that the associations were to a large degree independent of familial factors, and cognitive performance level did not moderate them. In conclusion, subclinical ADHD symptoms are associated with an increased risk for antisocial behavior at the population level. The association is not fully explained by familial background, and it is independent of cognitive performance level.

The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 21 twin studies from 5 countries (Australia, Denmark, Finland, Sweden, and United States) established to explore the nature of gene-environment interplay in cognitive, physical, and emotional health across the adult lifespan. The combined data from over 145,000 participants (aged 18 to 108 years at intake) has supported multiple research projects over the three phases of development since its inception in 2010. Phases 1 and 2 focused on launching and growing the consortium and supported important developments in data harmonization, analyses of data pooled across multiple studies, incorporation of linkages to national registries and conscription data, and integration of molecular genetic and classical twin designs. IGEMS Phase 3 focuses on developing appropriate infrastructure to maximize utilization of this large twin consortium for aging research.

We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

We examined the associations of midlife and old-age cardiovascular risk factors, education, and midlife dementia risk scores with cognition at 90 + years, using data from a population-based study with 48 years of follow-up. Participants were 96 individuals aged 90-97 from the older Finnish Twin Cohort study. Individual cardiovascular risk factors assessed via questionnaires in 1975, 1981, 1990, and 2021-2023 included blood pressure, body mass index, physical activity, and cholesterol, and self-reported educational attainment. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score and an educational-occupational attainment score were used as midlife dementia risk scores. Cognitive assessments included semantic fluency, immediate and delayed recall from a 10-word list learning task, and a composite cognitive score. Regression analyses were conducted with dementia risk factors predicting cognition at 90 + years, adjusting for age, sex, education, follow-up time, and apolipoprotein E genotype (ε4-carrier vs non-carriers). Results showed that higher education and higher educational-occupational score were associated with better cognitive performance in all cognitive measures. Those with high midlife blood pressure scored significantly higher in all cognitive tests than those with normal blood pressure. Conversely, those with high old-age blood pressure scored lower in semantic fluency and composite cognitive score, but not in immediate or delayed recall. Other cardiovascular risk factors and the CAIDE score did not show consistent associations with cognition. Education appears to have a long-lasting protective effect in cognitive aging, whereas midlife and old-age cardiovascular risk factors were not significantly associated with cognition at 90 + years.

OBJECTIVE:Remote assessment of episodic memory would be a cost-effective alternative to in-person visits for early detection of memory impairment related to Alzheimer's disease (AD), but there is a need for test development and studies in population-based samples. The aim of this study was to investigate the validity and correlates of a novel three-trial administration of 10-word list learning included in the modified Telephone Interview for Cognitive Status in a population-based study of 65- to 96-year-old individuals. METHOD:A total of 800 participants completed telephone-administered word list learning task that yielded immediate and delayed recall measures. We compared these to corresponding measures from in-person neuropsychological assessment and tested differences between cognitively normal individuals and those with cognitive impairment or neurodegenerative disease. Furthermore, we studied the associations of age, sex, education, and genetic risk of AD with telephone-administered memory measures. RESULTS:Telephone-administered three-trial word list learning task yielded normally distributed immediate and delayed recall measures that performed like corresponding measures from in-person assessment. Having cognitive impairment or AD-but not genetic risk of AD-were related to poorer memory performance. Younger age, being female, and having secondary education were related to better memory performance. CONCLUSION:Our study supports the validity of telephone-administered word list task with multiple learning trials. Remote assessment of memory can be used as an alternative to inviting people to in-person assessment and is also easily accessible for people living in remote areas and for those with physical disabilities or during restrictions related to in-person contact. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Major depressive disorder (MDD) is linked to a higher risk of premature aging, but the mechanisms underlying this association remain unclear. Using data from two population cohorts (UK Biobank and Finnish Twin Cohort), we evaluate the relationship between systemic and organ-specific proteomic and epigenetic aging acceleration and MDD. A lifetime history of MDD was associated with accelerated proteomic aging at both systemic and organ-specific levels-including the brain-in both cohorts, with stronger associations than those observed with systemic epigenetic aging. Systemic and brain-specific proteomic aging acceleration were linked to higher risks of incident MDD and a greater risk of Alzheimer's disease, related dementia, and mortality among individuals with MDD in the UK Biobank. Evidence of depressive episode remission attenuated the association between MDD and systemic and brain-specific proteomic aging acceleration. Finally, Mendelian randomization analyses revealed a causal effect of MDD on systemic and brain-specific proteomic aging acceleration. Our results suggest a strong bidirectional association between MDD and biological aging acceleration. Biological aging acceleration, assessed by proteomic systemic and organ-specific clocks, can serve as a novel therapeutic target for treating MDD and for mitigating the long-term risks of adverse health outcomes associated with this condition.

INTRODUCTION:Little is known about plasma phosphorylated tau 217 (p-tau217) in individuals without a clinical diagnosis of Alzheimer's disease (AD). We studied associations of plasma p-tau217 with age, sex, education, and genetic risk; estimated the heritability; and conducted a genome-wide association study (GWAS). METHODS:A population-based biobank recall study of 65- to 85-year-old twins (N = 697, mean [SD] age 76.2 [4.6] years; 53% women, 154 full pairs) excluding those with AD based on health registry data. RESULTS:Higher p-tau217 level and likelihood of AD neuropathologic change (p-tau217 > 0.42 pg/mL; evident in 39%) were associated with higher age and having an apolipoprotein E (APOE) ε4 allele. Heritability was 0.56 (95% confidence interval [CI]: 0.36-0.79) and GWAS indicated 45 single nucleotide polymorphisms (SNPs) (p < 5 × 10-08) centered around the APOE locus. DISCUSSION:Our results elucidate the characteristics and genetic associations of p-tau217 in a population-based setting. We found many 65- to 85-year-olds without a clinical diagnosis of AD to have AD neuropathologic change based on plasma p-tau217. Highlights:Plasma phosphorylated tau 217 (p-tau217) is a promising biomarker of Alzheimer's disease (AD).We studied plasma p-tau217 in a population-based sample of 65- to -85-year-olds.We excluded those with a clinical diagnosis of AD.Older age and having an apolipoprotein E (APOE) ε4 allele were associated with higher plasma p-tau217.Heritability of p-tau217 was 56% and a genome-wide association study (GWAS) implicated genes around the APOE region.

Background: Due to the continuous aging of the world′s population, early diagnosis of age-related diseases, such as Alzheimer′s disease (AD), has become a priority and should be improved by accessible, minimally invasive, comprehensive approaches. Methods: In this study, we explored the potential of epigenetic and proteomic aging clocks as complementary biomarkers to established cognitive tests and AD blood-based biomarkers (BBBs). Omics data were generated from blood samples of 153 cognitively unimpaired individuals, aged on average 62 years. BBBs and cognitive functioning were measured approximately nine years later. We used Generalized Estimating Equation models to investigate associations between biological aging and AD-related phenotypes, and how dementia risk factors modulate these. Findings: Proteomic mortality-based clocks showed more significant associations with cognitive measures and BBBs than epigenetic clocks. Accelerated systemic and brain-specific proteomic aging was linked to lower cognitive functioning and higher plasma levels of neurofilament light chain (NfL). Multiple organ-specific proteomic models were positively associated with plasma NfL, indicating that changes in biological processes and cellular components in these organs, captured by these models, may be implicated in neurodegeneration and AD pathogenesis. Interaction analysis showed that negative associations of proteomic aging with cognitive scores are stronger in individuals with lower genetic liability for type II diabetes and high levels of fasting glucose. Interpretation: In our modest-sized sample, proteomic clocks better captured variability in cognition and AD-related biomarkers than epigenetic clocks, and may have higher potential as auxiliary biomarkers of AD. Thus, our study highlights the importance of investigating proteomic aging in AD. Funding: EH-Epi data used in the analysis is deposited in the Biobank of the Finnish Institute for Health and Welfare (https://thl.fi/en/web/thl-biobank/forresearchers). It is available to researchers after written application and following the relevant Finnish legislation. ### Competing Interest Statement A.P. is the Chief Scientific Officer of the FinnGen project, which is funded by 14 industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis Pharma AG, Boehringer Ingelheim International GmbH, and Bayer. H.R. is currently employed at Insitro Inc. He is a former employee and holds stock at Merck & Co and Biogen Inc. The authors declare no other competing financial or non-financial interests. ### Funding Statement The TWINGEN study was funded by the FinnGen project. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb Inc. (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Johnson&Johnson Innovative Medicine Inc., Novartis AG, Boehringer Ingelheim International GmbH and Bayer AG. E.V. was supported by the Sigrid Jusélius Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The TWINGEN protocol received ethical approval by the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) (number 16831/2022), and the research plan was approved by THL Biobank (THLBB2022_83). All participants gave written informed consent before their participation and had the option to withdraw from the study at any point. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes TWINGEN data are stored at the THL Biobank for those participants who gave consent for transferring their data to the biobank. Data are available to qualified applicants from academia and companies. For further details on the application process, see: https://thl.fi/en/research-and-development/thl-biobank/for-researchers/application-process.

Understanding the neural basis of intelligence in humans remains an ongoing scientific pursuit. Early studies with small samples identified potential regions but lacked consistency across findings. Recent large-scale magnetic resonance imaging (MRI) datasets, using intelligence measures focused on verbal-numerical reasoning, now offer more robust opportunities for discovery. In this study (N=11,289), we showed the dorsolateral prefrontal cortex as exhibiting the strongest effect size and a significant causal relationship with intelligence, where larger surface area predicts higher intelligence as revealed by Mendelian randomization analyses. Additional regions, including the orbitofrontal and temporal cortices, also showed causal links to intelligence. These regions are critical for working memory, executive function, and language. Reverse causality analyses further indicated that higher intelligence contributes to increased total surface area and greater cortical thickness in the perisylvian language region. Our findings replicate prior evidence of a bidirectional relationship between total surface area and intelligence and further offer novel insights into regional cortical associations and causal effect. Collectively, these findings support a polyregional cortical configuration of intelligence, highlighting the dorsolateral prefrontal cortex-a key hub for cognitive ability.

We investigated the associations between several plasma biomarkers of AD and cognition in a population-based sample of 65–85-year-old individuals without prior diagnosis of dementia-causing neurodegenerative disease. This cross-sectional study included 701 twin participants of the TWINGEN study. The data were gathered at six study centers across Finland in 2023. During a research visit, we collected blood samples and participants performed cognitive assessments. The plasma biomarkers phosphorylated-tau181 ( p -tau181), phosphorylated-tau217 ( p -tau217), amyloid beta 1-42 to amyloid beta 1-40 ratio (Aβ1-42/Aβ1-40), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels were measured with Simoa HD-X Analyzer. A total cognitive score (with higher score indicating better cognition) was based on Episodic Memory Task (learning and recall), and Modified Trail Making A and B Tasks, assessed using web-based cCOG. We report cross-biomarker correlations and analyzed associations between biomarkers and cognition with hierarchical linear mixed-effect models. Covariates included age, sex and education as fixed effects, and family and study site effects as random intercepts. Nested models were compared with likelihood ratio tests, and multiple testing was accounted for using the Benjamini-Yekutieli correction for False Discovery Rate. Plasma biomarkers were associated with each other with absolute correlation coefficients ranging from 0.10 between GFAP and Aβ1-42/Aβ1-40 to 0.75 between p -tau181 and p -tau217. Regarding the associations between biomarkers and cognition, the models including either p -tau181 or p -tau217 had statistically significantly better model fit than the model with covariates alone. Adding NfL, GFAP or Aβ1-42/Aβ1-40 ratio did not improve model fit over the covariate model. In addition to p -tau181 (standardized β = -0.019, 95% CI [-0.031, -0.007]) and p -tau217 ( β = -0.031, 95% CI [-0.042, -0.020]), NfL had confidence interval differing from 0 ( β =-0.014, 95% CI [-0.025, -0.002]). Plasma p -tau181 and p -tau217 were negatively associated with cognition in a population-based sample of individuals without diagnosis of AD or dementia. Plasma p -tau has been shown to be associated with longitudinal changes in cognition and to differ between groups of individuals with normal cognition, mild cognitive impairment and AD. Our results highlight the potential value of p -tau in the detection of early cognitive changes.