Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network

Wagemann, Olivia; Li, Yan; Hassenstab, Jason; Aschenbrenner, Andrew J.; McKay, Nicole S.; Gordon, Brian A.; Benzinger, Tammie L. S.; Xiong, Chengjie; Cruchaga, Carlos; Renton, Alan E.; Perrin, Richard J.; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lopera, Francisco; Mori, Hiroshi; Noble, James M.; Sánchez‐Valle, Raquel; Schofield, Peter R.; Morris, John C.; Daniels, Alisha; Levin, Johannes; Bateman, Randall J.; McDade, Eric; Llibre‐Guerra, Jorge J.; ,

doi:10.1002/alz.13460

Cited by 4 publications

(1 citation statement)

References 73 publications

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“…They also present with broader atrophy associated with worse cognition at diagnosis [30]. Intriguingly, female EOAD carriers may have greater cognitive resilience to AD pathology and neurodegeneration [33] but exhibit a greater rate of neurodegeneration and memory impairment during disease progression [31,32]. The mechanisms underlying accelerated neurodegeneration in females is unknown but could be due to the sex-selective vulnerability of specific brain regions that have reciprocal connections to other regions [45,46], the interactions between tau pathology and sex-specific genes, chromosomes, and/or hormones [47], possible genetic modifying factors [28], and the sex-specific amyloid and/or tau dynamics.…”

Section: Consistency Across Ad Subtypesmentioning

confidence: 99%

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

Reed,

Keller-Norrell

2023

IJMS

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Research into Alzheimer’s Disease (AD) describes a link between AD and the resident immune cells of the brain, the microglia. Further, this suspected link is thought to have underlying sex effects, although the mechanisms of these effects are only just beginning to be understood. Many of these insights are the result of policies put in place by funding agencies such as the National Institutes of Health (NIH) to consider sex as a biological variable (SABV) and the move towards precision medicine due to continued lackluster therapeutic options. The purpose of this review is to provide an updated assessment of the current research that summarizes sex differences and the research pertaining to microglia and their varied responses in AD.

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Section: Consistency Across Ad Subtypesmentioning

confidence: 99%

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

Reed,

Keller-Norrell

2023

IJMS

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Clinical and research application of fluid biomarkers in autosomal dominant Alzheimer's disease and Down syndrome

Carmona-Iragui,

O'Connor,

Llibre-Guerra

et al. 2024

eBioMedicine

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Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Millar,

Gordon,

Wisch

et al. 2023

Mol Neurodegeneration

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Background “Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. Methods We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education. Results Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. Conclusions We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

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Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network

Cited by 4 publications

References 73 publications

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

Clinical and research application of fluid biomarkers in autosomal dominant Alzheimer's disease and Down syndrome

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

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