Drug Development.

Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid β

BackgroundBiomarkers for the prediction of cognitive decline in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD dementia are needed for inclusion of suitable patients in clinical trials. We therefore assessed the ability of tau‐PET, blood and cerebrospinal fluid (CSF) phospho‐Tau217 (pTau217), CSF neurofilament light (NfL) and cortical thickness to predict cognitive decline early symptomatic AD.Method73 amyloid‐β positive (CSF Aβ42/Aβ40<0.752) participants with MCI and mild AD dementia (MMSE ≥ 22) were assessed at baseline with cognitive testing, blood and cerebrospinal fluid (CSF)‐sampling, MRI and [18F]RO948 PET and were followed longitudinally with annual cognitive testing over 24 months. Slopes of change in MMSE and preclinical Alzheimer cognitive composite (PACC) were calculated over two years. We used linear regression models to assess the ability of biomarkers (plasma pTau217, CSF‐pTau217, temporal meta‐ROI [18F]RO948 PET standardized uptake value ratios (SUVR), CSF‐NfL and MRI “AD‐signature” cortical thickness) to predict cognitive decline both individually and in combination. The linear regression models were adjusted for age, sex, education, and baseline MMSE.ResultAll tested biomarkers individually showed significant associations with cognitive decline using both MMSE and PACC as outcome variables. For predicting longitudinal change in MMSE using individual biomarkers, [18F]RO948 SUVR showed the highest R2‐value (0.39, 95% CI [0.28‐0.67]) and best model fit (lowest Akaike Information Criterion score)(Table 1). Adding other biomarkers yielded a slightly higher R2‐value (0.44 [0.33‐0.63]), but did not improve the model fit. In a sensitivity analysis we performed a similar analysis in a subset of participants having undergone longitudinal testing with a modified PACC test battery (n=53). Results again showed the best performance for [18F]RO948 SUVRs, when tested alone, but with improved model fit and R2‐values with the addition of cortical thickness and CSF‐NfL data (Table 2).ConclusionTau‐PET imaging outperformed CSF, plasma and MRI measures when predicting cognitive decline in prodromal AD and mild AD dementia. Specifically, tau‐PET provided the best prediction alone for change in MMSE and in combination with NfL and cortical thickness for change in PACC, indicating that it would be a suitable biomarker for inclusion in clinical trials.

The association between obesity and Alzheimer's disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18F-flortaucipir PET, 18F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test-Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4. There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention.

Alzheimer's disease (AD) is a multifactorial disease including pre-clinical, prodromal and clinical phases. CSF "A/T/N" (Ab42, pTau181, tTau) biomarkers help characterize the biological state of AD. The primary aim was to assess contributions of eight CSF markers for predicting changes in cognition. CSF from 237 participants (CN: 176[74.3%], MCI: 33[13.9%], AD: 28[11.8%]) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing was used to measure Ab42 (GenII assay), pTau181, and tTau (Elecsys®) along with neurogranin, neurofilament light (NFL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells-2 (sTREM2), s100 calcium-binding protein B (s100B), and interleukin-6 (IL-6) from the NeuroToolKit (NTK) panel of exploratory prototype assays (all Roche Diagnostics International Ltd). NTK biomarker concentrations were measured amongst each of four ATN groups at baseline; 1) A-/T-/N- (reference group), 2) A+/T±/N± (amyloid+), 3) A-/T±/N± (amyloid-), and 4) A+/T+/N+. Change in cognition was assessed using the pre-clinical Alzheimer's cognitive composite (PACC) and the clinical dementia rating sum of boxes (CDR-SB) scores, in all four ATN groups, stratified by low/high NTK biomarker over a minimum of 36 months. The primary outcome was defined as change in cognition in amyloid+ participants modulated by the addition of NTK markers to ATN groups. A+/T+/N+ participants had faster cognitive decline on both PACC and CDR-SB over time compared to all other groups (Figure 1A, PACC; Figure 1B, CDR-SB). Within the amyloid+ group, participants with high sTREM2 (K+) had a faster rate of decline in PACC compared to those with low sTREM2 (K-, p = 0.04; Figure 1C), whilst participants with high α-synuclein had a faster increase in CDR-SB compared with those with low α-synuclein (p = 0.005; Figure 1D). Amongst participants who were A+/T+/N+, those with high YKL40 had a significantly faster rate of decline in PACC (p = 0.017; Figure 1E), and a faster increase in CDR-SB, (p = 0.017; Figure 1F) compared with those who with low YKL40. Biomarkers of microglial activation (sTREM2), synaptic function and synuclein metabolism (α-synuclein), and astrocytic activation (YKL-40) may be appropriate to discern rates of cognitive change within amyloid+ participants. Findings are being validated in a separate population.

BackgroundThe driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.MethodWe investigated 632 CU individuals (age 61.8±6.3, mean±SD) from the ALFA+, Wisconsin ADRC, and WRAP cohorts (Table 1), with available longitudinal MRI and cerebrospinal fluid biomarkers of Aß42/40, p‐tau181, neurogranin, NfL, total‐tau, a‐synuclein, GFAP, YKL‐40, sTREM2, s100B, and IL‐6 measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). We used non‐negative matrix factorization to decompose biomarkers into latent components. The per‐subject component weights were associated with voxel‐wise GM volume changes (years 3.5±0.9, mean±SD) and longitudinal performance on the preclinical Alzheimer's cognitive composite (PACC) using mixed model analysis.ResultSix biomarker components (C1‐C6) were identified (Figure 1). High expression of astrocyte biomarkers (C1) was related to GM volume increases in frontotemporal and subcortical regions, and faster cognitive decline in A+ individuals, while axonal damage with glial reactivity (C2) was associated with temporal atrophy. Microglial reactivity (C3) showed subtle associations with both increases and decreases in GM volume in different regions. A component primarily based on Aß pathology (C4) was strongly associated with widespread GM volume loss and faster cognitive decline. IL‐6 (C5) reflected non‐AD related inflammation. Finally, the co‐expression of tau pathology, neuronal injury, and synaptic damage (C6) showed robust associations with frontotemporal atrophy and cognitive decline in A+ individuals.ConclusionIn a large longitudinal sample, we provide in vivo evidence that in the earliest stages of AD, Aß pathology is also a strong contributor to future neuronal loss and cognitive decline besides neurofibrillary tangles and neuroaxonal damage. Astroglial reactivity (i.e. GFAP, s100B) in preclinical AD was associated with an increase in GM volume, which may suggest a neuroinflammatory response, and was associated with worse cognitive performance. These findings underscore the dynamic nature of structural brain changes within preclinical AD, shaped by the contributions from diverse pathophysiological processes.

Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses. Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

BackgroundPrevious cross‐sectional studies suggest that higher educational attainment (EA) may mitigate cognitive decline in Alzheimer’s disease (AD). This study systematically investigated the association between EA and longitudinal cognitive decline across various domains and explored its connections with β‐amyloid (Aβ) plaque, tau tangle, gray matter volume (GMV) and glucose metabolism in AD.MethodWe analyzed Aβ‐PET (A), tau‐PET (T), and 3D T1‐MRI images (N) from the ADNI cohort to identify 58 A+/T‐, 77 A+/T+, and 84 cognitively unimpaired (CU) participants without evidence of AD pathology and neurodegeneration (A‐/T‐/N‐/CU). All participants had longitudinal cognitive assessments covering the Preclinical Alzheimer Cognitive Composite (PACC), memory, executive function, language and visuospatial function. Additionally, a subset of 67 individuals had FDG‐PET images. Participants were divided into High‐Edu and Low‐Edu subgroups based on the median years of education of the whole cohort (16 years). Baseline and follow‐up cognitive measurements in various domains were compared between High‐Edu and Low‐Edu individuals. Furthermore, the association of EA, GMV, FDG, Aβ plaque, tau tangle, and cognitive changes were investigated.ResultSlower cognitive decline was specifically observed in PACC and language domains of the A+/T+ group among High‐Edu individuals compared to Low‐Edu individuals (Figure 1). The mediation analysis demonstrated that higher EA attenuated PACC decline through greater GMV in the middle temporal gyrus (MTG) and higher glucose metabolism in the left parahippocampal gyrus. Additionally, it mitigated language decline through greater GMV and glucose metabolism in the left inferior temporal gyrus. Furthermore, slower PACC and language decline in High‐Edu individuals was fully mediated through lower tau tangles in the MTG and left superior temporal gyrus (STG), rather than through an Aβ‐associated pathway (Figure 2). A four‐variable mediation analysis further confirmed that tau tangles and GMV in the MTG independently mediated the association between EA and PACC decline (Figure 3).ConclusionThese findings suggest that higher EA has a prominent protective effect in mitigating PACC and language decline among A+/T+ individuals. The protective effects of higher EA are mediated through the maintenance of greater GMV (or FDG) and lower tau tangles, and these pathways independently contribute to the attenuation of PACC and language decline.

To determine whether a digital clock-drawing test, DCTclock, improves upon standard cognitive assessments for discriminating diagnostic groups and for detecting biomarker evidence of amyloid and tau pathology in clinically normal older adults (CN). Participants from the Harvard Aging Brain Study and the PET laboratory at Massachusetts General Hospital were recruited to undergo the DCTclock, standard neuropsychological assessments including the Preclinical Alzheimer Cognitive Composite (PACC), and amyloid/tau PET imaging. Receiver operating curve analyses were used to assess diagnostic and biomarker discriminability. Logistic regression and partial correlations were used to assess DCTclock performance in relation to PACC and PET biomarkers. A total of 300 participants were studied. Among the 264 CN participants, 143 had amyloid and tau PET imaging (Clinical Dementia Rating [CDR] 0, Mini-Mental State Examination [MMSE] 28.9 ± 1.2). An additional 36 participants with a diagnosis of mild cognitive impairment or early Alzheimer dementia (CDR 0.5, MMSE 25.2 ± 3.9) were added to assess diagnostic discriminability. DCTclock showed excellent discrimination between diagnostic groups (area under the receiver operating characteristic curve 0.86). Among CN participants with biomarkers, the DCTclock summary score and spatial reasoning subscores were associated with greater amyloid and tau burden and showed better discrimination (Cohen d = 0.76) between Aβ± groups than the PACC (d = 0.30). DCTclock discriminates between diagnostic groups and improves upon traditional cognitive tests for detecting biomarkers of amyloid and tau pathology in CN older adults. The validation of such digitized measures has the potential of providing an efficient tool for detecting early cognitive changes along the AD trajectory. This study provides Class II evidence that DCTclock results were associated with amyloid and tau burden in CN older adults.

BackgroundPlasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice.ObjectivesTo evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD.DesignCross-sectional analyses from a prospective cohort.SettingA population-based study.ParticipantsVolunteers over 55 years without cognitive impairment or contraindications for complementary tests.MeasurementsPlasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-taul81, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A−/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor.ResultsWe screened 209 cognitively unimpaired volunteers with a mean age 64 years (60–69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=−0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85.ConclusionsPlasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.

Background Brainstem nuclei such as the locus coeruleus (LC) are amongst the earliest regions affected by tau pathology in Alzheimer's disease (AD). The LC's extensive noradrenergic projections shape brain network architecture and its structural integrity is associated with resilience against cognitive decline. However, the role of LC network connectivity in cognitive resilience remains unclear, as does its potential differential impact across distinct population subgroups who might specifically benefit from its augmentation. Methods We included 393 cognitively unimpaired Aβ+ individuals (centiloid &gt; 19) from the A4 study who underwent baseline resting‐state fMRI and florbetapir Aβ‐PET as well as longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) assessment. Pearsons's correlation coefficient was used to create maps of LC functional connectivity (LC‐FC) to 454 parcels of the Schaefer‐Tian parcellation which were harmonised across scanners using NeuroCombat. Mixed‐effects models with natural cubic splines (2 DOF) were used to test whether global, Yeo17 network, and individual parcel level LC‐FC moderated PACC decline over time as well as in interaction with centiloid, sex, and APOΕ4 status, controlling for age, education, framewise displacement, treatment, and sex (when not interacted). Analyses were deemed significant following Benjamini‐Hochberg false‐discovery rate correction for multiple comparisons. Results The LC showed widespread connectivity that was strongest within the limbic regions, hippocampus, and thalamus (Figure 1a). Greater global LC‐FC was associated with attenuated cognitive decline (Figure 1b, p = 0.014), especially at higher levels of Aβ (Figure 1c, p &lt;0.001). At the network level, LC‐FC resilience was predominantly related to task‐positive (control and dorsal/ventral attentional) networks, whilst in the default mode network greater LC‐FC was associated with reduced cognitive decline at lower Aβ (Figure 1b/c). The effect of LC‐FC on PACC decline was particularly pronounced in females at high Aβ levels (Figure 2b) and APOE‐e4 carriers (Figure 2c), demonstrating a synergistic effect of sex and genetic risk on LC‐mediated cognitive resilience (Figure 2d). Conclusions Our findings further support the role of the LC in cognitive resilience and suggest this particularly manifests from modulation of task‐positive attentional and frontoparietal control networks. Moreover, female e4‐carriers exhibit more pronounced attenuation of cognitive decline, suggesting they may especially benefit from augmentation of noradrenergic function.

Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aβ Status Groups in the A4 Study.

IntroductionAssessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. MethodsUnder the assumption that transformed versions of the Mini–Mental State Examination, the Clinical Dementia Rating Scale–Sum of Boxes, and the Alzheimer's Disease Assessment Scale–Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. ResultsOur results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini–Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale–Sum of Boxes and Alzheimer's Disease Assessment Scale–Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. ConclusionConsideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD.

BackgroundRise in plasma phospho‐tau (pTau) is hypothesized to reflect a physiological response to brain Aß plaques, preceding the formation of neurofibrillary tangles (NFT). An alternate explanation is poor sensitivity of tau PET for detection of early NFT formation. The tau tracer MK6240 has very low background “off‐target” binding and may better detect early tau aggregation. Choice of tau PET regions for analysis may also influence early detection of tau.MethodParticipants included 105 cognitively unimpaired (CU) and 178 cognitively impaired (CI), with plasma pTau217 Lumipulse® assay, 18F‐NAV4694 Aß PET and 18F‐MK6240 tau PET data. The entorhinal, amygdala and meta temporal (MT) ROI 18F‐MK6240 SUVR and pTau217 levels were modelled as a function of Centiloid (CL).ResultRise in plasma pTau217 slightly lagged the rise in amygdala MK6240 binding and paralleled the rise in the meta temporal ROI (Figure 1), consistent with our previous report using Janssen p217+Tau measured by Simoa®1. Our findings also suggest that amygdala and meta temporal ROI were more robust for early detection of aggregated tau than the entorhinal cortex possibly related to PART and small ROI volume producing wide variance in the entorhinal normal range in Ab‐ CU.ConclusionThis data suggests that the amygdala is a robust region for detecting early tau aggregation by MK6240 PET and that a rise in plasma pTau217 is associated with early formation of NFT rather than a direct physiological response to brain Aß plaques prior to NFT formation. Figure 1 legend: Modeling of 18F‐MK6240 quantification and pTau217 as a function of Centiloid. Biomarker values Z‐scored using the results from Aß‐ cognitively unimpaired to define the normal range for p217+tau level and each tau PET ROI SUVR. The horizontal line is +2 standard deviations (SD). 1Doré V, Doecke JD, …, Rowe CC. Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer’s continuum. Alzheimers Dement (Amst). 2022 Apr 5;14(1):e12307. https://doi.org/10.1002/dad2.12307. PMID: 35415202; PMCID: PMC8984092.

Existing positron emission tomography(PET) studies suggest that women exhibit greater regional tau burden than men, but the implications of this sex difference on cognitive trajectories remain elusive. We investigated sex differences on cognitive trajectories as a function of tau burden. Participants were 1009 clinically normal adults(mean age: 69.5; 363 APOEε4 carriers; Table 1) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial, the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study(A4/LEARN), the Harvard Aging Brain Study(HABS) and the Wisconsin Registry for Alzheimer's Prevention(WRAP), with at least one baseline tau-PET scan and one or more cognitive visits (mean (SD) =3.2(3.9) years, range=-9.9-11.1 years). Tau-PET imaging utilized Flortaucipir(FTP) in A4/LEARN and HABS, while MK-6240 was used in WRAP. Six Alzheimer's disease-related tau regions were selected for analysis: Entorhinal cortex, amygdala, parahippocampal gyrus, fusiform gyrus, inferior temporal and middle temporal gyri. Cognitive outcomes were measured using Preclinical Alzheimer's Cognitive Composite(PACC) scores. Random-effects regression models estimated the interaction between sex(male/female), regional tau(continuous), and PACC time(=PACC age - baseline tau-PET age) adjusting for baseline tau-PET age and education over time, including participant-specific intercepts and slopes. The three-way effects are summarized in the forest plot(Figure 1A) and visualized in model-predicted trajectories(Figure 1B, 1D for A4/LEARN and WRAP; Figure 1C for HABS). In A4/LEARN and WRAP, women with higher baseline amygdala and parahippocampal tau exhibited significantly faster cognitive decline compared to men, with additional effects observed in the entorhinal cortex for A4/LEARN. At low tau levels, women maintained higher PACC performance relative to men. In HABS, sex did not moderate the association between baseline tau and cognitive decline. Covarying for APOEε4-status and Aβ burden(Centiloid) did not attenuate existing sex effects. Among those with higher medial temporal tau, women exhibit faster cognitive decline compared to men. These findings suggest that early intervention with anti-tau therapies may be particularly important for women who exhibit medial temporal tauopathy. Future research should investigate sex differences in the spread of medial temporal tau to the neocortex, which may further elucidate faster cognitive decline among women.

Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial