Social interactions offset the detrimental effects of digital media use on children's vocabulary.

Young children's rapid vocabulary growth during the first few years is supported by input during social interactions with caregivers and, increasingly, from digital media. However, the amount of exposure to both sources can vary substantially across socioeconomic classes, and little is known about how social interactions and digital media use together predict vocabulary in the first few years of life. The current study takes a first step toward examining whether increased social interactions with other individuals may buffer the potentially detrimental effects of digital media use on language among a socioeconomically diverse sample. 305 caregivers of children between 17 and 30-months completed questionnaires about their family demographics, their child's technology use, and the child's daily routines and social interactions. Findings suggest children who experience fewer human interactions and greater technology exposure have smaller vocabularies than their peers who socialize more and use less technology, and this disparity becomes greater as children get older. Moreover, the number of social interactions moderates the link between SES, digital media, and vocabulary such that the negative impact of digital media on vocabulary for children from low SES households can be offset with increased social interactions. Together, this suggests that increasing the amount of human interactions may serve as a protective factor for vocabulary outcomes in a world where digital media use is prominent.

Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Association of 10 VEGF Family Genes with Alzheimer's Disease Endophenotypes at Single Cell Resolution.

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes ( VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1 , and NRP2 ) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with ß-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and ß-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more ß-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on ß-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

In vivo effect of LATE-NC on integrity of white matter connections to the hippocampus.

INTRODUCTION: TAR DNA-binding protein 43 (TDP-43) is a highly prevalent proteinopathy that is involved in neurodegenerative processes, including axonal damage. To date, no ante mortem biomarkers exist for TDP-43, and few studies have directly assessed its impact on neuroimaging measures utilizing pathologic quantification. METHODS: Ante mortem diffusion-weighted images were obtained from community-dwelling older adults. Regression models calculated the relationship between post mortem TDP-43 burden and ante mortem fractional anisotropy (FA) within each voxel in connection with the hippocampus, controlling for coexisting Alzheimer's disease and demographics. RESULTS: Results revealed a significant negative relationship (false discovery rate [FDR] corrected p < .05) between post mortem TDP-43 and ante mortem FA in one cluster within the left medial temporal lobe connecting to the parahippocampal cortex, entorhinal cortex, and cingulate, aligning with the ventral subdivision of the cingulum. FA within this cluster was associated with cognition. DISCUSSION: Greater TDP-43 burden is associated with lower FA within the limbic system, which may contribute to impairment in learning and memory. HIGHLIGHTS: Post mortem TDP-43 pathological burden is associated with reduced ante mortem fractional anisotropy. Reduced FA located in the parahippocampal portion of the cingulum. FA in this area was associated with reduced episodic and semantic memory. FA in this area was associated with increased inward hippocampal surface deformation.

Proteins linking APOE ɛ4 with Alzheimer's disease.

INTRODUCTION: The ɛ4 allele of the apolipoprotein E gene (APOE ɛ4) is the strongest genetic risk factor for Alzheimer's disease (AD), but the mechanisms connecting APOE ɛ4 to AD are not clear. METHODS: Participants (n = 596) were from two clinical-pathological studies. Tissues from dorsolateral prefrontal cortex were examined to identify 8425 proteins. Post mortem pathological assessment used immunohistochemistry to obtain amyloid beta (Aß) load and tau tangle density. RESULTS: In separate models, APOE ɛ4 was associated with 18 proteins, which were associated with Aß and tau tangles. Examining the proteins in a single model identified Netrin-1 and secreted frizzled-related protein 1 (SFRP1) as the two proteins linking APOE ɛ4 with Aß with the largest effect sizes and Netrin-1 and testican-3 linking APOE ɛ4 with tau tangles. DISCUSSION: We identified Netrin-1, SFRP1, and testican-3 as the most promising proteins that link APOE ɛ4 with Aß and tau tangles. HIGHLIGHTS: Of 8425 proteins extracted from prefrontal cortex, 18 were related to APOE ɛ4. The 18 proteins were also related to amyloid beta (Aß) and tau. The 18 proteins were more related to APOE ɛ4 than other AD genetic risk variants. Netrin-1 and secreted frizzled-related protein 1 were the two most promising proteins linking APOE ɛ4 with Aß. Netrin-1 and testican-3 were two most promising proteins linking APOE ɛ4 with tau.

Elevated protease-activated receptor 4 (PAR4) gene expression in Alzheimer's disease predicts cognitive decline.

Platelet activation of protease-activated receptor 4 (PAR4) and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation. We evaluated mRNA expression of the PAR4 gene F2RL3 in human brain and global cognitive performance in participants with and without cognitive impairment or dementia. Data were acquired from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). F2RL3 mRNA was elevated in AD cases and was associated with worse retrospective longitudinal cognitive performance. Moreover, F2RL3 expression interacted with clinical AD diagnosis on longitudinal cognition whereas this relationship was attenuated in individuals without cognitive impairment. Additionally, when adjusting for the effects of AD neuropathology, F2RL3 expression remained a significant predictor of cognitive decline. F2RL3 expression correlated positively with transcript levels of proinflammatory markers including TNFα, IL-1ß, NFκB, and fibrinogen α/ß/γ. Together, these results reveal that F2RL3 mRNA expression is associated with multiple AD-relevant outcomes and its encoded product, PAR4, may play a role in disease pathogenesis.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Association of Alzheimer's Disease and Other Neuropathologies with Functional Disability in Persons With and Without Dementia.

BACKGROUND: Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to impact functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of AD and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. METHODS: Participants were 1,509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and three other AD indices were examined, in addition to four non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43 and Lewy bodies, and four cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. RESULTS: AD and the other neuropathologies were associated with impaired IADL (all Ps<0.001) and with impaired BADL (Ps<0.01), except for atherosclerosis and CAA which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHFtau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL, and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. CONCLUSION: AD and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.

G-protein coupled estrogen receptor 1, amyloid-ß, and tau tangles in older adults.

Accumulation of amyloid-ß (Aß) and tau tangles are hallmarks of Alzheimer's disease. Aß is extracellular while tau tangles are typically intracellular, and it is unknown how these two proteinopathies are connected. Here, we use data of 1206 elders and test that RNA expression levels of GPER1, a transmembrane protein, modify the association of Aß with tau tangles. GPER1 RNA expression is related to more tau tangles (p = 0.001). Moreover, GPER1 expression modifies the association of immunohistochemistry-derived Aß load with tau tangles (p = 0.044). Similarly, GPER1 expression modifies the association between Aß proteoforms and tau tangles: total Aß protein (p = 0.030) and Aß38 peptide (p = 0.002). Using single nuclei RNA-seq indicates that GPER1 RNA expression in astrocytes modifies the relation of Aß load with tau tangles (p = 0.002), but not GPER1 in excitatory neurons or endothelial cells. We conclude that GPER1 may be a link between Aß and tau tangles driven mainly by astrocytic GPER1 expression.

MRI-Derived AD Signature of Cortical Thinning and Plasma P-Tau217 for Predicting Alzheimer Dementia Among Community-Dwelling Older Adults.

Background and Objectives: Structural brain MRI and blood-based phosphorylated tau (p-tau) measures are among the least invasive and least expensive Alzheimer's disease (AD) biomarkers to date. The extent to which these biomarkers may outperform one another in predicting future Alzheimer dementia diagnosis is poorly understood, however. This study investigated 2 specific AD biomarkers, i.e., a cortical thickness signature of AD (AD-CT) and plasma p-tau217, for predicting Alzheimer dementia. Methods: Data came from community-dwelling older participants of the Religious Orders Study or the Rush Memory and Aging Project. AD-CT was obtained from 3T MRI scans using a magnetization-prepared rapid acquisition gradient echo sequence and by averaging thickness from previously identified cortical regions implicated in AD. Plasma p-tau217 was quantified using an immunoassay developed by Lilly Research Laboratories on the MSD platform. Both MRI scans and blood specimens were collected at the same visits, and subsequent diagnoses of Alzheimer dementia were determined through annual detailed clinical evaluations. Cox proportional hazards models examined the associations of the 2 biomarkers with incident Alzheimer dementia, and prediction accuracy was assessed using c-statistics. Results: A total of 198 older adults, on average 84 years of age, were included. Over a mean follow-up of 4 years, 60 (30%) individuals developed Alzheimer dementia. AD-CT (hazard ratio: 1.71, 95% CI 1.26-2.31) and separately plasma p-tau217 (hazard ratio: 2.57, 95% CI 1.83-3.61) were associated with incident Alzheimer dementia. The c-statistic for prediction accuracy was consistently higher for plasma p-tau217 (between 0.74 and 0.81) than AD-CT (between 0.70 and 0.75) across a range of time horizons. Furthermore, with both biomarkers included in the same model, there was only modest improvement in the c-statistic due to AD-CT. Discussion: Plasma p-tau217 outperforms an imaging-based cortical thickness signature of AD in predicting future Alzheimer dementia diagnosis. Furthermore, the AD cortical thickness signature adds little to the prediction accuracy above and beyond plasma p-tau217.

Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology.

Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aß40, worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aß40 (ß = -0.44, p-value = 0.017) and replicated this interaction in ADNI (ß = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aß peptides in brain (Aß total ß = -0.14, p = 0.629; Aß1-38, ß = 0.11, p = 0.200). In contrast to the effects on Aß, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (ß = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aß levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Polygenic risk associated with Alzheimer's disease and other traits influences genes involved in T cell signaling and activation.

Introduction: T cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants. Methods: We first compute a polygenic risk score (PRS) for Alzheimer's disease (AD) using genomic sequencing data from a cohort of Alzheimer's disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes. Results: Several genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes. Discussion: Our findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions.

Limited but specific engagement of the mature language network during linguistic statistical learning.

Statistical learning (SL) is the ability to detect and learn regularities from input and is foundational to language acquisition. Despite the dominant role of SL as a theoretical construct for language development, there is a lack of direct evidence supporting the shared neural substrates underlying language processing and SL. It is also not clear whether the similarities, if any, are related to linguistic processing, or statistical regularities in general. The current study tests whether the brain regions involved in natural language processing are similarly recruited during auditory, linguistic SL. Twenty-two adults performed an auditory linguistic SL task, an auditory nonlinguistic SL task, and a passive story listening task as their neural activation was monitored. Within the language network, the left posterior temporal gyrus showed sensitivity to embedded speech regularities during auditory, linguistic SL, but not auditory, nonlinguistic SL. Using a multivoxel pattern similarity analysis, we uncovered similarities between the neural representation of auditory, linguistic SL, and language processing within the left posterior temporal gyrus. No other brain regions showed similarities between linguistic SL and language comprehension, suggesting that a shared neurocomputational process for auditory SL and natural language processing within the left posterior temporal gyrus is specific to linguistic stimuli.

Association of whole-person eigen-polygenic risk scores with Alzheimer's disease.

Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.

The Necessity of Taking Culture and Context into Account When Studying the Relationship between Socioeconomic Status and Brain Development.

Decades of research has revealed a relationship between childhood socioeconomic status (SES) and brain development at the structural and functional levels. Of particular note is the distinction between income and maternal education, two highly correlated factors which seem to influence brain development through distinct pathways. Specifically, while a families' income-to-needs ratio is linked with physiological stress and household chaos, caregiver education influences the day-to-day language environment a child is exposed to. Variability in either one of these environmental experiences is related to subsequent brain development. While this work has the potential to inform public policies in a way that benefits children, it can also oversimplify complex factors, unjustly blame low-SES parents, and perpetuate a harmful deficit perspective. To counteract these shortcomings, researchers must consider sociodemographic differences in the broader cultural context that underlie SES-based differences in brain development. This review aims to address these issues by (a) identifying how sociodemographic mechanisms associated with SES influence the day-to-day experiences of children, in turn, impacting brain development, while (b) considering the broader cultural contexts that may differentially impact this relationship.

The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.

BACKGROUND: Many studies have reported that impaired gait precedes cognitive impairment in older people. We aimed to characterise the time course of cognitive and motor decline in older individuals and the association of these declines with the pathologies of Alzheimer's disease and related dementias. METHODS: This multicohort study used data from three community-based cohort studies (Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study, all in the USA). The inclusion criteria for all three cohorts were no clinical dementia at the time of enrolment and consent to annual clinical assessments. Eligible participants consented to post-mortem brain donation and had post-mortem pathological assessments and three or more repeated annual measures of cognition and motor functions. Clinical and post-mortem data were analysed using functional mixed-effects models. Global cognition was based on 19 neuropsychological tests, a hand strength score was based on grip and pinch strength, and a gait score was based on the number of steps and time to walk 8 feet and turn 360°. Brain pathologies of Alzheimer's disease and related dementias were assessed at autopsy. FINDINGS: From 1994 to 2022, there were 1570 eligible cohort participants aged 65 years or older, 1303 of whom had cognitive and motor measurements and were included in the analysis. Mean age at death was 90·3 years (SD 6·3), 905 (69%) participants were female, and 398 (31%) were male. Median follow-up time was 9 years (IQR 5-11). On average, cognition was stable from 25 to 15 years before death, when cognition began to decline. By contrast, gait function and hand strength declined during the entire study. The combinations of pathologies of Alzheimer's disease and related dementias associated with cognitive and motor decline and their onsets of associations varied; only tau tangles, Parkinson's disease pathology, and macroinfarcts were associated with decline of all three phenotypes. Tau tangles were significantly associated with cognitive decline, gait function decline, and hand function decline (p<0·0001 for each); however, the association with cognitive decline persisted for more than 11 years before death, but the association with hand strength only began 3·57 years before death and the association with gait began 3·49 years before death. By contrast, the association of macroinfarcts with declining gait function began 9·25 years before death (p<0·0001) compared with 6·65 years before death (p=0·0005) for cognitive decline and 2·66 years before death (p=0·024) for decline in hand strength. INTERPRETATION: Our findings suggest that average motor decline in older adults precedes cognitive decline. Macroinfarcts but not tau tangles are associated with declining gait function that precedes cognitive decline. This suggests the need for further studies to test if gait impairment is a clinical proxy for preclinical vascular cognitive impairment. FUNDING: National Institutes of Health.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aß, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aß/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. HIGHLIGHTS: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.