Aims

Cardiovascular health plays a pivotal role in the development and progression of Alzheimer’s Disease (AD). Traditional cardiovascular risk factors impact cardiovascular health to different extents in men and women. Given recent evidence that women on the AD trajectory bear a larger burden of tau pathology than men, we investigated whether cardiovascular disease risk differentially impacts cortical tau in men and women.

Methods

We calculated the Framingham Heart Study Cardiovascular Disease (FHS-CVD) risk algorithm at baseline in 172 participants from the AD Neuroimaging Initiative study. Our sample was composed of 113 cognitively normal participants and 59 participants with mild cognitive impairment. We quantified cortical tau using Flortaucipir PET acquired on average 5.51 ± 1.3 years after baseline FHS-CVD assessment. We used linear regression analyses to test for interaction effects between sex and FHS-CVD on subsequent cortical tau, correcting for age, APOE e4 genotype and time between initial FHS-CVD assessment and tau PET.

Results

We found that women had significantly higher levels of tau then men in areas including BRAAK 3&4, (p = 0.001; BRAAK 5&6,(p < 0.0001) regions. We found significant interaction effects of sex and FHS-CVD on subsequent BRAAK 3&4 (p=0.017) and BRAAK 5&6 tau (p=0.019). When stratifying by sex, higher baseline FHS-CVD measurement was associated with higher cortical tau in women (BRAAK 3&4, p=0.029; BRAAK 5&6, p=0.026) but not men.

Conclusions

These results suggest that despite being at lower cardiovascular disease risk, women are more heavily impacted by the effects of cardiovascular risk on tau pathology than men.

Aims

Elucidating sex-dependent mechanisms resulting in greater vulnerability in females in Alzheimer’s disease (AD) is important for therapeutic strategy and personalized medicine. Here, we aimed to elucidate the sex-dependent microglial effect on neurodegeneration and cognition using multimodal imaging biomarkers.

Methods

A total of 143 participants (50 males, 93 females; 92 CN, 32 MCI, 19 AD) from the TRIAD cohort underwent T1, 3 PET, and CDR-SB procedures. VBM was generated using the DARTEL pipeline while static [¹¹C]PBR28, [¹⁸F]AZD4694, and [¹⁸F]MK6240 SUVR images were generated using an in-house pipeline. Then, all images were normalized to the ADNI template with 8 mm smoothing. A multiple linear regression model was used to evaluate the effect of sex on VBM, [¹¹C]PBR28, or the relationship between VBM and [¹¹C]PBR28. Then, the effect of VBM and [¹¹C]PBR28 on cognition was evaluated using mediation analysis. All analyses included age, education, APOEε4, amyloid-beta, tau, and diagnosis as covariates.

Results

Females showed a significantly lower VBM while they also showed a significantly greater [¹¹C]PBR28 SUVR in medial temporal regions compared to males. Also, there was a substantial positive association between VBM and [¹¹C]PBR28 in the medial temporal regions only in males. Consequently, the effect of [¹¹C]PBR28 on CDR-SB was significantly mediated by VBM in the medial temporal lobe only in males but not in females.

Conclusions

This study highlights a sex-dependent disease mechanism in medial temporal regions; males showed lower activated microglia, greater VBM, and a protective relationship between VBM and microglia on cognition after adjusting for the AD hallmarks compared to females.

Aims

The familial Parkinson's Disease (PD) E46K mutation - being promoted by its amplification (‘3K’) - impairs normal alpha-synuclein (αS) homeostasis by increased binding to vesicle membranes, resulting in neuronal loss and a robust PD-like motor decline in 3K mice. Resembling clinical PD, female sex delays phenotypes in 3K mice, while estrogen treatment increases dopamine neurite fiber densities and vesicle turnover, suggesting neuroprotective action at the synaptic site. In this study, we further investigate estrogen effects of female sex on αS-induced synaptic pathophysiology in low expressing (‘3KL’) αS mutant mice.

Methods

We longitudinally analyzed motor and cognitive performance of 3KL and wild-type (WT) αS-expressing mice using open field, gait-scan and Morris-Water Maze. Synaptic plasticity was analyzed by electrophysiological measurements of acute striatal and hippocampal slices. αS solubility was evaluated by sequential extractions and cytopathology dissected using STED, confocal, and immuno-EM.

Results

At 6 and 12 months, changes in gait, explorative behavior and spatial memory were more pronounced in male vs. female 3KL compared to WT mice. In the cortex and hippocampus, STED and EM analyses showed that the multifold membrane-association of 3K compared to WT αS resulted in serine 129 phosphorylated αS+ profiles in somata, neurites and at synaptic vesicle clusters, which was paralleled by subcellular redistribution of estrogen receptor alpha (ERα). Further, electrophysiological recordings revealed estrogen-modulated long-term potentiation deficits in 3KL mice.

Conclusions

The present study highlights ERα as a new player in αS-induced synaptic pathologies. Since synaptic ERα availability preserves neuronal function, our study supports its targeting may benefit PD.

Aims

Upon aging, changes occur in the brain, including compromised communication between neurons, changes that are also affected by sex. Moreover, aging is a major risk factor for neurodegenerative diseases, including Alzheimer’s disease, and females and males differ in the incidence of the disease. Extracellular vesicles (EVs) in the normal brain play a role in neuronal homeostasis, by removing intracellular accumulated material and regulating cell-to-cell communication. We investigated age- and sex-dependent differences in EV levels and content in the brain.

Methods

EVs were isolated and fractioned from the right hemibrains of 3, 6, 12, 18, and 24-month-old female and male C57BL/6 mice. Morphometric EV sizes and numbers were investigated by nanoparticle tracking analysis. EV constituents were characterized by Western blotting.

Results

Using biochemical analyses of brain EVs, we investigated the amount of the plasma membrane-derived microvesicles, late endosome-derived exosomes, and mitochondria-derived mitovesicles, recently identified in our laboratory. We found an age-associated increase in the number of microvesicles, exosomes and mitovesicles in the brain of both sexes. The number of these EVs was higher in the brain of females compared to males. Analysis of the EV content of the amyloid β precursor protein and its metabolites (APP-carboxyl-terminal fragments) revealed an increased load of β-CTF in exosomes with age in both sexes.

Conclusions

These findings reveal age-dependent altered generation and secretion of EVs into the brain extracellular space and a difference in exosome generation between females and males, likely a compensation mechanism that impacts successful brain aging and sex-dependent susceptibility to age-related neurodegenerative diseases.

Aims

The effects of central nervous system (CNS) insulin on cognition and metabolism are modified by apolipoprotein E (apoE) isoform, sex, and dietary lipids (e.g, a high-fat diet (HFD)). In humans, there are three major apoE isoforms, E2, E3, and E4. Compared to E3, E4 is the major genetic risk factor for the onset of Alzheimer’s disease (AD). Insulin in the CNS is primarily derived from blood insulin, which is transported across the blood-brain barrier (BBB). An alternative way to increase brain insulin levels is by delivering insulin via the intranasal (INL) route, bypassing the BBB and limiting the glucose regulatory effects of insulin. Mild cognitive impairment (MCI) and AD female and male patients with E4 and female patients without E4 respond less well to INL insulin, suggesting an exaggerated deficiency in insulin’s action. Our studies show how transport of insulin across the BBB or following INL delivery may be altered.

Methods

Using radiolabeled insulin, we measured the pharmacokinetics across the BBB in addition to measuring the distribution following INL delivery in E3 and E4 targeted-replacement mice.

Results

Insulin BBB transport varies regionally and the rate and level of vascular binding varies due to apoE isoform, sex, and diet. Following INL delivery, insulin appears throughout the brain within 5 min and remains elevated up to 60 min later.

Conclusions

These results suggest that these three risk factors for AD (apoE isoform, sex, and diet) play a role in regulating insulin transport into the CNS.

Aims

Biological sex is increasingly recognized as a modifier of Alzheimer’s disease (AD) pathophysiology and disease progression. We aimed to assess the effect of sex on cognitive and biomarker measures of AD in adults with Down syndrome, who have an ultra-high risk for developing AD dementia.

Methods

Cross-sectional study of 494 adults with Down syndrome recruited from two sites. We compared clinical characteristics and AD biomarkers between men (n=268) and women (n=226). Participants had at least one biomarker assessment among plasma NfL, Aβ1-42/1-40, p-Tau-181, tau and NfL in CSF, PET with amyloid tracers or 18F-fluorodeoxyglucose and/or MRI. We compared age at symptom onset and used within-group local regression models with confidence intervals to compare the trajectory of biomarker changes with age.

Results

The mean age at which women were diagnosed with dementia was 53 years vs. 53.6 for men (p=0.46). Women with Down syndrome showed earlier decreases in CSF Aß1-42, however no differences were found when comparing the Aß1-42/Aß1-40 ratio. The biomarker trajectories of plasma NfL and CSF NfL, p-Tau-181 and tau were similar across ages between men and women. Women had smaller head sizes and hippocampal volumes, but there were no differences in hippocampal volumes when adjusted for differences in head size. There were no differences in age-associated changes in cerebral amyloid deposition (Centiloid) or glucose metabolism (FDG-PET).

Conclusions

In adults with Down syndrome, sex does not modify the age at diagnosis of dementia or the trajectories of plasma, CSF and imaging biomarkers. Reporting of negative results is important to avoid publication bias.

Abstract Body