Carol E Franz

University of California, San Diego | UCSD · Department of Psychiatry

Attachment theory has become a key framework for understanding responses to and consequences of trauma across the life course. We predicted that more severe post-traumatic stress (PTS) symptoms at age 37 years would be associated with insecure attachment at age 55 and with worse PTS symptoms 24 years later at age 61, and that age 55 attachment woul...

In a 36-yr prospective study of the children of the R. R. Sears et al (1957) Patterns of Child Rearing sample, the relationship was examined between mothers' childrearing practices when the child was age 5 yrs, other childhood experiences, and conventional social accomplishment at age 41 yrs. Having a warm and affectionate father or mother was sig...

To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife. A 35-year longitudinal and cross-sectional twin study of cog...

High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggest...

Background Early identification of Alzheimer’s disease (AD) risk prior to irreversible brain damage is critical for improving the success of interventions and treatment. Cortical thickness is a macrostructural measure typically used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy a...

Background Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vul...

Background Chronic pain leads to tau accumulation and hippocampal atrophy in mice. Tau accumulation in the locus coeruleus (LC) precedes medial temporal accumulation in humans. Here we provide one of the first human studies examining the association of chronic pain with hippocampal volume, LC integrity, and Alzheimer’s Disease (AD)‐related plasma b...

Background Poor social relations of older adults have been linked to cognitive decline, dementia risk, morbidity and mortality. However, this history of poor social relations may have started earlier in life and may be related to personality traits. Here we investigate how attachment style, a personality trait, can function as a protective factor f...

Background Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vul...

Background Early identification of Alzheimer’s disease (AD) risk prior to irreversible brain damage is critical for improving the success of interventions and treatment. Cortical thickness is a macrostructural measure typically used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy a...

Background Chronic pain leads to tau accumulation and hippocampal atrophy in mice. Tau accumulation in the locus coeruleus (LC) precedes medial temporal accumulation in humans. Here we provide one of the first human studies examining the association of chronic pain with hippocampal volume, LC integrity, and Alzheimer’s Disease (AD)‐related plasma b...

Background The locus coeruleus (LC) is one of the earliest sites of tau accumulation and integrity of the rostral‐middle LC may be a particularly early marker of AD‐related changes. LC dysfunction may also promote further pathological accumulation. We examined relationships between LC integrity and plasma phospho‐tau (pTau) and the astrocytic marke...

Objective: Alcohol use is common in older adults and linked to poor health and aging outcomes. Studies have demonstrated genetic and environmental contributions to the quantity of alcohol consumption in mid-to-late life, but less is known about whether these influences are moderated by sociodemographic factors such as age, sex, and educational atta...

Background Subjective Cognitive Complaints (SCCs) can often precede mild cognitive impairment and dementia longitudinally. While increasingly considered an early prodromal stage of dementia, SCCs can also be a symptom of depression. Previous research found that SCCs in the absence of cognitive impairment, controlling for symptoms of depression, wer...

Background Alzheimer's Disease (AD) and traumatic brain injuries (TBI) are frequently associated in medical literature, with a significant prevalence of TBI history observed among individuals diagnosed with AD. Our investigation focuses on this intersection, explicitly examining the risk of AD in individuals with a history of TBI. While current tar...

Objectives: Childhood disadvantage is associated with lower general cognitive ability (GCA) and brain structural differences in midlife and older adulthood. However, the neuroanatomical mechanisms underlying childhood disadvantage effects on later-life GCA remain poorly understood. Although total surface area (SA) has been linked to lifespan GCA d...

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of g...

Background: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with AD-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation. Methods: Participants were men without dementia. Chronic pain was defined a...

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our da...

Multivariate network‐based analytic methods such as weighted gene co‐expression network analysis are frequently applied to human and animal gene‐expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene‐expression patterns and network connectivit...

INTRODUCTION The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. METHODS Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were m...

Background: Increased exposure to ambient air pollution, especially fine particulate matter ≤2.5μm (PM2.5) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse...

Abstract: Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions...

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study ent...

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are being increasingly applied to human and animal gene-expression data to estimate module eigengenes (MEs). MEs represent multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. Although this...

Background Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. Methods W...

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European anc...

Objectives: Subjective health (SH) is not just an indicator of physical health, but also reflects active cognitive processing of information about one's own health and has been associated with emotional health measures, such as neuroticism and depression. Behavior genetic approaches investigate the genetic architecture of SH, i.e., genetic and env...

Background The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer’s disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period. Methods Participants were 1,286 community-dwelling men from the Vietnam Era...

Background The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). Methods The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the M...

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Con...

Background Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecu...

Background Frailty refers to a person’s physical and functional capabilities and increases during aging. Abnormal white matter (AWM; e.g., hyperintensities on T2‐weighted MRI) is a neuroimaging marker of small‐vessel vascular disease associated with increased risk of Alzheimer’s Disease and related dementias. While some studies have found associati...

Background Predicted brain age difference (PBAD) scores are novel metrics which compare chronological age to age predicted from neuroimaging data. PBADs are highly relevant to Alzheimer’s disease (AD) and cognitive aging. Individuals with AD have predicted brain ages about 10 years older than their chronological age (Franke et al. 2010). Less is kn...

Background Before onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify...

Background Alzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with A...

Background Neuroimaging signatures based on cortical thickness or volume in regions vulnerable to Alzheimer’s disease (AD) pathology are tools developed to identify brain changes specific to mild AD. Lower thickness/volume signatures (indicating comparatively thinner cortex) are commonly associated with risk of future decline. In contrast, some evi...

Background Late‐life ambient air pollution exposures are associated with increased Alzheimer’s disease (AD) risk ¹ . Cortical thinning in temporal areas vulnerable to AD is associated with memory decline, neuropathological changes, and increased AD risk. However, most neuroimaging studies on air pollution neurotoxicity analyzed volumetric indices t...

Background Frailty—feelings of weakness, fatigue, and lack of physiological resiliency—places older adults at increased risk for Alzheimer’s Disease (AD) and related dementias. A possible mechanism underlying these associations may be the effects of frailty on brain aging prior to old age. Method A prospective observational study of approximately...

Background Inferences about cognitive reserve and related constructs may be subject to reverse causation, but too often the possibility of reverse causation is not addressed in research on reserve and resilience. A lifespan perspective can shed light on the relationships among education, IQ, and related constructs and what can be concluded about ca...

Background Neuroimaging signatures based on cortical thickness or volume in regions vulnerable to Alzheimer’s disease (AD) pathology are tools developed to identify brain changes specific to mild AD. Lower thickness/volume signatures (indicating comparatively thinner cortex) are commonly associated with risk of future decline. In contrast, some evi...

Background Alzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with A...

Objective US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health eff...

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ance...

INTRODUCTION Despite their increased application, the heritability of Alzheimer's disease (AD)–related blood‐based biomarkers remains unexplored. METHODS Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t‐tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ = 67.0, SD = 2.6). Twin models were used...

Importance: Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings. Objective: To assess...

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Inter...

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a...

Background: Childhood disadvantage is a prominent risk factor for cognitive and brain aging. Childhood disadvantage is associated with poorer episodic memory in late midlife and functional and structural brain abnormalities in the default mode network (DMN). Although age-related changes in DMN are associated with episodic memory declines in older...

Background: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD). Objective: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprote...

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory...

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples ma...

The process by which aging leads to increased risk for Alzheimer’s disease and dementia is not entirely understood, but one hypothesized contributor is the occurrence of low-grade inflammation in older age. In this study, we examined how peripheral levels of C-reactive protein (CRP), a measure of systemic inflammation, relate to brain structure and...

Subjective memory concern is a risk factor for dementia in older adults, yet it also appears to be stable over time. Few studies examine memory concern starting in midlife in cognitively normal adults or the role of genetic influences on memory concern. We focused on the stability of subjective memory concern from early midlife into older adulthood...

Aging‐related episodic memory (EM) decline and Alzheimer’s disease (AD)‐related brain changes begin in late middle age around age 60. However, rate and severity of cognitive decline do not consistently correspond to the extent of neuropathological changes, suggesting a high degree of heterogeneity in EM trajectories. We tested if brain maintenance...

About 7 million older American adults are affected by frailty (Bandeen‐Roche et al., 2015). Frailty places older adults at an increased risk of adverse physical and mental health outcomes, including Alzheimer’s Disease (AD). However, prior to old age, frailty or its relationship to AD biomarkers such as beta‐amyloid 40 and 42 (Aβ40, Aβ42), tau, and...

Cortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to ca...

Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures,' are tools developed to identify brain changes specific to mild AD. In recent work from our group, we found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s...

Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures’, are tools developed to identify brain changes specific to mild AD. We found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year pr...

Air pollution exposure is a notable public health hazard with adverse effects on multiple health outcomes as well as with increased risk of developing cognitive impairment, Alzheimer’s disease, and related dementias. Few studies examine associations between air pollution exposure in midlife or the transition from midlife to old age. We examined ass...

Executive functions encompass effortful top‐down cognitive processes crucial for daily functioning. They are particularly vulnerable to aging in older adults and are often affected early in the course of Alzheimer’s disease. However, the neural mechanisms underlying aging‐related decline in executive functions are not well understood. Modal control...

Objectives Abnormal tau, a hallmark Alzheimer’s disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here...

Background Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration...

Background: Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molec...

Background Studies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contr...

Background The amyloid‐tau‐neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The costs and invasiveness of methods relying on cerebrospinal fluid or positron emission tomography imaging have led to efforts to develop sensitive blood‐based biomarkers. Although AD is highly heritable, the biometri...

Air pollution, which includes exposure to tiny particulate matter (PM2.5) and Nitrogen Dioxide (NO2) is a notable public health hazard. Exposure has adverse effects on multiple health outcomes as well as with increased risk of developing cognitive impairment and Alzheimer’s disease and related dementias. Although the primary cognitive focus in Alzh...

Executive function encompasses effortful cognitive processes that are particularly susceptible to aging. Functional brain networks supporting executive function—such as the frontoparietal control network and the multiple demand system—have been extensively investigated. However, it remains unclear how structural networks facilitate and constrain th...

Background The cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions. Methods We quantified cerebe...

Background: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. Objective: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the t...

Background and objectives: Vascular theories of cognitive aging have focused on macrovascular changes and cognitive decline. However, according to the artery size hypothesis, microvascular changes, such as those that underlie changes in erectile function, may also play an important role in contributing to cognitive decline. Thus, we examined assoc...

Posttraumatic stress disorder (PTSD) is a heritable (h² = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms...

The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimers disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood...

INTRODUCTION Genetic influences on the stability of subjective memory concerns (SMC) may confound its interpretation as a state-related risk indicator. METHODS We estimated genetic influences on SMC and SMC change from average ages 38 to 67, genetic correlations of SMC with memory and depressive symptoms at average ages 56, 62, and 67, and correla...