Welcome to the AD/PD™ 2022 Interactive Program
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APOE GENOTYPE, AGE AND SEX AFFECT LONGITUDINAL CHANGE OF CEREBROSPINAL FLUID BIOMARKERS: FINDINGS FROM THE SWEDISH BIOFINDER COHORT
Abstract
Aims
Aims
In this study we assessed the effects of APOE genotype, age, and sex on the longitudinal change of CSF biomarkers of Alzheimer’s disease (p-tau181), astrocytosis (YKL-40, GFAP) and microglial activation (sTREM2) in the longitudinal Swedish BioFINDER cohort.
Methods
Methods
CSF was collected at baseline and 2-, 4-, 6-, 8- and 10-years’ follow-up from cognitively unimpaired (CU, n=801) or MCI (n=265) patients. Aβ status was defined based on the CSF Aβ42/40 ratio in CSF. Biomarkers were measured with NeuroToolKit (Roche). Reliability of change index (RCI) was calculated in Ab negative CU to define “stable” (slope of change over time=+/-RCI) and “increasers” (slope>RCI) groups in the cohort. Logistic regression was used to assess effects of APOE, age and sex on the “stable” vs. “increaser” outcome.
Results
Results
Increases in CSF p-tau181 over time due to APOE genotype are fully mediated by Aβ+ status (p<0.0001, OR 7.6). GFAP and sTREM2 increased less in women than in men over time, independently of Aβ status (GFAP: p=0.01, OR 0.6; sTREM2: p=0.003, OR 0.4). Increase in YKL-40 over time was affected by age, independently of Aβ status (p=0.02, OR 1.1).
Conclusions
Conclusions
Aβ status, age, and sex affect longitudinal change of CSF biomarkers. The present findings warrant for adjustment for these variables in longitudinal studies.
INTERACTION EFFECT OF SEX AND ONSET OF ALZHEIMER’S DISEASE—RATES OF PROGRESSION AND PROGNOSIS
Abstract
Abstract Body
Objectives: To investigate the interaction effect of sex and early vs. late onset of Alzheimer’s disease (AD) on long-term cognitive and functional outcomes and survival.
Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicentre study of clinical practice involving 1,017 participants diagnosed with mild-to-moderate AD at the start of cholinesterase inhibitor treatment. The patients were evaluated using cognitive and functional assessment scales at baseline and semi-annually over 3 years. The date of death was recorded for 20 years.
Results: Women with late-onset AD (LOAD) showed a higher frequency of apolipoprotein E (APOE) ε4-carriers than did men with LOAD (71% vs. 58%, p<0.001). This sex difference was not detected in early-onset AD (EOAD). The annual decline in Alzheimer’s Disease Assessment Scale–cognitive subscale was faster in women with EOAD compared with women with LOAD (mean, 95% confidence interval) (5.8, 3.9–7.8 vs. 3.0, 2.3–3.7 points; p=0.013), but this difference was not observed in men. Functional deterioration rates did not differ between the groups. The survival time after AD diagnosis was longer in women with LOAD than in men with LOAD (7.0, 6.7–7.3 vs. 5.4, 5.1–5.8 years; p<0.001), but this sex difference was not found in EOAD.
Conclusions: Women, but not men, with EOAD demonstrated almost twice as fast long-term cognitive decline compared with the LOAD groups. Women with LOAD had a lower education, exhibited a high proportion of APOE ε4-carriers and approximately 50% lived alone. Men with LOAD had a shorter lifespan after diagnosis than did all other patients.
SEX AND GENDER CONSIDERATIONS IN NEURODEGENERATIVE DISEASES: SCIENTIFIC EVIDENCE, BIASES, AND OPPORTUNITIES FOR PRECISION MEDICINE
Abstract
Abstract Body
Cumulating evidence has indicated high degree of patient variability in neurodegenerative disorders. Precision medicine, as already in use in oncology, might provide substantial progress in the field, from molecular diagnosis to tailored treatments.
In this regard, sex and gender differences are emerging as leading features driving patient heterogeneity in a variety of brain diseases, including Alzheimer. These differences offer therefore a useful starting point to discuss potential applications of precision medicine in neurology.
Taking the example of Alzheimer’s and Parkinson Disease, in this talk I will discuss the role of sex and gender differences in biomarker research, clinical trial design and development of digital health technologies, highlighting the work that the non-profit organization Women's Brain Project is doing in this field.
A proper understanding of sex and gender-differences will be key towards a precision medicine paradigm for neurodegenerative diseases, beyond a ‘one size fits all’ approach and towards sustainability.
SEX DIFFERENCES IN FUNCTIONAL BRAIN CONNECTIVITY OVER THE COURSE OF AGING IN A LARGE COHORT
Abstract
Aims
The brain is a complex network that relies on the interaction between its various regions. Although studies have shown that this network undergoes complex changes with aging, scarcely any assessed how they were affected by sex, partly owing to small sample sizes. Here, we aim to address this limitation by assessing functional connectivity (FC) changes in large cohort using novel multilayer brain connectivity approaches.
Methods
We analyzed the resting-state FC data from 37365 individuals of the UK Biobank cohort (17484 men; 19881 women; aged 47-79 years). For each individual, we built two FC networks consisting of the positive and negative temporal correlations between 21 nodes, each corresponding to resting-state functional network (Fig.1a-b). The networks were integrated into a two-layer multilayer network by connecting nodes with their replicas in adjacent layers (Fig.1c). We characterized their topology by calculating several measures using the BRAPH 2.0 software.
Results
The number of negative connections decreased as a function of age in both sexes. Younger men had stronger negative connectivity compared to women (p<0.001); both sexes had similar functional connectivity at older ages. The single-layer clustering coefficient showed no differences between sexes, while global efficiency was higher in men (p<0.001). In the multilayer networks, men showed higher participation coefficient (p<0.001), which decreased with age.
Conclusions
These findings provide a deeper insight into the sex differences that occur in functional connectivity over the course of aging. They indicate that multilayer networks provide a natural way to integrate the information from positive and negative functional connections.
CSF PROTEOME CHANGES DEPEND ON APOE GENOTYPE, AGE AND SEX IN PRODROMAL AD
Abstract
Aims
APOE, a major genetic risk factor for Alzheimer’s disease (AD), shows a complex interaction with age and sex on CSF amyloid and tau biomarkers in prodromal AD. We studied whether sex-, age-, and APOE-dependent alterations in the CSF proteome can be defined by distinct biological processes.
Methods
CSF proteomics analysis was performed using TMT-MS in 77 prodromal AD individuals from EMIF (age 70 years, 42 (55%) female). 1178 proteins were detected in ≥54 (70%) individuals. Associations between protein concentrations and APOE genotype were tested with linear regressions including a three-way interaction between APOE, age and sex. The STRING database was used for biological pathway enrichment analysis on proteins with significant interaction-terms (p-values<0.1).
Results
Two hundred and thirty-five (20%) proteins had a significant interaction between APOE, age and sex. Females showed linear APOE Ɛ4 dosage effects on protein concentrations depending on age: younger Ɛ4Ɛ4 females (<70 years) had high levels of proteins involved in neuronal plasticity pathways, while these proteins were low in older Ɛ4Ɛ4 females. Males showed non-linear APOE Ɛ4 dosage effects depending on age: younger Ɛ3Ɛ4 males had high levels of neuronal plasticity-related proteins, and low levels of proteins involved in the complement and coagulation cascade, while in older Ɛ3Ɛ4 males these proteins showed changes in the opposite direction.
Conclusions
The CSF proteome of prodromal AD individuals shows sex-, age- and APOE Ɛ4 dose-dependent alterations, which were associated with distinct biological processes, including neuronal plasticity and in males also complement and coagulation pathways. These differences should be considered in future therapy development.
LIFESTYLE AFFECTS AMYLOID BURDEN AND COGNITION DIFFERENTLY IN MEN AND WOMEN
Abstract
Aims
The aggregation of amyloid-β is hypothesized to be an early event that might eventually pave the way to clinical Alzheimer’s disease. To understand factors that aid personalized disease prevention we studied a healthy elderly population to examine the influence of lifestyle factors on brain amyloid burden and cognition specifically testing for different associations among women and men.
Methods
178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective population-based study who completed 18F-Flutemetamol amyloid positron emission tomography. Using structural equation modeling, we examined the ability of latent constructs representing metabolic/vascular risk, physical activity, and cognitive activity to predict global amyloid burden and cognitive performance. Further, we examined the moderating effect of sex.
Results
Overall, higher cognitive activity predicted better cognitive performance and higher physical activity predicted lower amyloid burden. When we subsequently examined the moderating effect of sex in the model, we revealed an inverse association of metabolic/vascular risk with cognition in men and a tendency towards higher amyloid burden in women. Further, an inverse association between physical activity and amyloid burden was found only in men whereas the apolipoprotein epsilon 4 allele predicted higher amyloid burden only in women.
Conclusions
Sex moderates effects of certain lifestyle-related factors on amyloid burden and cognition. Most importantly, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer’s disease through distinct paths in women and men.
MOLECULAR PATHWAYS DRIVING SEX-DEPENDENT VULNERABILITY TO BLOOD-BRAIN BARRIER DYSFUNCTION IN ALZHEIMER'S BRAIN
Abstract
Aims
Objective: To determine BBB dysfunction in female versus male Alzheimer’s disease (AD) patients and transgenic mice.
Methods
Gene expression data from male and female AD patients (ROSMAP, APOE33) was obtained. Differential gene expression and data-driven pathway analysis was conducted. The impact of genes and pathways, thus identified, on the BBB integrity and function was assessed using SPECT/CT and PET/CT imaging.
Results
Growth factor signaling and inflammatory pathways are differentially expressed in male versus female AD patients. Insulin signaling, MAPK, mTOR pathways are significantly activated in male patients compared to females(FDR<0.05). Moreover, pathways that regulate BBB integrity, tight junctions and cellular adhesion molecules (VCAM1), are activated in male AD patients compared to females. Similar sex-dependent changes were also observed in APP/PS1 mice but not in wild type controls. Disruption of BBB integrity as determined by increased luminal-to-abluminal permeability of 125I-Albumin as well as 125I-Abeta42, and higher binding of 125I-VCAM1 antibody to the BBB endothelium was observed in female APP/PS1 mice than in male mice. Moreover, selectivity of BBB transport represented by luminal-to-abluminal transport of 18FDG and 125I-Insulin as well as the abluminal-to-luminal clearance of 125I-Abeta42 is more disrupted in female mice compared to male mice.
Conclusions
Growth factor signaling pathways are activated in males, and inflammatory pathways are activated in female AD patients and APP/PS1 mice. Consequently, loss of BBB integrity and selectivity of BBB transport regulated by these pathways are disrupted in females compared to their male counterparts.