Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage.

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer's disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.

Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10-8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.

This study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer's disease (AD) neuropathology in elders with mild cognitive impairment (MCI).

Background Subtle reductions in cardiac output relate to lower cerebral blood flow, especially in regions where Alzheimer's disease pathology first develops. Apolipoprotein E (APOE)-ε4 is a genetic susceptibility risk factor for Alzheimer's disease that also moderates vascular damage. This study investigated whether APOE-ε4 carrier status modifies the cross-sectional association between cardiac output and cognition. Methods and Results Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia (n=306, 73±7 years, 42% female) underwent echocardiography to determine cardiac output (L/min), comprehensive neuropsychological assessment, and venous blood draw to determine APOE genotype and ε4 carrier status. Linear regressions related cardiac output to neuropsychological test performance, adjusting for age, sex, education, race/ethnicity, body surface area, cognitive diagnosis, Framingham Stroke Risk Profile, and APOE-ε4 status. Main effect models were null (P>0.19). With identical covariates, models were repeated testing a cardiac output×APOE-ε4 status interaction and again stratified by ε4 carrier status. Cardiac output×APOE-ε4 status related to naming (β=0.91, P=0.0009), category fluency (β=1.2, P=0.01), information processing speed (β=-5.4, P=0.001), visuospatial skill (β=0.85, P=0.003), and executive function performances (β=0.22, P=0.002). Stratified models suggested that lower cardiac output was associated with worse neuropsychological performances among APOE-ε4 carriers. Conclusions APOE-ε4 carrier status appears to modify the cross-sectional association between cardiac output and neuropsychological performance such that lower cardiac output relates to poorer performances among carriers of the ε4 allele. These findings add to increasing evidence that APOE-ε4 carrier status has important implications for associations between vascular and brain health in aging adults.

Although hippocampal volume has served as a long-standing predictor of cognitive decline, diffusion magnetic resonance imaging studies of white matter have shown similar relationships. Still, it remains unclear if gray matter and white matter interact to predict cognitive impairment and longitudinal decline. Here, we investigate whether free-water (FW) and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume. Using data from the Vanderbilt Memory & Aging Project (n = 319), we found that FW was associated with baseline memory and executive function beyond that of hippocampal volume and other comorbidities. Longitudinal analyses demonstrated significant interactions of hippocampal volume and inferior longitudinal fasciculus (p = 0.043) and cingulum bundle (p = 0.025) FAT on memory decline and with fornix FAT (p = 0.025) on decline in executive function. Results suggest that FW metrics of white matter have a unique role in cognitive decline and should be included in theoretical models of aging, cerebrovascular disease, and Alzheimer's disease.

While Alzheimer's disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

Subclinical reductions in cardiac output correspond to lower cerebral blood flow (CBF), placing the brain at risk for functional changes.

Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults.

Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures.

Late-onset Alzheimer's disease (LOAD) is a polygenic disorder with a long prodromal phase, making early diagnosis challenging. Twin studies estimate LOAD as 60-80% heritable, and while common genetic variants can account for 30% of this heritability, nearly 70% remains "missing". Polygenic risk scores (PRS) leverage combined effects of many loci to predict LOAD risk, but often lack sensitivity to preclinical disease changes, limiting clinical utility. Our group has built and published on a resilience phenotype to model better-than-expected cognition give amyloid pathology burden and hypothesized it may assist in preclinical polygenic risk prediction. Thus, we built a LOAD PRS and a resilience PRS and evaluated both in predicting cognition in a dementia-free cohort (N=254). The LOAD PRS had a significant main effect on baseline memory (β=-0.18, P=1.68E-03). Both the LOAD PRS (β=-0.03, P=1.19E-03) and the resilience PRS (β=0.02, P=0.03) had significant main effects on annual memory decline. The resilience PRS interacted with CSF Aβ on baseline memory (β=-6.04E-04, P=0.02), whereby it predicted baseline memory among Aβ+ individuals (β=0.44, P=0.01) but not among Aβ- individuals (β=0.06, P=0.46). Excluding APOE from PRS resulted in mainly LOAD PRS associations attenuating, but notably the resilience PRS interaction with CSF Aβ and selective prediction among Aβ+ individuals was consistent. Although the resilience PRS is currently somewhat limited in scope from the phenotype's cross-sectional nature, our results suggest that the resilience PRS may be a promising tool in assisting in preclinical disease risk prediction among dementia-free and Aβ+ individuals, though replication and fine-tuning are needed.

White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of β-amyloid42 deposition (Aβ42), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 ± 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-ε4 carrier status. Aβ42 (β = -0.001, p = 0.007) and NFL (β = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Aβ42 accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury.

Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (n = 77), early mild cognitive impairment (n = 15), and MCI (n = 55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values < 0.05). An NFL × diagnosis interaction (excluding early mild cognitive impairment) on WM microstructure (p-values < 0.05) was detected, with associations strongest among MCI. Multiple NFL × CSF biomarker interactions were detected. Associations between NFL and worse WM metrics were strongest among amyloid-β42-negative, tau-positive, and suspected nonamyloid pathology participants. Findings suggest increased NFL, a biomarker of axonal injury, is correlated with compromised WM microstructure. Results highlight the role of elevated NFL in predicting WM damage in cognitively impaired older adults who are amyloid-negative, tau-positive, or meet suspected nonamyloid pathology criteria.

Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.

This study evaluated neuroimaging and biological correlates, psychometric properties, and regression-based normative data of the 12-word Philadelphia Verbal Learning Test (PVLT), a list-learning test.

Arterial stiffening is associated with cognitive impairment and prodromal Alzheimer's disease. This study tested the interaction between arterial stiffening and an Alzheimer's disease genetic risk factor (apolipoprotein E [APOE] genotype) on cognition among older adults. Vanderbilt Memory & Aging Project participants with normal cognition (n = 162, 72 ± 7 years, 29% APOE-ε4 carrier) and mild cognitive impairment (n = 121, 73 ± 8 years, 42% APOE-ε4 carrier) completed neuropsychological assessment and cardiac MRI to assess aortic stiffening using pulse wave velocity (PWV, m/s). Linear regression models stratified by cognitive diagnosis related aortic PWV × APOE-ε4 status to neuropsychological performances, adjusting for demographic and vascular risk factors. PWV × APOE-ε4 related to poorer performance on measures of lexical retrieval (β = -0.29, p = 0.01), executive function (β = -0.44, p = 0.02), and episodic memory (β = -3.07, p = 0.02). Among participants with higher aortic PWV, APOE-ε4 modified the association between central arterial stiffening and cognition, such that carriers had worse performances than noncarriers. Findings add to a growing body of evidence for APOE-vascular interactions on cognition in older adults and warrant further research into less heart-healthy cohorts where the association between PWV and cognition among older adults might be stronger.

Biomarker definitions for preclinical Alzheimer's disease (AD) have identified individuals with neurodegeneration (ND+) without β-amyloidosis (Aβ-) and labeled them with suspected non-AD pathophysiology (SNAP). We evaluated Apolipoprotein E (APOE) ε2 and ε4 allele frequencies across biomarker definitions-Aβ-/ND- (n = 268), Aβ+/ND- (n = 236), Aβ-/ND+ or SNAP (n = 78), Aβ+/ND+ (n = 204)-hypothesizing that SNAP would have an APOE profile comparable to Aβ-/ND-. Using AD Neuroimaging Initiative data (n = 786, 72±7 years, 48% female), amyloid status (Aβ+ or Aβ-) was defined by cerebrospinal fluid (CSF) Aβ-42 levels, and neurodegeneration status (ND+ or ND-) was defined by hippocampal volume from MRI. Binary logistic regression related biomarker status to APOE ε2 and ε4 allele carrier status, adjusting for age, sex, education, and cognitive diagnosis. Compared to the biomarker negative (Aβ-/ND-) participants, higher proportions of ε4 and lower proportions of ε2 carriers were observed among Aβ+/ND- (ε4: OR = 6.23, p<0.001; ε2: OR = 0.53, p = 0.03) and Aβ+/ND+ participants (ε4: OR = 12.07, p<0.001; ε2: OR = 0.29, p = 0.004). SNAP participants were statistically comparable to biomarker negative participants (p-values>0.30). In supplemental analyses, comparable results were observed when coding SNAP using amyloid imaging and when using CSF tau levels. In contrast to APOE, a polygenic risk score for AD that excluded APOE did not show an association with amyloidosis or neurodegeneration (p-values>0.15), but did show an association with SNAP defined using CSF tau (β = 0.004, p = 0.02). Thus, in a population with low levels of cerebrovascular disease and a lower prevalence of SNAP than the general population, APOE and known genetic drivers of AD do not appear to contribute to the neurodegeneration observed in SNAP. Additional work in population based samples is needed to better elucidate the genetic contributors to various etiological drivers of SNAP.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.