Kevan Patrick Clifford

The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age- sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the gene’s roles in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model ( Frem3 -cKO) and computed genetically regulated expression of FREM3 ( FREM3 - GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3 - cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3- GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age- sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.

Major depressive disorder (MDD) impacts females and males differently and post-mortem gene expression profiling reveals distinct transcriptomic signatures of the disorder in each sex. Using genes that are transcriptionally altered in MDD in both sexes, we recently developed a novel transcriptome-based polygenic risk score (tPRS), which had sex-specific associations with brain structure and depressive symptoms in both adolescents and adults. Identifying the neurodevelopmental signatures of genetically-induced shifts toward a depression-like brain transcriptome in each sex during a crucial stage, when sex differences in MDD vulnerability initially manifest, could provide useful information about the developmental pathways of early MDD risk. Leveraging sex-specific MDD gene expression data, we sought to develop female- and male-specific tPRSs (tPRS-F and tPRS-M, respectively) and evaluate their impact on regional cortical thickness, cortical surface area, subcortical volume, and depressive symptoms at baseline and 2-year follow-up in a developmental sample of 5002 adolescents (46.6% female, aged 8.9-11.0). In males, tPRS-M was associated with higher depressive symptoms at both timepoints and thicker left posterior cingulate at follow-up. In females, tPRS-F was associated with lower volumes of the right accumbens area, right caudate, and bilateral hippocampi at follow-up. Subcortical volumes of the right caudate and right hippocampus further mediated an indirect effect of tPRS-F on depressive symptoms. For each sex-specific PRS, no effects emerged in the opposite sex. Our findings suggest that sex-specific depression-like shifts in gene expression may contribute to unique vulnerability phenotypes for future MDD risk via distinct mechanisms in each sex.

The mechanisms linking a history of major depressive disorder (MDD) to an increased risk of Alzheimer’s disease and related dementia (ADRD) are not fully understood. Using the UK Biobank, we evaluated the biological mechanisms linking the conditions. In participants without history of MDD, 493 proteins were significantly associated with the risk of ADRD. By contrast, in participants with a history of MDD at baseline, a smaller set of six proteins were significantly associated with ADRD risk (NfL, GFAP, PSG1, VGF, GET3 and HPGDS), with GET3 being specifically associated with ADRD risk in the latter group. Two-sample Mendelian randomization analysis showed that the apolipoprotein E and IL-10 receptor subunit B genes were causally linked to incident ADRD. Finally, we developed a proteomic risk score (PrRS_MDD-ADRD), which showed strong discriminative power (C statistic = 0.84) to identify participants with MDD who developed ADRD on follow-up. Here we show that plasma proteins associated with inflammation and amyloid-β metabolism are causally linked to a higher ADRD risk in individuals with MDD. Moreover, the PrRS_MDD-ADRD can be useful to identify individuals with the highest risk of developing ADRD in a highly vulnerable population.

The world population is shifting sharply toward an older-age demographic. To navigate the escalating burden of physical and cognitive decline common to aging, and heightened risk of neurodegenerative and neuropsychiatric disease, we require advances in treatment and prevention interventions. These advances are predicated on attaining a deeper understanding of the molecular processes underlying brain aging. Here, we employed novel cis-eQTL and GWAS-based polygenic risk scores (cis-eQTLAGE-PRS and GWASAGE-PRS) indexing genetic risk for accelerated molecular brain aging, and examined their associations with cortical thickness and performance in age-sensitive cognitive domains in 31 384 participants (16 392 women, ages 46-82) from the UK Biobank. While GWASAGE-PRS was nominally associated with lower cortical thickness in frontotemporal regions, cis-eQTLAGE-PRS displayed robust associations with greater cortical thickness in age-sensitive frontal, temporal, and parietal regions, including the left and right precentral (pFDR<0.0001, pFDR=0.05), left insula (pFDR=0.05), as well as the right supramarginal (pFDR=0.05) and precuneus (pFDR=0.05) regions. Similar pFDR trending associations occurred bilaterally in the caudal middle frontal (pFDR=0.052, pFDR=0.078) and right insula (pFDR=0.071). These structural findings co-occurred alongside increased executive function performance on the Trail Making Test B (pFDR=0.035), suggesting a potential neurostructural and cognitive reserve phenotype. This resilience profile may reflect previously uncharacterized pathways of brain reserve in age-related pathology, informing future translational research identifying novel treatment and prevention targets.

The world population is shifting sharply toward an older-age demographic. To navigate the escalating burden of physical and cognitive decline common to aging, and heightened risk of neurodegenerative and neuropsychiatric disease, we require advances in treatment and prevention interventions. These advances are predicated on attaining a deeper understanding of the molecular processes underlying brain aging. Here, we employed novel GWAS and cis-eQTL-based polygenic risk scores ( ^GWAS AGE-PRS and ^cis-eQTL AGE-PRS) indexing genetic risk for accelerated molecular brain aging, and examined their associations with cortical thickness and performance in age-sensitive cognitive domains in 31 384 participants (16 392 women, age 64.1±7.65) from the UK Biobank. While ^GWAS AGE-PRS was nominally associated with lower cortical thickness in frontotemporal regions, ^cis-eQTL AGE-PRS displayed robust associations with greater cortical thickness in age-sensitive frontal, temporal, and parietal regions, including the left and right precentral (pFDR<0.0001, pFDR=0.05), left insula (pFDR=0.05), as well as the right supramarginal (pFDR=0.05) and precuneus (pFDR=0.05) regions. Similar pFDR trending associations occurred bilaterally in the caudal middle frontal (pFDR=0.052, pFDR=0.078) and right insula (pFDR=0.071). These structural findings co-occurred alongside increased executive function performance on the Trail Making Test B (pFDR=0.035), suggesting a potential neurostructural and cognitive reserve phenotype. This resilience profile may reflect previously uncharacterized pathways of brain reserve in age-related pathology, informing future translational research identifying novel treatment and prevention targets.

Introduction: As the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. Methods: Young (2m, n=10), middle-age (10m, n=10) and old (22m, n=9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume, residualized for total brain volume, and associations between volume and cognitive performance on the Y-maze task were tested. General linear models with total brain volume as a covariate, and logistic regression for sample wide associations were employed respectively, correcting for multiple comparisons. Structural covariance networks were generated using the R package ‘igraph’. Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5–40%), using 5,000 (1,000 for degree) permutations with significance criteria of p2 =2.325, p bh =0.044) and larger volume of the hippocampal formation (χ ² =-2.180, p bh =0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. Conclusions/Implications: These findings offer a foundational account of age effects on brain volume, structural brain networks, and cognition in mice, informing future work in facilitating translation between rodent models and human brain aging.