Biology subjects

Raikes, A. C.

Publications and source records attributed to Raikes, A. C..

4 recordsLinked to original sources

bioRxiv2026

Addition of humanized APP to humanized APOE mouse model reduces brain size and increases the ratio of cortical representation

INTRODUCTION: Age, Apolipoprotein E4 (APOE4) genotype, and biological sex are major risk factors for late-onset Alzheimer's disease (LOAD), and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE4 has not recapitulated LOAD-relevant brain volume phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (hAPOE) may therefore improve translational modeling of structural brain changes characterized by neuroimaging. METHODS: Aged mice (mean age = 23.25 months) carrying murine (m) or humanized (h) APP and either murine Apoe or hAPOE3/3 (hAPOE3-HOM), hAPOE3/4 (hAPOE4-HET), or hAPOE4/4 (hAPOE4-HOM) underwent in-skull ex vivo volumetric MRI. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with FDR correction applied within contrasts. RESULTS: Brain volumes were primarily determined by APP background, with hAPP globally reducing total and regional volumes relative to mAPP mice. Across hAPP models, hAPOE4-HOM exhibited the greatest brain-wide reductions, which was mitigated by a single hAPOE3 allele. In contrast, mouse APP exerted modest effect in hAPOE, with hAPOE4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, hAPP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independent of APP or APOE genotype. DISCUSSION: hAPP induces distinctly smaller brain volumes in this humanized APOE knock-in model, and hAPOE4 homozygosity amplifies that effect, indicating genotype-dependent susceptibility. Because this study is cross-sectional and lacks histopathological confirmation, volume differences may reflect developmental or constitutive effects rather than neurodegeneration. Humanized APP and APOE are therefore necessary but not sufficient to recapitulate the complete volumetric signature of established LOAD. Longitudinal and histological studies are required to determine whether these differences reflect a prodromal trajectory or a developmental effect.

neuroscience↗

bioRxiv2025

Diffusion MRI Processing in the HEALthy Brain and Child Development Study: Innovations and Applications

The landmark ongoing HEALthy Brain and Cognitive Development (HBCD) study will longitudinally chart brain development in a large sample (projected n=7,200) of infants through age 10 years with multimodal neuroimaging that includes an advanced diffusion MRI (dMRI) acquisition. Here, we detail advances in dMRI image processing developed for HBCD, incorporated into the widely used QSIPrep pipeline. Major changes to preprocessing include improvements in infant brain extraction, distortion correction, and normalization to infant-specific templates. Additionally, we describe a new software package - QSIRecon - that yields rich derived data including diverse maps of tissue microstructure as well as person-specific white matter bundles. Using dMRI data from a subset of the HBCD 1.0 release where age information was available (n=529 sessions across two time points), we observe critical improvements in data quality with preprocessing and see expected developmental patterns. Moving forward, the publicly-available data from HBCD will rapidly grow to become the largest study of brain development in infancy and early childhood using dMRI. QSIPrep and QSIRecon are openly available and can be applied to other infant and pediatric dMRI datasets.

neuroscience↗

bioRxiv2025

Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: Implications for translational validity to the human

Translational validity of mouse models of human aging and late-onset Alzheimers disease (LOAD) risk are essential for both fundamental mechanistic science and therapeutic development. Given that the strongest risk factors for LOAD are age, female sex, and APOE-{varepsilon}4 carriership, models must reflect these biological variables and disease phenotypes. The use of mouse models with humanized APOE (hAPOE) is a key strategy to advance translational validity. To initially address translational validity of the hAPOE mouse model, we conducted ex-vivo magnetic resonance imaging analysis of brain volumes in male and female mice across APOE genotypes ({varepsilon}3/{varepsilon}3, {varepsilon}3/{varepsilon}4, {varepsilon}4/{varepsilon}4) and ages corresponding to a human lifespan of approximately 30-70 years (6-25 months in mice). The primary outcomes indicated that total MRI brain volume increased with age (an average of 2.12mm3 per month), irrespective of sex or APOE genotype. Additionally, APOE-{varepsilon}4 carriers had greater total brain volumes than non-carriers. No sex differences were observed in total brain volume. Voxelwise analyses revealed a pattern of localized morphometric changes independent of differences in total brain volume. Age-related volumetric increases were distributed across subcortical regions (e.g., thalami, hippocampi), while age-related decreases were evident across cortical regions, notably the bilateral parieto-temporal and frontal lobes. Additionally, sex differences were evident after controlling for total brain volume, with females showing greater cortex-dominant volumes while males showed a pattern of greater volumes in regions including cerebellar cortices, olfactory bulbs, and striata. No genotypic effects were observed in the voxelwise analysis after correcting for multiple comparisons, suggesting that APOE genotype does not drive localized volume differences independent of total brain volume. These findings indicate that, at the MRI level of analysis, this humanized APOE mouse model does not recapitulate the volumetric atrophy typically seen in human brain aging and Alzheimers disease. The results suggest that humanized APOE alone is insufficient to induce the LOAD atrophy phenotype. This model may better serve as a platform for studying vulnerable aging rather than a primary model for progressive neurodegenerative atrophy.

neuroscience↗

bioRxiv2025

White matter micro- and macrostructural properties in midlife individuals at risk for Alzheimer's disease: Associations with sex and menopausal status

Women are at greater lifetime risk for Alzheimers disease (AD), potentially due to midlife fractional anisotropy (FA) and lower mean diffusivity in fornix and corpus callosum, indicating more densely organized white matter. Perimenopausal women were the exception, with white matter profiles closely resembling those of men. Perimenopausal women exhibited minimal or absent fiber cross-section and FDC sex differences and a reversal of the fornix FA advantage observed in pre- and postmenopausal women. These cross-sectional results are consistent with sex differences in white matter organization. Importantly, the perimenopause emerges as a critical window of neural reorganization in the female midlife aging brain characterized by temporary convergence toward male-like white matter organization. Longitudinal analyses are key to identifying women who do or do not revert to a premenopausal profile, which may inform AD risk.

neuroscience↗