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BackgroundGreater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated.ObjectivesTo determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial.Design, setting, participantsFour thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163).MeasurementsPrior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report.ResultsIndependent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p

Objective: Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults., Methods: We leveraged cross-sectional data from 1,579 stroke- and dementia-free Framingham Heart Study Offspring participants at exam 8 (age 65.7 ± 8.8 years, 53% women). Vascular risks were assessed using components of the Framingham Stroke Risk Profile (FSRP) and diastolic blood pressure (DBP). White matter hyperintensity volume (WMH), total cerebral brain volume (TBV), and covert brain infarcts were quantified using MRI. We examined whether vascular risk factors were associated with MRI measures across the combined cohort, and then determined whether sex modified these associations., Results: Higher FSRP and specifically systolic blood pressure (SBP) were associated with greater WMH. These associations were stronger in women and remained after adjusting for menopause age and hormone therapy use. By contrast, diabetes and lower DBP were associated with smaller TBV primarily in men. The DBP-atrophy relationship was only observed in men with declining DBP or prior hypertension., Interpretation: Our findings highlight differential vulnerability to the impact of vascular risk factors on white matter health in women and global atrophy in men, supporting the development of sex-specific guidelines to better preserve vascular brain health in aging. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Introduction: While the influence of cross-sectional β-amyloid (Aβ) on longitudinal changes in cognition is well established, longitudinal change-on-change between Aβ and cognition is less explored., Methods: A series of bivariate latent change score models (LCSM) examined the relationship between changes in 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) and the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) while adjusting for covariates, including cross-sectional medial temporal lobe (MTL) tau-PET burden. We selected 352 clinically normal older participants with up to 9 years of PiB-PET and PACC-5 data from the Harvard Aging Brain Study (HABS)., Results: Aβ accumulation was associated with subsequent cognitive decline beyond the effects of cross-sectional Aβ burden. Within this model including covariates such as age, sex, and apolipoprotein ε4 (APOEε4) status, we found no evidence supporting previously published associations between cross-sectional tau-PET and cognitive intercept/slope., Discussion: Short-term Aβ changes are significantly associated with cognitive decline in clinically normal older adults and may eclipse the effect of cross-sectional Aβ and MTL tau., Highlights: Aβ accumulation is associated with subsequent cognitive decline. High Aβ burden is not the sole metric signaling impending cognitive decline. Contrary to prior work, MTL tau-PET and cognition were not associated in our models. Models of bivariate latent Aβ and cognitive change may eclipse the effects of MTL tau., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage and a more hemorrhagic disease course compared to women. In this cohort study, we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases., Methods: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo magnetic resonance imaging (MRI) markers and local cortical iron burden and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodeling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database., Results: In 6120 individuals from the NACC database (45% women, mean age 80 years), the presence of parenchymal amyloid-β (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53-0.88)) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75 years), a lower microbleed count (p < 0.001) but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p < 0.001) compared to women. CAA percentage area was comparable in men and women (p = 0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p = 0.03)., Conclusion: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodeling, may contribute, but future studies are necessary to replicate our findings in larger data sets and to further investigate the underlying mechanisms behind these complex sex differences., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.A.K. reports independent support in the form of travel grants from Alzheimer Nederland, the Dutch Heart Foundation and Academy Van Leersum grant of the Academy Medical Sciences Fund, Royal Netherlands Academy of Arts & Sciences, and from the Dutch CAA foundation. V.P. reports independent support from the German Research Foundation (DFG) (454245528). W.M.F. reports independent support from Alzheimer Nederland (WE.03-2018013) and the Alzheimer’s Disease Research program of the BrightFocus Foundation (A2021007F). H.L. reports no disclosures. M.G.K. reports independent support from a Heitman Foundation Career Development Award and a Rappaport Foundation Research Fellowship. G.T.C. reports independent support from the Alzheimer’s Association (AARF-23-1151259) and the Alzheimer’s Society of Canada (22-08). R.F..B reports support from the NIH (R00AG061238, DP2AG082342, R01AG079142). M.J.H.W. reports independent support from de Nederlandse Organisatie voor Wetenschappelijk Onderzoek ZonMw (VIDI grant 91717337), the Netherlands Heart Foundation (2016T86), and the Dutch CAA foundation. S.M.G. reports independent support from the NIH. S.J.v.V. reports independent support from NIH, the AHA/Bugher Foundation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ZonMw (VENI grant 91619021).

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Conflict of interest Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes., Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults., Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded., Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite., Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition., Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline., Methods: Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+., Results: EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL., Discussion: These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials., Highlights: Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR., Methods: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women)., Results: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline., Conclusion: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity., (© 2024. The Author(s).)

Background and Objectives: Self-reported cognitive decline is an early behavioral manifestation of Alzheimer disease (AD) at the preclinical stage, often believed to precede concerns reported by a study partner. Previous work shows cross-sectional associations with β-amyloid (Aβ) status and self-reported and study partner-reported cognitive decline, but less is known about their associations with tau deposition, particularly among those with preclinical AD., Methods: This cross-sectional study included participants from the Anti-Amyloid Treatment in Asymptomatic AD/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies (N = 444) and the Harvard Aging Brain Study and affiliated studies (N = 231), which resulted in a cognitively unimpaired (CU) sample of individuals with both nonelevated (Aβ-) and elevated Aβ (Aβ+). All participants and study partners completed the Cognitive Function Index (CFI). Two regional tau composites were derived by averaging flortaucipir PET uptake in the medial temporal lobe (MTL) and neocortex (NEO). Global Aβ PET was measured in Centiloids (CLs) with Aβ+ >26 CL. We conducted multiple linear regression analyses to test associations between tau PET and CFI, covarying for amyloid, age, sex, education, and cohort. We also controlled for objective cognitive performance, measured using the Preclinical Alzheimer Cognitive Composite (PACC)., Results: Across 675 CU participants (age = 72.3 ± 6.6 years, female = 59%, Aβ+ = 60%), greater tau was associated with greater self-CFI (MTL: β = 0.28 [0.12, 0.44], p < 0.001, and NEO: β = 0.26 [0.09, 0.42], p = 0.002) and study partner CFI (MTL: β = 0.28 [0.14, 0.41], p < 0.001, and NEO: β = 0.31 [0.17, 0.44], p < 0.001). Significant associations between both CFI measures and MTL/NEO tau PET were driven by Aβ+. Continuous Aβ showed an independent effect on CFI in addition to MTL and NEO tau for both self-CFI and study partner CFI. Self-CFI (β = 0.01 [0.001, 0.02], p = 0.03), study partner CFI (β = 0.01 [0.003, 0.02], p = 0.01), and the PACC (β = -0.02 [-0.03, -0.01], p < 0.001) were independently associated with MTL tau, but for NEO tau, PACC (β = -0.02 [-0.03, -0.01], p < 0.001) and study partner report (β = 0.01 [0.004, 0.02], p = 0.002) were associated, but not self-CFI (β = 0.01 [-0.001, 0.02], p = 0.10)., Discussion: Both self-report and study partner report showed associations with tau in addition to Aβ. Additionally, self-report and study partner report were associated with tau above and beyond performance on a neuropsychological composite. Stratification analyses by Aβ status indicate that associations between self-reported and study partner-reported cognitive concerns with regional tau are driven by those at the preclinical stage of AD, suggesting that both are useful to collect on the early AD continuum.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition., Methods: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French)., Results: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (β = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; β = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; β = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; β = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (β = -0.005, 95% CI -0.032 to 0.021, p = 0.69)., Discussion: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

Objective: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants' own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment., Method: Multiday BRANCH was administered remotely to 181 cognitively unimpaired older adults using their own electronic devices. For 7 consecutive days, participants completed three tests with associative memory components (Face-Name, Groceries-Prices, Digit Signs), using the same stimuli, to capture multiday learning curves for each test. We assessed the feasibility of capturing learning curves across the 7 days. Additionally, we examined the reliability and associations of learning curves with demographics, and traditional cognitive and subjective report measures., Results: Multiday BRANCH was feasible with 96% of participants completing all study assessments; there were no differences dependent on type of device used ( t = 0.71, p = .48) or time of day completed ( t = -0.08, p = .94). Psychometric properties of the learning curves were sound including good test-retest reliability of individuals' curves (intraclass correlation = 0.94). Learning curves were positively correlated with in-person cognitive tests and subjective report of cognitive complaints., Conclusions: Multiday BRANCH is a feasible, reliable, and valid cognitive measure that may be useful for identifying subtle changes in learning and memory processes in older adults. In the future, we will determine whether Multiday BRANCH is predictive of the presence of preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer's disease related pathology and neurodegeneration in smaller cohort studies., Objectives: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ)., Design: Longitudinal mixed., Setting: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study., Participants: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive)., Measurements: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version., Results: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline., Conclusions: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline., Competing Interests: All authors confirm that they do not have conflicts of interest pertinent to this manuscript.

Background: Disparities in Alzheimer's disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities., Objectives: To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and β-amyloid (Aβ) status groups., Design, Setting, Participants: Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan., Measurements: Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aβ status., Results: Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aβ- and 1309 were classified as Aβ+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aβ status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aβ status groups., Conclusions: Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aβ status groups examined in this study., Competing Interests: MR, MWA, HCM, TR, RA, RFB, WS, JSR have nothing to disclose. RAS has served as a paid consultant for AC Immune, Acumen, Alynlam, Cytox, Genentech, Janssen, JOMDD, Nervgen, Neuraly, Neurocentria, Oligomerix, Prothena, Renew, Shionogi, Vigil Neuroscience, Ionis, Vaxxinity. SB has served as a paid consultant for Roche, Biogen, NovoNordisk. She serves on the advisory board for Conference Board of Canada, World Dementia Council, National Institute of Neurological Disorders and Stroke, University of Rochester Contribution to the Mission and Scientific Leadership of the Small Vessel VCID Biomarker Validation Consortium.

Introduction: We investigated how the associations between tau and cognitive measures differ by sex in the preclinical Alzheimer's disease (AD) stage., Methods: A total of 343 cognitively unimpaired, amyloid-positive individuals (205 women, 138 men) who self-identified as non-Hispanic White from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study were included. We assessed sex-stratified associations between 18 F-flortaucipir positron emission tomography (PET) standardized uptake value ratio (SUVR) in the meta-temporal region and Preclinical Alzheimer's Cognitive Composite (PACC) and Computerized Cognitive Composite (C3) components., Results: We observed that higher tau level was significantly associated with worse cognitive performance only in women: PACC and its components except for Mini-Mental State Examination (MMSE) and C3 components: First Letter Name Recall (FNLT) and One-Card Learning Reaction Time (OCL RT). These associations except for FNLT were apolipoprotein E (APOE) ε4 independent., Discussion: Women show stronger associations between tau PET and cognitive outcomes in preclinical AD. These findings have important implications for sex-specific tau-targeted preventive AD clinical trials., Highlights: The tau positron emission tomography (PET) signal in the meta-temporal region was associated with poor cognitive performance in preclinical Alzheimer's disease (AD). After sex stratification, the associations between regional tau PET and cognitive outcomes were observed only in women. The associations between tau PET and some cognitive outcomes were independent of apolipoprotein E (APOE) ε4., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Clinically normal females exhibit higher 18 F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau., Methods: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aβ imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline., Results: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline ( R 2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers., Discussion: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Introduction: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples., Methods: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately., Results: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010)., Discussion: In NHW adults, APOE ε2 may protect men but not women against cognitive decline., Highlights: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Spatial cognition is associated with Alzheimer's disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and β-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer's Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau 181 , β-amyloid 1-42 (Aβ 1-42 ) and p-tau 181 /Aβ 1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau 181 , Aβ 1-42, and p-tau 181 /Aβ 1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau 181 /Aβ 1-42 ratio showed the largest effect sizes (β = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (β = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau 181 and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau 181 and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer's disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; M age = 58.2), and in Aβ- CU older adults (n = 71; M age = 71.8). Aβ- CU middle-aged ε4 carriers showed lower CSF Aβ 42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen's d: 0.30-0.56). In Aβ- CU older adults, ε4 carriers also had lower CSF Aβ 42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen's d: 0.65-0.74). In both Aβ- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aβ- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aβ, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aβ- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aβ- adults., Competing Interests: Declaration of Competing Interest Y.Y. Lim, N. Yassi, L. Bransby, S. Ayton, R.F. Buckley, D. Eratne, D. Velakoulis, Q.X. Li, C. Fowler, and C.L. Masters have no relevant conflicts of interest to disclose. Paul Maruff is a full-time employee of Cogstate Ltd., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Studies of modifiable dementia risk factors (MDRFs) generally consider MDRFs individually, despite strong evidence that they co-occur in adult populations. In a large sample of middle-aged adults, this study aimed to determine the frequency and co-occurrence of MDRFs, spanning five domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology). The relationship between number of domains in which MDRFs were reported with cognitive performance and subjective cognitive concerns was then determined., Method: Middle-aged adults ( n = 1,610) enrolled in the Healthy Brain Project and completed self-report surveys about their health and lifestyle. Participants also completed the Cogstate Brief Battery and the Cognitive Function Instrument, a measure of subjective ratings of cognition. Participants were classified according to number of domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology) in which they reported at least one MDRF (0-5). Age, sex, education, and ethnicity were adjusted for in analyses., Results: Most individuals (66.5%) reported MDRFs in two or more domains. Compared with individuals displaying no MDRFs, individuals with MDRFs in 3-5 domains showed worse learning/working memory performance and greater subjective cognitive concerns, with the magnitude of these differences moderate-to-large ( d = 0.30-0.93). Individuals displaying MDRFs in five domains also showed worse attention/psychomotor function ( d = 0.58) compared to those displaying no MDRFs., Conclusions: These findings may suggest that multidomain MDRFs are highly frequent in middle-aged adults and are related to poorer cognition. This supports that modifiable dementia risk is multidimensional and raises the possibility that multidomain behavioral intervention trials in middle-aged adults may be useful to delay or prevent cognitive impairment or decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Importance: Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high β-amyloid (Aβ). The biological mechanisms associated with higher tau deposition in female individuals remain elusive., Objective: To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aβ, both measured with positron emission tomography (PET)., Design, Setting, and Participants: This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021., Exposures: Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported., Main Outcomes and Measures: Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aβ PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET., Results: Of 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aβ, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized β = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized β = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized β = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aβ compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (β = 0.49; 95% CI, 0.27-0.43; P = .001)., Conclusions and Relevance: In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aβ. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aβ elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

Objective: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies., Method: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies., Results: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change., Conclusions: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC., Method: We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts ( n = 2,712). We further demonstrated our method with the Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease (A4) Study prerandomized data ( n = 4,492). For the harmonization method, we used confirmatory factor analysis (CFA) on the final visit of the longitudinal cohorts to determine parameters to generate latent PACC (lPACC) scores. Overlapping tests across studies were set as "anchors" that tied cohorts together, while parameters from unique tests were freely estimated. We performed validation analyses to assess the performance of lPACC versus the common standardized PACC (zPACC)., Results: Baseline (BL) scores for the zPACC were centered on zero, by definition. The harmonized lPACC did not define a common mean of zero and demonstrated differences in baseline ability levels across the cohorts. Baseline lPACC slightly outperformed zPACC in the prediction of progression to dementia. Longitudinal change in the lPACC was more constrained and less variable relative to the zPACC. In combined-cohort analyses, longitudinal lPACC slightly outperformed longitudinal zPACC in its association with baseline β-amyloid status., Conclusions: This study proposes procedures for harmonizing the PACC that make fewer strong assumptions than the zPACC, facilitating robust multicohort analyses. This implementation of item response theory lends itself to adapting across future cohorts with similar composites. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10 -311 , MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10 -09 , MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10 -10 , MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10 -09 , MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10 -08 , MAF = 0.006, sex-interaction P = 9.8 × 10 -07 ) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10 -08 , MAF = 0.004, sex-interaction P = 1.3 × 10 -03 ). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies., (© 2023. The Author(s).)