DeCarli, Charles

Importance Multidomain lifestyle interventions slow cognitive decline in at-risk older adults, but effects on cerebrovascular injury and whether any effect differs by age or across magnetic resonance imaging (MRI) markers remain unclear. Objectives To test whether a structured multidomain lifestyle intervention, vs a self-guided program, alters trajectories of cerebrovascular MRI markers and whether baseline diffusion MRI estimates subsequent vascular injury. Design, Setting, and Participants POINTER Imaging was a prespecified secondary imaging analysis of the US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) randomized clinical trial conducted at multiple US sites. Starting August 1, 2020, and continuing until March 1, 2023, all newly enrolled US POINTER trial participants who met criteria, including being 60 to 79 years of age and at increased risk for cognitive decline, were given the opportunity to enroll in POINTER Imaging. Annual MRIs were performed at baseline and up to 2 follow-up visits at 12 and 24 months. The imaging study ended May 14, 2025. Interventions Structured multidomain lifestyle arm (supervised exercise, dietary counseling, cognitive and social engagement, and health coaching) vs self-guided educational arm. Main Outcomes and Measures Primary outcomes were cerebrovascular MRI markers of global white matter free water (FW), fractional anisotropy (FA), peak width of skeletonized mean diffusivity (PSMD), analysis along the perivascular space (ALPS) index, white matter hyperintensity (WMH) volume, and incident cerebral microbleeds (CMBs). Age-group analyses (<70 vs ≥70 years) were prespecified. Linear mixed-effects models tested time, intervention arm, age group, and interactions for continuous outcomes; logistic regression evaluated incident CMBs. All analyses were adjusted for sex, hypertension, diabetes, and smoking and were conducted for the evaluable population. Data were analyzed September 5 to December 11, 2025. Results For 959 participants included in the analysis, the mean (SD) age was 68 (5) years, and 594 (61.9%) were female. A significant time × arm × age group interaction was observed for FW (β = 0.050; SE = 0.018; P = .006). In participants younger than 70 years, the structured intervention, compared with the self-guided intervention, attenuated the FW increase over time (β = −0.031; SE = 0.012; P = .009); no intervention arm difference was observed in participants aged 70 years or older (β = 0.019; SE = 0.014; P = .18). No intervention-related interactions were detected (eg, time × intervention arm interaction) for WMH (β = 0.002; SE = 0.016; P = .90), FA (β = 0.016; SE = 0.016; P = .30), PSMD (β = −0.011; SE = 0.021; P = .60), or ALPS (β = 0.006; SE = 0.021; P = .79). Overall, greater odds of incident CMBs were associated with higher baseline FW (odds ratio, 1.63 [95% CI, 1.24-2.14]; P < .001) and PSMD (odds ratio, 1.40 [95% CI, 1.08-1.81]; P < .001). Greater WMH progression was associated with higher baseline FW (β = 0.014; SE = 0.006; P = .02) and lower baseline FA (β = −0.018; SE = 0.006; P = .004). Conclusions and Relevance In this secondary imaging analysis of a randomized clinical trial, FW was the cerebrovascular MRI marker most responsive to lifestyle intervention in adults 60 to 70 years of age, showing attenuated small-vessel disease–related injury. Findings suggested greater microvascular benefit when intensive lifestyle intervention is implemented earlier in late life. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

Abstract Background Extensive evidence links cognition, tau, and neurodegeneration in Alzheimer's disease (AD). However, in U.S. POINTER imaging (a community‐recruited clinical trial cohort selected for high cardiovascular risk, ethnoracial diversity, and increased risk of cognitive decline and dementia) tau PET is more closely linked to cognition than in ADNI. Here, we further explore how ADNI and POINTER differ with respect to relationships between cross‐sectional AD biomarkers, cortical thickness, and different cognitive domains. Method U.S. POINTER imaging (Baseline; N = 775; 68.9±5.2 years, 62.8% female) and ADNI ( N = 405; 69.9±5.4 years, 58% female) were matched by age, sex, clinical status, and APOE4 genotype (Table 1). We examined associations between baseline AD biomarkers (Amyloid‐beta (Aβ) PET in centiloids, harmonized tau PET measures of MK6240 in POINTER and FTP in ADNI), regional cortical thickness, and verbal memory (Delayed Story Recall), executive function (Trail‐Making B), and global cognition (Preclinical Alzheimer's Cognitive Composite scores) across each cohort, controlling for age, sex, and education. Result Aβ burden in ADNI was associated with worse executive function ( p < .001) and global cognition ( p < .001) but not memory, whereas in POINTER Aβ burden was not associated with any cognitive domain (Figure 1A). Among Aβ+ individuals, tau burden was associated with poorer performance across domains in ADNI, but only with poorer verbal memory in POINTER (Figures 1B&1C). Additionally, there were stronger positive associations between cortical thickness and executive function and global cognition compared to verbal memory, particularly in ADNI Aβ+ individuals even after adjusting for entorhinal tau ( p < .01; Figure 2). Conclusion Cognitive performance was linked to all biomarkers (Aβ, tau, cortical thickness) but these associations were consistently stronger in ADNI compared to POINTER, particularly in Aβ+ individuals. The stronger thickness‐cognition relationships in ADNI were not driven by tau, indicating that there is a tau‐independent role of thickness in explaining cognition. In ADNI, there were subtle differences between cognitive domains such that executive function was more closely linked than verbal memory to Aβ and cortical thickness, whereas verbal memory was linked to tau in both cohorts. Our study highlights that frequently‐reported AD biomarker associations may be attenuated in heterogeneous, community‐recruited cohorts.

Abstract Background Our objective is to examine the generalizability of the relationships between four MRI markers of CVD: DTI‐derived free water (FW), fractional anisotropy (FA), perivascular space (PVS) and white matter hyperintensities (WMH) volume, with vascular risk factors (VRF) and cognition in the baseline POINTER Imaging and Framingham Heart Study (FHS) cohorts. Method We studied 907 U.S. POINTER and 797 FHS Offspring participants with available baseline demographic, clinical and imaging data (Table 1). Continuous FW, FA, WMH (log‐transformed) and PVS measurements were regressed against total cranial volume (TCV). Cognitive outcomes included a Global Cognitive Composite and executive function composite score for POINTER and FHS. For each MRI marker, we used linear and logistic regressions to assess the effect of age, sex, hypertension, diabetes and smoking status, adjusting for ethnicity. We then assessed, for each cognitive outcome, the individual effect of MRI markers using separate linear regressions adjusted for demographic and clinical factors, as well as TCV‐adjusted gray matter volume to control for atrophy. Result POINTER and FHS differed across most demographic and biomarker characteristics (Table 1). Despite these differences, there were similar associations between demographic and VRF and the 4 MRI vascular markers in POINTER and FHS (Figure 1): increased age was associated with worse outcomes for the 4 markers, hypertension was associated with increased FW, PVS and lower FA, diabetes was associated with increased FW only, smoking status did not impact any of the four markers. Only exception was that female had lower FW and increased WMH in POINTER and increased PVS in FHS. Associations between CVD measures and cognition were also similar across cohorts: reduced cognitive performance was significantly associated with both decreased FA and increased FW (Figure 2), but not with WMH nor PVS. Conclusion Our study explores four imaging markers representing diverse mechanisms by which CVD could impact brain structure and function in the POINTER and FHS studies. Despite differences in cohort characteristics, we found mostly consistent CVD relationships with demographic, VRF, and cognitive measures between cohorts which supports the generalizability of the relation of these markers with VRF and cognition identified in the POINTER cohort.

Abstract Background Given low representation of diverse populations in Alzheimer's disease (AD) research, it remains unclear if AD biomarker relationships observed primarily in non‐Hispanic White (NHW) cohorts generalize to other groups. Here we evaluate associations between key AD biomarkers and cognitive performance among cognitively unimpaired non‐Hispanic Blck (NHB) and NHW participants across 2 cohorts with unique sample characteristics. Method Participants included cognitively unimpaired NHB and NHW participants with Aβ and tau PET in ADNI (69 NHB, 402 NHW) and POINTER Imaging (135 NHB, 637 NHW). We examined harmonized measures of global Aβ (in centiloids), entorhinal cortex (EC) tau (quantified with MK6240 in POINTER and FTP in ADNI) and Preclinical Alzheimer's Cognitive Composite (PACC) scores. Regression models within each ethnoracial group evaluated relationships between 1) Aβ and EC tau, and 2) EC tau and PACC performance. Interaction models within each cohort were also conducted to assess differences in these associations by ethnoracial group. All models were adjusted for age and gender. Models with PACC additionally adjusted for education. Result In US POINTER, NHBs had lower Aβ and EC tau burden compared to NHWs (Table 1). In ADNI, there was no difference in EC tau between groups, and no differenence in Aβ after adjusting for age and gender. In US POINTER, the positive Aβ‐EC tau relationship was observed in both ethnoracial groups whereas in ADNI, Aβ was associated with higher EC tau in the NHW but not the NHB group. In both cohorts, EC tau was associated with worse PACC performance in both NHB and NHW and there were no differences in this association by ethnoracial group in interaction models (Figure 1). Conclusion NHBs had lower Aβ and EC tau than NHWs in POINTER but not ADNI, and there were inconsistent associations between Aβ and EC tau across cohorts. Despite these differences, AD biomarkers appear similarly related to cognitive outcomes across ethnoracial groups in both cohorts. Future analyses will attempt to further determine the generalizability of AD biomarker relationships in diverse samples by considering matching on relevant health and demographic characteristics, and inclusion of additional cohorts with harmonized biomarker and cognitive measurements.

AbstractBackgroundThere is limited information on biomarker‐defined Alzheimer’s disease (AD) pathology in community‐recruited individuals of diverse racial and ethnic groups. Here, we assessed the association of race/ethnicity with baseline biomarkers and cognitive measures and hypothesized a lower impact of AD pathology in non‐Hispanic White (nHW) participants in the U.S. POINTER study clinical trial, which evaluates the benefits of a multidomain lifestyle intervention on cognition of community‐recruited at‐risk elderly individuals.MethodWe included 879 participants from the U.S. POINTER study enrolled in the imaging substudy (∼50% of participants) who self‐identified as nHW (n=644), African American/Black (AA/B, n=132), Asian (n=29), and Hispanic (n=74). Outcomes measures included global Aβ pathology (18F‐florbetaben), temporal meta‐ROI tau (18F‐MK‐6240), MRI‐measured white matter hyperintensity volume (WMH) volumes, global clinical dementia rating (gCDR), and global, executive, and memory standardized cognitive scores. The nHW participants were selected as reference. Power transformations normalized skewed distributions. Multivariable linear regressions include age, sex, education, Framingham risk score, and area deprivation index (ADI) as covariates.ResultAA/B harbored lower WMHs, and meta‐temporal tau ROI values. In the full model, 0.5 gCDR participants had higher centiloid values, were more likely to be AA/B and Hispanic, and had a greater burden of WMHs. In addition, higher centiloid values were associated with a 0.5 gCDR in all groups except for the AA/B participants. Hispanic, AA/B, and Asian participants had lower cognitive scores than the nHW group. A higher ADI score was associated with lower global and executive cognitive scores but not with WMH volume or Aβ centiloid score.ConclusionThe analyses of the community‐based U.S. POINTER indicate that AA/B individuals present differences in AD and related dementia biomarker values. nHW had higher fully adjusted cognitive scores. These results indicate a significant heterogeneity in the cognitive testing performance and biomarker values of individuals at risk for dementia in the community.

AbstractBackgroundThe Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks.MethodWe applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs.ResultModel fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91).ConclusionThe harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E ( APOE ) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E ( APOE ) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory