Kaitlin Blackstone Casaletto

Menopause is a hallmark process in biological aging that has been implicated in later neurodegenerative risk, but the pathways underlying this connection remain unclear. Here we used blood proteomics data from several cohorts to identify biological changes associated with menopause and its links to brain aging. In n = 80 rigorously staged (STRAW+10) pre-, peri- and postmenopausal women (aged 43–58 years) with serum NULISAseq proteomics, we show that spontaneous menopause is characterized by dysregulation in inflammatory, synaptic, metabolic and Alzheimer’s disease biologic processes, which tracked more strongly with hormones than with age. Validation analyses in age-matched pre-/peri- and postmenopausal women ( n = 2,814) with plasma Olink proteomics replicated the observed proteomic shifts and revealed broader menopause-related upregulation of inflammatory and catabolic processes plus accelerated organ and cell aging, including brain aging. In four independent cohorts of older women (average age, 60.7–72.1 years; total n = 11,925), higher menopause proteomic scores associated consistently with cognitive aging and dementia risk. The molecular signatures of menopause may inform the selection of biomarkers or therapeutic targets for brain health in midlife women.

Background and ObjectivesPlasma growth differentiation factor 15 (GDF15), a TGFbeta family cytokine, has been robustly identified from proteomics discovery work as linked to adverse brain aging; im...

Progressive cognitive decline and loss of white matter integrity are observed during aging, but whether these two processes are connected remains unclear. We propose the Decoherence via Demyelination Hypothesis (DDH) as a mechanism linking non-uniform, tract-specific myelin loss during aging, which results in the degradation of conduction timing that is required to coordinate long-range neuronal assemblies. This impairs the dynamic assembly of task-dependent functional networks and promotes age-associated cognitive change. Axonal myelination determines conduction velocity as well as signal transmission fidelity, properties essential for phase-locked integration of long-distance inputs with local oscillations and for the assembly of mesoscale functional brain networks. If myelin loss is heterogeneous across tracts, the resulting timing perturbations should be heterogeneous as well, with disproportionate impact on networks supporting higher-order cognition. To test this, we analyzed structural and microstructural MRI in 638 individuals aged 40–99, quantifying fasciculation in different white matter pathways as well as neurite orientation dispersion and density imaging (NODDI) to the gray–white matter interface beneath cortical regions. We observed tract-specific, non-uniform myelin decline, with significant nonlinear losses in tracts serving high order cognition and memory (uncinate fasciculus, fornix, corpus callosum), consistent with accelerated late-life vulnerability in pathways implicated in cognitive aging and increased risk for neurodegenerative diseases. Tract-level degeneration tracked with age-related shifts in network organization and cognition. These findings may support DDH as a framework for age-associated cognitive change. Particularly, tract-specific timing perturbations drive the breakdown of coordinated network activity in aging.

Sleep and circadian disturbances are common yet understudied in frontotemporal dementia (FTD). Advances in non-invasive digital monitoring technology enable capture of real-time objective nighttime behaviors in naturalistic settings. We examined feasibility and utility of an unobtrusive, under-the-mattress sensor to monitor long-term bed behaviors in a sample of adults with FTD and their study partners. This longitudinal observational study continuously monitored bed behaviors in participants with FTD recruited from the ALLFTD study for up to two years using an Emfit^™ Movement Monitor. Metrics were derived from each session in bed: duration in bed, time of bed-entry/exit, number of tosses/turns, and number of bed-exits. Bivariate relationships between baseline bed behaviors (aggregated across the first 30 days) and clinical characteristics (FTD vs. control; clinical dementia rating) were tested. Linear mixed-effects regressions examined longitudinal associations between baseline clinical severity and bed behaviors over time. To examine differential seasonal shifts in nightly bed behaviors, Fourier basis functions modeled nightly duration in bed over a full calendar year separately by clinical severity groups (controls vs. mild FTD vs. moderate-to-severe FTD). Participants were 16 adults with FTD (mean age = 67; 69% male) and 12 study partner comparators (mean age = 62; 33% male). At baseline, participants with FTD had higher average durations in bed (mean difference=1.8, 95%CI [0.03, 3.61], p=0.046), more variability in durations in bed across days (mean difference=1.8, 95%CI [0.14, 3.37], p=0.035), and more bed exits than study partners (log-transformed; mean difference=0.5, 95%CI [0.02, 1.06], p=0.042). Longitudinally, person-specific linear trajectories of bed behaviors revealed that higher baseline clinical severity associated with significantly steeper increases in tosses/turns over time (β=0.15, 95%CI [0.05, 0.25], p=0.009). Those with more severe FTD also had an attenuated sleep-behavioral response to seasonal daylight shifts (β=0.23, 95%CI [0.13, 0.33], p<0.001). Findings demonstrate the feasibility of long-term, non-invasive nighttime behavior monitoring using bed sensors, highlighting their utility to monitor disease progression in FTD with potential to detect person-specific changes and assess treatment effects. Further research is needed to explore underlying mechanisms of sleep disturbances in FTD and develop targeted interventions to improve sleep and subsequent quality of life for individuals with FTD.

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts ( N >3,000) to identify biological changes underlying menopause and its links to brain aging. In N =80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer’s disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women ( N =94; N =100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics ( N =2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

Background: Tissue inhibitor of metalloproteinases 2 (TIMP2) has been shown to revitalize aspects of synaptic plasticity and hippocampus-dependent cognition in aged mice. We examined TIMP2’s relevance in human brain aging and tested whether TIMP2 may be modifiable via known pro-plasticity behaviors in humans and mice. Methods: Plasma TIMP2 levels were quantified via SomaScan in three independent human cohorts, including two cross-sectional (UCSF: n=83; Stanford: n=31) and one with longitudinal measurement (ROSMAP: n=213). We examined associations of plasma TIMP2 with cognitive performance, brain volumes, and engagement in neuroprotective lifestyle behaviors, including objectively measured physical activity (UCSF) and a multi-domain lifestyle composite (ROSMAP). We used mouse models to directly test effects of environmental enrichment on (1) plasma TIMP2 levels and (2) hippocampal neurogenesis in wildtype versus TIMP2 knockout mice. Results: Higher plasma TIMP2 associated with better global cognition and larger brain volumes across human cohorts. Longitudinal decreases in plasma TIMP2 associated with steeper cognitive decline. Physical activity positively associated with plasma TIMP2 cross-sectionally, and longitudinal changes in multi-domain lifestyle factors positively associated with change in TIMP2 levels over time in humans. Mice exposed to an enriched environment for 3 weeks exhibited elevated plasma TIMP2 levels. While wildtype mice exposed to enrichment exhibited elevated adult hippocampal neurogenesis, this effect was lost in mice in which TIMP2 had been deleted. Conclusions: TIMP2 demonstrates clinical relevance for brain aging in humans and may represent a mechanism through which lifestyle behaviors confer neuroprotection. Further examination of TIMP2 as a potential therapeutic target for prevention of cognitive decline is warranted.

Background: Sex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). Method: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Disease stage was operationalized by the FTLD‐CDR (0=asymptomatic, 0.5=MCI, ≥1=dementia). Linear mixed‐effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). Result: Of 337 participants (99 MAPT , 83 GRN , and 191 C9orf72) , 204 (61%) were female and mean age was 50.64 (14.4) years. 185 (50%) were symptomatic at baseline. Whereas genotype, baseline demographics, and most clinical outcomes did not statistically differ between sexes, females demonstrated higher baseline NfL than males, and more rapid NfL accumulation over time regardless of disease stage. While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. Among asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants. Conclusion: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations, especially early in disease.

Objective: To investigate how sex and age at menopause influence the interplay between Alzheimer's disease (AD) and Lewy body disease (LBD) neuropathologies, and their associations with cognitive decline. Methods: We analyzed data from: (1) three Rush Alzheimer's Disease Center cohorts (i.e., the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study), and (2) the National Alzheimer's Coordinating Center Neuropathology Data Set. Neuropathological evaluation assessed LBD (neocortical/limbic‐type vs none) and AD, including neuritic plaques (β‐amyloid plaques surrounded by dystrophic neurites) and neurofibrillary tangles. In each dataset, we tested interactive associations between LBD and sex on neuritic plaques, neurofibrillary tangles, and cognitive decline. Additionally, in the Rush dataset, we tested whether age at spontaneous menopause modified the associations of LBD with neuritic plaques, neurofibrillary tangles, and cognitive decline in women. Results: In the Rush dataset, we included 1,277 women and 579 men. In the National Alzheimer's Coordinating Center dataset, we included 3,283 women and 3,563 men. Across both datasets, men were more likely to have LBD, whereas women showed greater neuritic plaque and neurofibrillary tangle burdens. Sex modified the associations of LBD with neurofibrillary tangles (but not neuritic plaques), whereby LBD was more strongly associated with greater neurofibrillary tangle burden in women than men. Men showed faster LBD‐related cognitive decline, whereas women showed faster neurofibrillary tangle‐related decline, after adjusting for copathologies (neuritic plaques, neurofibrillary tangles, and LBD, as appropriate). In women, earlier age at menopause exacerbated the associations of LBD with neurofibrillary tangle burden and episodic memory decline. Interpretation: Sex may influence AD and LBD neuropathologies, highlighting the need for precision approaches to dementia prevention and intervention. ANN NEUROL 2025;98:1014–1026

INTRODUCTION: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD).METHODS: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL).RESULTS: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants.DISCUSSION: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations.Highlights: Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.