About

Dr. Rachel Buckley is an Assistant Professor based at Massachusetts General Hospital, with research interests centered on preclinical Alzheimer’s disease, specifically focusing on sex differences and risk and resilience factors. Her lab investigates the biological mechanisms underlying the higher levels of brain tau burden observed in women compared to men, exploring avenues such as endocrinological aging, reproductive health markers like menopause, hormone therapy, and surgical history, as well as gene expression on X-inactivated escaping genes from brain tissue and plasma RNA sequencing. Additionally, her work in risk and resilience involves harmonizing data from approximately 15 observational human studies of Alzheimer’s disease to develop predictive algorithms of cognitive resilience and brain resistance to pathology over 5, 10, and 15 years, utilizing machine learning and AI approaches. Dr. Buckley co-leads the HABS Data & Informatics team, chairs the Sex & Gender Differences in Alzheimer’s Disease Professional Interest Area for ISTAART, and serves on the editorial boards for Neurology and Alzheimer’s & Dementia: DADM. She is funded by NIH grants including a K99/R00, an R01, and a DP2 New Innovator award.

Research topics

• Medicine
• Neuroscience
• Internal medicine
• Biology
• Psychiatry
• Gerontology
• Environmental health
• Clinical psychology
• Psychology
• Genetics
• Pathology

Selected publications

• Number of live births as a protective factor against clinical and covert brain infarcts: The Framingham heart study

  Research Repository UCD (University College Dublin) · 2026-03-18

  otherOpen access

  Background Female‐specific reproductive factors have been associated with stroke risk, although evidence for some factors (eg, live births) remains conflicting. We determined the association between number of live births and other female‐specific reproductive factors and subsequent risk of stroke and magnetic resonance imaging markers of vascular brain injury in a community‐based cohort. Methods This was a prospective cohort study of 1882 (mean age, 61.3±9.6 years) women from the FHS (Framingham Heart Study) Offspring cohort who were stroke free at the baseline examination (1998–2001). Reproductive factors included number of live births, age at menopause, postmenopausal hormone replacement therapy use and serum estradiol and estrone levels. The primary outcome was incident all‐cause stroke, with covert brain infarcts and white matter hyperintensity volume on brain magnetic resonance imaging as cross‐sectional secondary outcomes. Results During a median 18‐year follow‐up, 126 women had a stroke. On multivariable Cox proportional hazards models controlling for vascular risk factors, ≥3 live births (versus 0, reference) was associated with a reduced risk of stroke (hazard ratio, 0.51 [95% CI, 0.31–0.85]; P<0.01). More live births (≥3 versus 0) was cross‐sectionally associated with decreased risk of covert brain infarct (odds ratio, 0.52 [95% CI, 0.30–0.92]; P=0.03). No significant association was detected between other reproductive factors and incident stroke or magnetic resonance imaging markers of vascular brain injury. Conclusions A greater number of live births was associated with a decreased risk of stroke and covert brain infarct in women and may be an important factor to include in female‐specific clinical prediction rules for stroke.

  PublisherDOI

• Sex differences in neuromodulatory subcortical systems and their implications for Alzheimer's disease

  Alzheimer s & Dementia · 2026-03-01

  articleOpen access

  Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia-related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex-specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non-disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex-specific AD susceptibility and potential footholds for sex-based interventions targeting these systems. We conclude by outlining immediate and long-term actions to address the intersection of NSSs, sex, and AD.

  PublisherDOI

• Baseline cortical amyloid-β levels are associated with subsequent study-partner-rated apathy in community-dwelling older adults

  Journal of Alzheimer s Disease · 2026-04-06

  article

  BackgroundApathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) and has been linked to greater levels of AD biomarkers (amyloid-β, tau). However, it is unclear whether early patterns of amyloid deposition may impact development of apathy symptoms in the future.ObjectiveWe sought to examine whether amyloid-β levels, both globally and in brain regions associated with motivation, could predict future apathy symptoms.MethodsParticipants (n = 199, mean age = 79.9) were part of the Harvard Aging Brain Study, a longitudinal observational cohort of individuals without cognitive or psychiatric impairment at baseline. All underwent MRI and Pittsburgh Compound B (PiB)-PET for amyloid-β at baseline and completed questionnaires of self- and study-partner-rated apathy 7.8 ± 1 years later using the Apathy Evaluation Scale. Linear regression models assessed whether regional PiB levels predicted future apathy scores.ResultsHigher baseline cortical PiB levels in a frontal, lateral parieto-temporal, and retrosplenial aggregate were associated with greater study-partner-rated apathy, but not self-rated apathy, and no specific regional associations were observed outside of the aggregate.ConclusionsThese results provide insight into early neurobiological underpinnings of AD-related apathy. Additionally, these data may have clinical implications regarding the risk of developing apathy symptoms in amyloid-β-positive individuals as cognition declines.

  PublisherDOI

• Number of Live Births as a Protective Factor Against Clinical and Covert Brain Infarcts: The Framingham Heart Study

  Journal of the American Heart Association · 2026-03-18

  articleOpen access

  Background Female‐specific reproductive factors have been associated with stroke risk, although evidence for some factors (eg, live births) remains conflicting. We determined the association between number of live births and other female‐specific reproductive factors and subsequent risk of stroke and magnetic resonance imaging markers of vascular brain injury in a community‐based cohort. Methods This was a prospective cohort study of 1882 (mean age, 61.3±9.6 years) women from the FHS (Framingham Heart Study) Offspring cohort who were stroke free at the baseline examination (1998–2001). Reproductive factors included number of live births, age at menopause, postmenopausal hormone replacement therapy use and serum estradiol and estrone levels. The primary outcome was incident all‐cause stroke, with covert brain infarcts and white matter hyperintensity volume on brain magnetic resonance imaging as cross‐sectional secondary outcomes. Results During a median 18‐year follow‐up, 126 women had a stroke. On multivariable Cox proportional hazards models controlling for vascular risk factors, ≥3 live births (versus 0, reference) was associated with a reduced risk of stroke (hazard ratio, 0.51 [95% CI, 0.31–0.85]; P <0.01). More live births (≥3 versus 0) was cross‐sectionally associated with decreased risk of covert brain infarct (odds ratio, 0.52 [95% CI, 0.30–0.92]; P =0.03). No significant association was detected between other reproductive factors and incident stroke or magnetic resonance imaging markers of vascular brain injury. Conclusions A greater number of live births was associated with a decreased risk of stroke and covert brain infarct in women and may be an important factor to include in female‐specific clinical prediction rules for stroke.

  PublisherDOI

• Plasma phosphorylated tau 217 and longitudinal trajectories of Aβ, tau, and cognition in cognitively unimpaired older adults

  Nature Communications · 2026-04-14 · 1 citations

  articleOpen access

  Plasma phosphorylated tau 217 (pTau217) is an excellent biomarker of Alzheimer’s disease (AD) pathology, but it remains uncertain whether pTau217 can predict amyloid-β (Aβ) and tau accumulation prior to Aβ positron emission tomography (PET) positivity. Here, we leverage data from a well-characterized prospective cohort of cognitively unimpaired older adults to examine mass spectrometry-based plasma %pTau217 (pTau217/non-phosphorylated-Tau217×100) relative to changes in Aβ/tau PET and cognition. A higher baseline %pTau217 was associated with faster Aβ and tau accumulation on PET, which then led to greater cognitive decline. Among individuals Aβ PET-negative at baseline, higher %pTau217 levels presaged increases in Aβ and tau PET signals. Together, our results suggest that very low %pTau217 in cognitively unimpaired older adults is associated with a minimal risk of AD pathology accumulation and cognitive decline. Plasma phosphorylated tau 217 levels predict future accumulation of Alzheimer’s disease pathology in cognitively unimpaired older adults without elevated brain amyloid-β (“A-”) on positron emission tomography.

  PublisherOA PDFDOI

• Independent, but not synergistic, associations of <i>APOE</i> ε4 and systemic inflammation on cognitive decline: findings from the Women’s Health Initiative

  Journal of Clinical and Experimental Neuropsychology · 2026-01-06

  articleOpen accessSenior authorCorresponding

  INTRODUCTION: Understanding the risk factors that associate with early cognitive decline in Alzheimer's disease (AD) is important to identify high-risk individuals and initiate early intervention. Existing studies show that APOEε4, systemic inflammation, and diabetes may play roles in cognitive decline, but the extent to which these factors interact with each other remains unclear. Our objective was to examine the main effects and higher-order interactions between APOEε4, high sensitivity-C-reactive protein (hs-CRP) as a measure of systemic inflammation, and diabetes on domain-specific measures of cognitive function in two ancillary studies of post-menopausal women from the Women's Health Initiative (WHI). METHOD: We identified 2979 cognitively unimpaired women from the WHI Epidemiology of Cognitive Health Outcomes and the WHI Memory Study of Younger Women with cognitive follow-up of up to 13 years. Linear mixed-effects models examined the main and interactive effects of APOEε4, hs-CRP, and diabetes on longitudinal changes in the personal communication for Cognitive Status-modified Test (TICS-m), East Boston Memory Test (immediate and delayed; EBMT), Oral Trail Making Test (OTMT), Verbal Fluency Test (VF-A), Digit Span Test Backwards (DST-backward), and the California Verbal Learning Test (CVLT). All models were adjusted for baseline age, education, body mass index, the WHI randomization arm, and the cohort. RESULTS: APOEε4 carriers had steeper cognitive decline in TICS-m, EBMT (immediate and delayed), VF-A, and CVLT scores relative to non-carriers. Higher levels of hs-CRP were associated with steeper cognitive decline in the DST-backwards scores. There was no association of diabetes or any evidence of interactive effects on cognitive decline in our study. CONCLUSIONS: In this large longitudinal study of post-menopausal women, our findings support the hypothesis that genetic risk and systemic inflammation independently influence cognitive decline, but there was no evidence of synergistic effects in postmenopausal women. Further research is needed to elucidate the mechanistic pathways underlying these associations with cognitive decline.

  PublisherOA PDFDOI

• Defining patient‐centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease

  Alzheimer s & Dementia · 2026-01-01

  articleOpen access

  INTRODUCTION: Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis. METHODS: By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset. RESULTS: We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET-inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001). DISCUSSION: This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline. HIGHLIGHTS: Younger age is related to faster amyloid-related tau accumulation in men. We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy. Crossing the amyloid PET-defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.

  PublisherOA PDFDOI

• Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease

  The Journal of Prevention of Alzheimer s Disease · 2026-03-13 · 1 citations

  articleOpen access

  BACKGROUND: Prevention of Alzheimer's disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits. OBJECTIVES: [F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition. DESIGN: Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures. SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites. PARTICIPANTS: 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN. MEASUREMENTS: EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ- to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR- individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread). CONCLUSIONS: EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.

  PublisherDOI

• Blood-Based Circular RNAs Enable Early and Accurate Alzheimer’s Disease Diagnosis

  Research Square · 2025-12-09

  preprintOpen access
  PublisherOA PDFDOI

• Relationship between Polygenetic Risk Score of BrainAge and plasma biomarkers in the A4/LEARN studies

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  Abstract Background The BrainAge Gap estimates the discrepancy between predicted and chronological brain age based on neuroimaging. Calculating a Polygenic Risk Score (PRS) from a BrainAge Gap estimate quantifies the genetic predisposition to accelerated brain aging. The objective of this study is to examine the association between the genetic propensity for higher or lower BrainAge Gap and plasma biomarkers of AD. Linking genetic predisposition to brain aging with early AD related changes could improve our understanding of the early disease mechanisms and risk factors Methods We examined 3014 cognitively normal participants from the A4 and LEARN studies (71.4 ± 4.6 age; 40% male). PRS of BrainAge models were calculated for each subject using the summary GWAS statistics of Wen et. al, Nature Communications 2024 for three types of BrainAge models: Grey Matter (GM), White Matter (WM) and Functional Connectivity (FC). We focused on the following plasma biomarkers gathered at baseline: p ‐tau 217 (Eli‐Lilly, N = 736), GFAP (Roche Diagnostic, N = 1643) and NfL (Roche Diagnostic, N = 1641). We used a general linear model to study the association between each of the 3 plasma biomarkers with each of the 3 PRS measures, and additionally including the interaction between age and PRS for each BrainAge model. Results None of the BrainAge PRS were found to be significantly different by Aβ‐PET status, APOE ε4 carriership, age, sex or education. BrainAge GM PRS was positively associated with p ‐tau 217 levels ( p = 0.01), particularly among the older adults ( p = 0.007). In sensitivity analyses, covaring sex, APOE ε4 status and years of education did not alter the results. None of the BrainAge PRS were associated with GFAP or NFL. Conclusion Genetic factors associated with increased propensity for accelerated brain aging in the grey matter is associated with p ‐tau 217 , an early and sensitive marker of AD. These genetic predispositions were more pronounced in older age, highlighting the importance of age as a critical factor that may interact with genetic susceptibility to brain aging, potentially through cumulative lifetime exposures, increasing vascular burden, or age‐related declines in cellular repair mechanisms. Associations solely with BrainAge GM PRS implies the specificity of accelerated brain aging in grey matter as a potential early marker of AD risk.

  PublisherOA PDFDOI

Recent grants

• Building predictive algorithms to identify resilience and resistance to Alzheimer's disease

  NIH · $4.0M · 2023–2028

• The inactive X: discovering sex genes that influence female vulnerability to Alzheimer's disease

  NIH · $2.5M · 2022–2027

• Elucidating the mechanisms underlying sex differences in cognitive decline due to preclinical Alzheimer's disease

  NIH · $273k · 2019–2021

• Sex differences in the progression of Alzheimer's disease: is menopause the key?

  NIH · $747k · 2021–2024

Frequent coauthors

• Reisa A. Sperling

  Harvard University

  1729 shared

• Keith A. Johnson

  Massachusetts General Hospital

  1340 shared

• Dorene M. Rentz

  Harvard University

  1149 shared

• Aaron P. Schultz

  Massachusetts General Hospital

  1000 shared

• Bernard Hanseeuw

  Cliniques Universitaires Saint-Luc

  716 shared

• Rebecca E. Amariglio

  Massachusetts General Hospital

  614 shared

• Jennifer S. Rabin

  Sunnybrook Health Science Centre

  613 shared

• Jasmeer P. Chhatwal

  Brigham and Women's Hospital

  603 shared

Labs

• Rachel Buckley LabPI

Awards & honors

• NIH-NIA K99/R00
• R01 (NIA)
• NIH DP2 New Innovator award