Sex-specific modulation of amyloid-ß on tau phosphorylation underlies faster tangle accumulation in females.

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-ß (Aß) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aß and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aß plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aß and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aß predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aß-positive females presented higher CSF p-tau181 concentrations compared with Aß-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aß-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aß and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aß in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aß plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.

Sex differences in patterns of associative memory-related activation in individuals at risk of Alzheimer's disease.

The risk of developing Alzheimer's disease dementia is higher in females compared to males and is greater in individuals with subjective cognitive decline and mild cognitive impairment than in healthy controls. We used a multivariate behavioral partial least square correlation analysis to examine how relationships between memory-related activation and associative memory performance vary as a function of sex and clinical status. This was assessed in 182 participants from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort, which were stratified according to sex (Male, Female) and clinical status (healthy controls, subjective cognitive decline, mild cognitive impairment). We found 6 significant latent variables mainly expressing: (1) overall sex differences; (2) between-sex differences according to clinical status; and (3) within-sex differences according to clinical status in relationships between whole-brain memory-related activation and memory performance. These patterns of activation mostly involved the default mode and fronto-parietal networks. Our results have implication in understanding the macro-scale functional processes possibly contributing to the higher risk of cognitive decline in females compared to males in the context of aging and early Alzheimer's disease.

Sex differences in the relationship between age, performance, and BOLD signal variability during spatial context memory processing.

Recent work suggests that the relationship between age and memory-related brain activity are different for men and women. We sought to extend this work by examining sex differences in the association between age, memory performance, and brain signal variability during context memory tasks in neurotypical adults (aged 19-76 years; N = 128, 87 women). We measured blood oxygen level-dependent standard deviation (BOLD SD) during encoding and retrieval in easy and difficult spatial context memory tasks and investigated sex-specific, age- and performance-associated BOLD SD patterns. Behavioral analysis revealed age-related decreases in memory retrieval, but no sex differences nor an age-by-sex interaction. Imaging results indicated that both sexes showed a negative correlation between BOLD SD and retrieval accuracy in memory-related regions. We also identified significant sex differences: women exhibited age-associated increases in BOLD SD which were negatively associated with performance. Men exhibited both age-associated decreases and increases, which were not related to performance. Our results revealed sex differences in the relationship between age and BOLD SD during high-demand episodic memory tasks.

Interactive rather than independent effect of APOE and sex potentiates tau deposition in women.

The apolipoprotein E gene (APOE) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-ß and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE, yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE-by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [18F]AZD4694 and [18F]MK6240 were used to assess amyloid-ß and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [18F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression.

The ratio of posterior-anterior medial temporal lobe volumes predicts source memory performance in healthy young adults.

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC:PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory.

Measurement Variability Following MRI System Upgrade.

Major hardware/software changes to MRI platforms, either planned or unplanned, will almost invariably occur in longitudinal studies. Our objective was to assess the resulting variability on relevant imaging measurements in such context, specifically for three Siemens Healthcare Magnetom Trio upgrades to the Prismafit platform. We report data acquired on three healthy volunteers scanned before and after three different platform upgrades. We assessed differences in image signal [contrast-to-noise ratio (CNR)] on T1-weighted images (T1w) and fluid-attenuated inversion recovery images (FLAIR); brain morphometry on T1w image; and small vessel disease (white matter hyperintensities; WMH) on FLAIR image. Prismafit upgrade resulted in higher (30%) and more variable neocortical CNR and larger brain volume and thickness mainly in frontal areas. A significant relationship was observed between neocortical CNR and neocortical volume. For FLAIR images, no significant CNR difference was observed, but WMH volumes were significantly smaller (-68%) after Prismafit upgrade, when compared to results on the Magnetom Trio. Together, these results indicate that Prismafit upgrade significantly influenced image signal, brain morphometry measures and small vessel diseases measures and that these effects need to be taken into account when analyzing results from any longitudinal study undergoing similar changes.