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INTRODUCTION A crucial step before clinical use of Alzheimer's disease (AD) blood biomarkers is the development of effective methods for disclosing results. This mixed‐method study developed educational materials to disclose the dementia risk based on plasma phosphorylated tau (p‐tau) results. METHODS Participants diagnosed with mild cognitive impairment (MCI; n = 8) and their care partners (n = 7) participated in focus groups discussing the utility of an educational tool and communication preferences. Focus groups were recorded, transcribed, and analyzed using NVivo, with two independent coders conducting thematic analysis. RESULTS Participants rated the materials highly regarding value and comprehension. Thematic analysis revealed confusion about dementia progression and terminology. Participants preferred varied communication modes. Participants found utility in these materials but sought additional information on risk reduction. DISCUSSION These findings highlight the utility of educational materials to aid in the disclosure of AD dementia risk based on plasma p‐tau to individuals with MCI and their loved ones. Highlights Individuals with mild cognitive impairment (MCI) find value in receiving blood biomarker results. Additional risk reduction information is helpful when communicating dementia risk. Individuals prefer medical information communicated visually.

INTRODUCTION Plasma phosphorylated tau‐181 (p‐tau181) associations with global cognition and memory are clear, but the link between p‐tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and included 1185 adults >55 years of age with plasma p‐tau181 and neuropsychological test data. Linear regression models related plasma p‐tau181 to neuropsychological composite and SCD scores with follow‐up models examining plasma p‐tau181 interactions with cognitive diagnosis, apolipoprotein E (APOE) ε4 carrier status, age, and sex on cognitive outcomes. RESULTS Higher plasma p‐tau181 level was associated with worse memory, executive functioning, and language abilities, and greater informant‐reported SCD. Visuospatial abilities and self‐report SCD were not associated with plasma p‐tau181. Associations were generally stronger in mild cognitive impairment (MCI) or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION Higher levels of plasma p‐tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex. Highlights Greater plasma p‐tau181 was associated with lower cognition across most domains. Associations between p‐tau181 and cognition were modified by age and sex. Level of p‐tau181 was more strongly associated with cognition in people with mild cognitive impairment (MCI) and apolipoprotein E (APOE) ε4.

Objective This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non‐demented older adults. Methods Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow‐up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. Results In main effect models, higher SCD was associated with more amyloidosis (p‐values <0.004). SCD was not associated with tau, p‐tau, or neurofilament light (NFL) levels (p‐values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p‐values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p‐values <0.003), men (p = 0.0003), and higher education. No SCD score × reading‐level interaction was found (p‐values >0.51) though SCD related to amyloid markers in the higher reading‐level group (p‐values <0.004). Interpretation Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD‐related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.

Women are at an increased risk of dementia due to Alzheimer's disease (AD) compared to men, a difference due in part to the role of female sex hormones. Estrogen, in particular, plays a key role in neuroplasticity. However, as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable. This study investigates the interaction of sex with a marker of neuroplasticity, growth-associated protein-43 (GAP-43), on AD biomarkers and cognitive decline. Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 161, 72±6 years, 31% female) underwent fasting lumbar puncture and comprehensive neuropsychological assessment at study entry and serially over a mean 6.4-year follow-up period. Cerebrospinal fluid (CSF) levels of GAP-43, b-amyloid (Ab ), tau, and phosphorylated-tau (p-tau) were analyzed in batch. Linear regression models related baseline CSF GAP-43 cross-sectionally and longitudinally to CSF biomarkers and cognition adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)-e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow-up models assessed GAP-43 x sex interactions on AD biomarkers and cognitive outcomes. In cross-sectional analyses, higher GAP-43 was associated with higher levels of all CSF AD biomarkers (p-values<0.0001), worse language performance (b=-0.0005, p = 0.04) and worse visuospatial performance (b=-0.0004, p = 0.005). GAP-43 interacted with sex on CSF tau and p-tau levels (p-values<0.0001) such that associations were stronger in females compared to males. In longitudinal analyses, higher baseline GAP-43 was associated with declining Ab42 levels (b=-0.01, p <0.0001) and declining performance in tasks of language, executive function, and visuospatial abilities (p-values<0.02), indicating greater AD pathology and declining cognition. GAP-43 interacted with sex on longitudinal language, processing speed, executive functioning, and visuospatial performance trajectories (p-values<0.05), such that significant associations were found in women (p-values<0.02) but not men (p-values>0.26). In this cohort of community-dwelling older adults, we found higher baseline levels of GAP-43, indicating increased neuroplasticity, are related to cross-sectional increases in tau pathology, especially in women, and longitudinal decline in cognition, exclusively in women. Findings suggest that differential responses to neuroplasticity in aging could help explain long-recognized sex differences in tau pathology and cognitive decline.

INTRODUCTION Sedentary behavior may be a modifiable risk factor for Alzheimer's disease (AD). We examined how sedentary behavior relates to longitudinal brain structure and cognitive changes in older adults. METHODS Vanderbilt Memory and Aging Project participants (n = 404) completed actigraphy (7 days), neuropsychological assessment, and 3T brain MRI over a 7‐year period. Cross‐sectional and longitudinal linear regressions examined sedentary time in relation to brain structure and cognition. Models were repeated testing for effect modification by apolipoprotein E (APOE) ε4 status. RESULTS In cross‐sectional models, greater sedentary time related to a smaller AD‐neuroimaging signature (β = ‐0.0001, p = 0.01) and worse episodic memory (β = ‐0.001, p = 0.003). Associations differed by APOE‐ε4 status. In longitudinal models, greater sedentary time related to faster hippocampal volume reductions (β = ‐0.1, p = 0.008) and declines in naming (β = ‐0.001, p = 0.03) and processing speed (β = ‐0.003, p = 0.02; β = 0.01, p = 0.01). DISCUSSION Results support the importance of reducing sedentary time, particularly among aging adults at genetic risk for AD. Highlights Greater sedentary behavior is related to neurodegeneration and worse cognition. Associations differed by APOE‐ε4 carrier status in cross‐sectional models. Sedentary behavior is an independent risk factor for Alzheimer's disease.

INTRODUCTION Plasma phosphorylated tau231 (p‐tau231) has shown great promise for early identification of amyloid pathology. We tested various plasma biomarker combinations with p‐tau231 in relation to cerebrospinal fluid (CSF) amyloid positivity. METHODS One hundred and fifty‐five dementia‐free older adults were included. Plasma p‐tau231, glial fibrillary acidic protein (GFAP), β‐amyloid42/40, and neurofilament light chain (NfL) were related to amyloid positivity via logistic regression. Subsequent models assessing various combinations of biomarkers were compared to a base model containing only p‐tau231. RESULTS In single predictor models, p‐tau231 (AUC = 0.87, p = 0.005) and GFAP (AUC = 0.87, p = 0.01) were associated with amyloid positivity, and p‐tau231 remained significant in all multi‐predictor models (p‐values < 0.02). In comparison to the base model with p‐tau231 only, models adding GFAP improved the prediction of amyloid positivity (p < 0.03). DISCUSSION Plasma p‐tau231 and GFAP were associated with amyloid positivity. Models including both p‐tau231 and GFAP performed best, while including β‐amyloid42/40 and NfL did not produce a better fitting model. Highlights Plasma p‐tau231 and glial fibrillary acidic protein (GFAP) are accurate predictors of amyloid positivity. Combining plasma p‐tau231 and GFAP improves accuracy. Adding other biomarkers beyond p‐tau231 and GFAP does not improve models.

INTRODUCTION Little is known about change in sleep duration over time and Alzheimer's Disease and Related Dementias (ADRD) risk. METHODS ADRD cases were identified among Southern Community Cohort Study participants enrolled in Medicare. Sleep duration was reported at enrollment and first study follow‐up and categorized (short (< 7 hours), recommended (7‐9) and long (> 9)), change was calculated between timepoints. Adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD. RESULTS We identified 2,093 ADRD cases among 17,945 participants. Compared to maintaining optimal sleep duration (7‐9 hours) over 5 years, suboptimal changes were associated with 20‐69% greater ADRD risk: adjusted HR (95% CI) was 1.50 (1.23‐1.82) for long‐recommended, 1.56 (1.21‐2.01) for long‐long, 1.69 (1.25‐2.27) for long‐short, 1.49 (1.16‐1.91) for short‐long, and 1.20 (1.06‐1.36) for short‐short. DISCUSSION Suboptimal 5‐year change in sleep durations were associated with ADRD risk among lower‐income adults underrepresented in ADRD research. Highlights The study calculated 5‐year change in sleep duration in a large community‐based cohort of predominately lower‐income adults. Cases of Alzheimer's Disease and Related Dementias (ADRD) were ascertained from Medicare claims data among 17,945 participants with up to 12 years of follow‐up. Compared to maintaining 7‐9 hours of sleep, older adults with suboptimal sleep categories were consistently at a greater risk of ADRD.

INTRODUCTION We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth‐associated protein‐43 (GAP‐43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p‐tau)) and neurodegeneration (tau). METHODS Baseline GAP‐43 levels in 161 non‐demented older adults were related to cross‐sectional and longitudinal (mean follow‐up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP‐43 x AD risk factor interaction terms. RESULTS Higher GAP‐43 was cross‐sectionally related to all AD biomarkers (p‐values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups. DISCUSSION We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4‐year mean follow‐up period. Highlights Cerebrospinal fluid growth‐associated protein‐43 (GAP‐43) is associated with Alzheimer's disease (AD) biomarkers cross‐sectionally and longitudinally. GAP‐43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis.

Plasma phosphorylated tau (p-tau ) has shown great promise for early identification of amyloid pathology. We tested various plasma biomarker combinations with p-tau231 in relation to cerebrospinal fluid (CSF) amyloid positivity. One hundred and fifty-five dementia-free older adults were included. Plasma p-tau231, glial fibrillary acidic protein (GFAP), β-amyloid42/40, and neurofilament light chain (NfL) were related to amyloid positivity via logistic regression. Subsequent models assessing various combinations of biomarkers were compared to a base model containing only p-tau . In single predictor models, p-tau231 (AUC = 0.87, p = 0.005) and GFAP (AUC = 0.87, p = 0.01) were associated with amyloid positivity, and p-tau231 remained significant in all multi-predictor models (p-values < 0.02). In comparison to the base model with p-tau231 only, models adding GFAP improved the prediction of amyloid positivity (p < 0.03). Plasma p-tau231 and GFAP were associated with amyloid positivity. Models including both p-tau231 and GFAP performed best, while including β-amyloid42/40 and NfL did not produce a better fitting model. Plasma p-tau231 and glial fibrillary acidic protein (GFAP) are accurate predictors of amyloid positivity. Combining plasma p-tau231 and GFAP improves accuracy. Adding other biomarkers beyond p-tau231 and GFAP does not improve models.

INTRODUCTION The impact of chronic kidney disease (CKD) on Alzheimer's disease (AD) plasma biomarkers is poorly understood. We tested whether kidney function decline affects the predictive accuracy of plasma biomarkers on neuropsychological or neuroimaging outcomes. METHODS Three hundred thirty‐three non‐demented older adults were included. Linear regressions related plasma glial fibrillary acidic protein, neurofilament light chain (NfL), amyloid beta 42, and phosphorylated tau231, with a blood‐based biomarker x estimated glomerular filtration rate (eGFR) interaction term, to cross‐sectional and longitudinal (mean follow‐up time = 6.4 ± 2.8 years) neuropsychological and neuroimaging outcomes. RESULTS Plasma NfL interacted with eGFR on the longitudinal trajectory of nearly all neuropsychological outcomes (p values < 0.02) and several neuroimaging outcomes (p values < 0.02). Associations were stronger in individuals with no CKD/stage 1 and stage 2 CKD, while associations were weaker or not significant in individuals with stage 3 CKD. DISCUSSION Among older adults free of severe CKD, the ability of plasma NfL to predict key AD‐related biomarker outcomes was moderated by renal function. Highlights Reduced kidney function was associated with increased blood biomarker levels. The predictive accuracy of neurofilament light chain was reduced in participants with kidney dysfunction. Even mild kidney dysfunction can affect blood biomarkers of Alzheimer's disease.