Structured Abstract
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) 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 lifestyle intervention.
Design:
Ancillary study of participants enrolled in the 2-year, single-blind, multicenter randomized US POINTER clinical trial (2020–2025).
Setting:
Participants were enrolled into the POINTER Imaging study following a standard procedure at five clinical sites in the US.
Participants:
Participant eligibility criteria included age 60–79 years, sedentary lifestyle, and suboptimal diet, plus at least two additional risk criteria for cognitive decline and no contraindications for neuroimaging. 1,943 parent trial participants were assessed for eligibility, 1,305 were eligible, 1,060 consented, 1,052 were randomized and 983 underwent at least one MRI or PET scanning session.
Interventions:
Participants were randomly assigned to structured (STR; n = 516) or self-guided (SG; n = 467) interventions. 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 beta-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume and white matter hyperintensity (WMH) volume. The primary cognitive measure was a global cognitive composite.
Results:
In 983 participants (62% F; 68.4±5.24 years), there were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention arm 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 SG group that was attenuated in the STR group (difference in association: 0.289 [95% CI, 0.029–0.550], interaction p=0.03). Lower baseline HC volume was associated with greater cognitive benefit for STR over SG (lower HC: 0.077 SD [95% CI, 0.022–0.132]; higher HC: 0.002 SD [95% CI, −0.037–0.041]; interaction p=0.03).
Conclusion and Relevance:
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.
The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (US POINTER) study was a two-year randomized controlled trial that evaluated the cognitive effects of two multidomain lifestyle interventions of differing intensities in older adults without objective cognitive impairment but at increased risk for cognitive decline and dementia due to lifestyle factors, cardiovascular disease (CVD), and family history.1–3 A primary goal of the US POINTER trial was to demonstrate that an intervention modeled on the successful Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial4,5 could be adapted to a more diverse, US-based population. US POINTER was a successful trial reporting cognitive improvement in both intervention groups but a statistically greater benefit among participants randomized to the structured group.3 The POINTER Imaging ancillary study enrolled 50% of US POINTER parent trial participants. POINTER Imaging participants underwent serial MRI and beta amyloid (Aβ) and tau PET scanning during their two-year participation in US POINTER.6 Here, we follow the parent trial results with a report on the POINTER Imaging subsample and the primary MRI and PET outcome measures.
Clinical trials testing non-pharmacological interventions designed to prevent cognitive decline in older adults are increasingly utilizing neuroimaging approaches for risk stratification and to reveal mechanisms of intervention efficacy. POINTER Imaging was designed to do this by measuring well-established brain biomarkers of Alzheimer’s disease (AD), cerebrovascular disease and neurodegeneration.7 The 4 primary outcome variables (1 for each primary neuroimaging modality) of the POINTER Imaging study were global Aβ burden, medial temporal tau burden, hippocampal (HC) volume and white matter hyperintensity (WMH) volume.
The POINTER Imaging topline results presented here were focused on prespecified Primary and Secondary Aims (Supplement 2) testing whether 1) brain biomarker trajectories significantly differ by intervention arm (Primary Aim 1), 2) associations between change in brain biomarker measures and simultaneous change in cognition significantly differ by intervention arm (Primary Aim 2), and 3) prespecified baseline subgroups significantly affect intervention effects on cognition or imaging outcomes (Secondary Aims 3–5).
Methods
US POINTER Parent Trial
The US POINTER study design, baseline characteristics of enrolled participants and topline results are published.1–3 US POINTER was a phase 3, 5-site, 2-year, single-blind randomized controlled clinical trial of two multidomain lifestyle interventions: a higher intensity structured (STR) intervention arm and a lower intensity self-guided (SG) intervention arm. Participants in US POINTER were older adults (aged 60–79 at enrollment) and at risk for cognitive decline based on pre-established criteria.1–3
POINTER Imaging
Starting in August 2020, all newly enrolled US POINTER trial participants who met criteria (i.e., no contraindications for neuroimaging) were given the opportunity to enroll in POINTER Imaging.6 POINTER Imaging enrolled 1,052 (50% of) participants from the parent trial and baseline characteristics of this subsample, including comparisons to parent trial participants who did not enroll, have been previously published.6 The POINTER Imaging study protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively. POINTER Imaging participants underwent MRI scanning sessions at baseline, 12 months and 24 months post intervention initiation and Aβ-PET and tau-PET scanning sessions at baseline and 24 months.
Participant and Cognitive Outcome Measures
Age, sex, racial and ethnic identity, and years of education were collected via self-report. Five baseline subgroups explored by the parent trial and subsequently also included as prespecified subgroups in POINTER Imaging (Supplement 2) were analyzed: age, sex, APOEε4 status, prevalent cardiovascular disease (CVD)/Framingham Risk Score (FRS) and baseline cognitive status (BCS) (Table 1).3 Details on the definition of each of these subgroups can be found in Supplement 3 and the US POINTER parent trial topline results.3 Per parent trial protocol, participants underwent cognitive testing at baseline and every 6 months using the POINTER modified Neuropsychological Test Battery (PmNTB).1 A global cognitive composite score constructed from equally weighted domain composites of executive function, episodic memory, and processing speed (Supplement 3) was the prespecified primary cognitive outcome in these analyses.1–3
Table 1:
Baseline Cohort Characteristics by Intervention Arm
| Total (n=983) |
STR (n=516) |
SG (n=467) |
|
|---|---|---|---|
| Age (yrs) | 68.44 (±5.24) | 68.36 (±5.26) | 68.52 (±5.21) |
| Sex (% F) | 605 (62%) | 317 (61%) | 288 (62%) |
| Edu (yrs) | 15.92 (±2.26) | 16.02 (±2.26) | 15.81 (±2.25) |
| URG (% Yes) | 312 (32%) | 162 (31%) | 150 (32%) |
| Ethnoracial Group | |||
| White | 669 (68%) | 353 (69%) | 316 (68%) |
| Black | 143 (15%) | 75 (15%) | 68 (15%) |
| White (Hispanic) | 76 (8%) | 36 (7%) | 40 (9%) |
| Asian | 30 (3%) | 18 (4%) | 12 (3%) |
| Other | 63 (6%) | 33 (6%) | 30 (6%) |
| APOEε4 (% APOEε4+) | 290 (30%) | 143 (28%) | 147 (32%) |
| FRS/CVD group | |||
| Low | 232 (24%) | 116 (23%) | 116 (25%) |
| Medium | 307 (31%) | 157 (30%) | 150 (32%) |
| High | 283 (29%) | 145 (28%) | 138 (30%) |
| Prevalent CVD | 158 (16%) | 98 (19%) | 60 (13%) |
| BCS (% < median score) | 518 (53%) | 273 (53%) | 245 (53%) |
| MCI (%Y) | 57 (6%) | 27 (5%) | 30 (6%) |
| Global Aβ (CL) | 17.01 (±25.6) | 16.94 (±26.4) | 17.10 (±24.6) |
| Global Aβ Status (% +) | 271 (29%) | 128 (26%) | 143 (32%) |
| ERC Tau (SUVR) | 1.11 (±0.3) | 1.12 (±0.3) | 1.10 (±0.2) |
| ERC Tau Status (% +) | 130 (14%) | 68 (14%) | 62 (14%) |
| ERC Tau in Aβ+ (SUVR) | 1.26 (±0.41) | 1.33 (±0.50) | 1.19 (±0.30) |
| HC Vol. | 6.57 (±0.6) | 6.59 (±0.6) | 6.56 (±0.6) |
| HC Vol. Status (% HC N+) | 321 (33%) | 169 (34%) | 152 (33%) |
| WMH Vol. | 0.91 (±0.7) | 0.89 (±0.7) | 0.92 (±0.7) |
| WMH Status (% WMH+) | 320 (33%) | 169 (34%) | 151 (33%) |
Table values are shown as mean (standard deviation) or count (percent). STR=structured intervention arm; SG=self-guided intervention arm; yrs=years; Edu=education; URG=underrepresented groups; APOE ε 4=apolipoprotein e ε 4 allele; FRS=Framingham risk score; CVD=cardiovascular disease; BCS=baseline cognitive status; MCI=mild cognitive impairment; Aβ=beta amyloid; CL=centiloids; ERC=entorhinal cortex; HC=hippocampal; Vol.=volume; WMH=white matter hyperintensities. 1 STR and 1 SG participant elected to not self-report enthoracial group. Details on MCI adjudication can be found in Supplement 3. 3 SG participants did not have FRS information.
The single institutional review board (IRB) at Wake Forest University School of Medicine approved the US POINTER parent trial and the POINTER Imaging ancillary study with concurrence by local site IRBs. All participants provided written informed consent for both the parent trial and the Imaging ancillary study.
MRI Outcome Measures
The primary MRI outcomes were HC volume and WMH volume. Each MRI scanning session included a 3D T1 MPRAGE and 3D FLAIR. Detailed standardized acquisition parameters and image processing steps have been previously published.6 Briefly, HC volume was calculated from 3D T1 images using a multi-atlas approach8 and WMH volume was calculated using a Bayesian approach that combines 3D T1 and 3D FLAIR images.9 HC and WMH volumes were adjusted for intracranial volume (ICV) using a residual adjustment strategy.10 After further adjustment for age and sex, we generated tertiles for HC and WMH volumes and defined two at-risk groups: lowest tertile of HC volume (HC neurodegeneration+; HC N+) and highest tertile of WMH volume (WMH+).
PET Outcome Measures
The primary PET outcomes were global Aβ burden and tau burden in a key medial temporal region, the entorhinal cortex (ERC). Details of PET acquisitions and processing have been previously published.6 Briefly, florbetaben (FBB) and MK6240 images were intensity normalized using the whole cerebellum or inferior cerebellar gray, respectively.11 FreeSurfer parcellations were used to define ROIs for PET quantification12 MRI-free PET processing was used when an MRI was not available (Supplement 3). FBB global cortical standardized uptake value ratios (SUVRs) and global centiloids (CL) were calculated and participants were classified as Aβ+ with a global SUVR >1.08 (18 CL).11,13,14 MK6240 SUVR was calculated in FreeSurfer-defined ERC.15 The ERC tau positivity threshold was SUVR>1.293 (Supplement 3). Tau-PET SUVRs were log transformed before statistical analysis to address skewness and reduce the effect of outliers.
Adverse Events and Incidental Findings
All scans were reviewed by site clinicians and centrally by core imaging analysis teams to record adverse events (AEs) and promptly report clinically urgent incidental findings.6
Statistical Analysis
We followed an intent-to-treat approach by including all available applicable scans in each prespecified model. In addition to this approach, we completed a set of prespecified sensitivity analyses (Supplement 3) where applicable including 1) removing participants who had an MRI or PET scanner change and 2) removing the 10% worst out-of-window scans. Across all analyses, missing data were assumed to be missing at random. Two-tailed type I error was set at 0.05 with no multiple comparison correction. Statistical analyses were completed using Rv4.5.0.
Linear mixed effects models (LMEMs) were used to test for differences between intervention groups on longitudinal outcomes. Cognitive outcome models (Primary Aim 2, Secondary Aim 3) included time (coded as 0, 0.5, 1, 1.5, 2 and treated continuously), site, baseline age, and cognitive test version. Secondary Aim 3 analyses additionally included a counter for number of prior cognitive assessments (to adjust for practice effects), and a test session counter × age interaction as fixed effects in accordance with the parent trial topline results.3 Consistent with the parent trial, the cognitive assessments counter variable was not included as a covariate for Primary Aim 2 analyses (Supplement 2). Imaging outcome models (Primary Aim 1) included time since the baseline scan as a continuous measure and additional fixed effects of baseline age and a time-varying scanner variable. A random effect for participant intercept was also included for all models, while random slopes were included except in PET models for which there were a maximum of two observations per participant.
Differences in intervention effects on global cognition or imaging outcomes by baseline subgroups (demographic, genetic, clinical groups prespecified by the parent trial; imaging-based groups prespecified by POINTER Imaging) were assessed through a 3-way interaction term of baseline subgroup, intervention arm, and time in LMEMs (Secondary Aims 3–5). For the 4 imaging biomarkers, we also explored the 3-way interaction using continuous imaging data in place of the baseline subgroup.
Linear regression was used to test for an interaction between intervention arm and participant-specific imaging measure slope (change over time) predicting participant-specific global cognitive slope (Primary Aim 2): details on the estimation of participant-specific imaging and cognitive slopes are provided in Supplement 3.
Results
Participants
983 (516 STR, 467 SG) participants enrolled in the POINTER Imaging ancillary study and had at least 1 acquired scan (Figure 1). Participants enrolled in the Imaging ancillary study were more likely to be male and had greater cardiovascular risk than those not enrolled in Imaging.6 The characteristics of the overall sample and by intervention arm are presented in Table 1. Intervention arms were generally balanced across demographic, clinical and imaging measures except ERC tau in Aβ+ participants which was notably higher in STR compared to SG. Longitudinal slopes for imaging measures as well as cognitive composite scores did not differ by intervention arm (eTable 1).
Figure 1: POINTER Imaging Participant Flowchart.
The flow of participants related to POINTER Imaging following the standardized CONSORT diagram approach.
*159 people did not list a reason for non-interest, and multiple reasons for non-interest could be selected
^Five people were interested but not assessed for eligibility
**Most common other reasons were ‘implanted items’ 56, ‘dentures’ 45, and ‘claustrophobia’ 32
***Multiple reasons for non-interest could be selected
****Note that 172 participants that were eligible and interested in imaging were NOT eligible or NOT interested in the main trial
*****Did not come back for BL-b visit when randomization occurred
Adverse Events and Incidental Findings
Across all scanning sessions for MRI and PET, there were no severe AEs reported. There was a total of 4 procedure-related AEs (3 in STR, 1 in SG) and 94 non-urgent (46 STR, 48 SG) and 5 urgent (2 STR, 3 SG) incidental findings. Additional details on AEs and incidental findings can be found in eTable 2.
Intervention Arm Differences in Imaging Measure Trajectories (Primary Aim 1)
There were no significant intervention arm differences in change over time in our primary imaging variables (eTable 3, eFigure 1). Sensitivity analyses were consistent with these results (eTable 4). Subgroup analyses (Secondary Aims 4 & 5) revealed that imaging outcome trajectories were generally not significantly different by intervention arm even in specific subgroups related to baseline demographic, clinical and imaging characteristics, with just a few exceptions (eTables 5–8).
Intervention Arm Differences in Associations between Longitudinal Imaging and Cognitive Measures (Primary Aim 2)
We next tested whether there were intervention arm differences in the relationship between imaging measure change over time (slope) and global cognitive slope. The interaction between ERC tau slope and intervention arm was significant (0.289 [95% CI: 0.029–0.550]; p=0.03) such that the expected negative association between ERC tau accumulation and global cognition was attenuated in the STR group (eTable 9; Figure 2A). There was also a similar effect of HC volume slope such that the expected positive association between HC atrophy and global cognition was attenuated in the STR group, but this effect as not significant in models including all scans (p=0.07; eTable 9; Figure 2B). This effect was significant (p=0.02) in the no scanner change sensitivity analysis and p=0.05 in the reduced out-of-window scans sensitivity analysis (eTable 10). Other imaging measures did not show a significant intervention arm by imaging slope interaction effect on global cognitive trajectory and sensitivity analyses were consistent except where already noted.
Figure 2: Attenuated Relationships between Imaging Change and Cognitive Change in STR.
Relationships between A) entorhinal tau change (slope) or B) hippocampal volume change (slope) and global cognitive composite change (slope) by intervention arm. Global cognition slopes were generated with a linear mixed effects model (LMEM) with fixed independent effects of time, recruitment site, baseline age and test version and random participant intercepts and slopes. For entorhinal tau slope, where only 2 timepoints were available, we calculated annualized SUVR change between baseline and 24 months for each participant and included covariates for baseline scanner type, a binary variable indicating if there was a scanner change at follow-up and baseline age. For hippocampal volume slope, a LMEM was fit with fixed independent effects of time, scanner type (which could vary over time accounting for any scanner changes) and baseline age with random effects of participant intercept and slope. STR=structured intervention arm; SG=self-guided intervention arm; ERC=entorhinal cortex; HC=hippocampal.
Intervention Arm Differences in Associations between Baseline Imaging Measures and Cognitive Trajectories (Secondary Aim 3)
Individuals with lower baseline HC volume (HC N+) benefited more from the STR intervention over SG compared to individuals with higher baseline HC volume (HC N+: 0.077 SD [95% CI, 0.022–0.132]; HC N-: 0.002 SD [95% CI, −0.037–0.041]; p=0.03 for interaction; Figure 3). There was also a effect suggesting WMH+ individuals may benefit more from the STR intervention, but it did not meet statistical significance (WMH+: 0.056 SD [95% CI, 0.000–0.111]; p=0.05). The intervention group differences on global cognition did not significantly differ by Aβ or ERC tau status. In a sensitivity analysis, results were consistent except the WMH+ group effect was significant (p=0.04) while the interaction remained not significant (p=0.15; eTable 11).
Figure 3: Intervention Arm Differences in Associations between Baseline Imaging Measures and Global Cognitive Trajectory.
Changes per year in adjusted global cognitive composite z scores (SDs) for prespecified imaging subgroups by intervention group assignment and differences between groups after adjustment for site, baseline age, count of cognitive testing sessions, and test version. The p-values compare intervention arm changes over time within a subgroup level. The p-value interaction tests the interaction across subgroup levels by intervention group assignment. P-values are not adjusted for multiple comparisons. STR=structured intervention arm; SD=standard deviation; CI=confidence interval; SG=self-guided intervention arm; Aβ=beta amyloid; ERC=entorhinal cortex; HC=hippocampal; Vol.=volume; Neurodegen.=neurodegeneration; WMH=white matter hyperintensities.
Using continuous imaging measures, the expected association between lower baseline HC volume and worse global cognitive trajectory was attenuated in the STR group compared to SG (interaction p=0.02; Figure 4A; eTable 12). A similar but non-significant effect was also observed for WMH volume such that the expected association between higher WMH volume and worse global cognitive trajectory was attenuated in the STR group (interaction p=0.11, p=0.08 in sensitivity analysis; Figure 4B; eTable 12). Neither baseline global Aβ burden nor baseline ERC tau burden interacted with intervention arm to predict global cognitive trajectory (eTable 12). These findings were consistent in sensitivity analyses (eTable 12).
Figure 4: Moderating Effects of Baseline Continuous Imaging Measures on Intervention Response.
Associations between A) baseline hippocampal volume or B) baseline white matter hyperintensities volume and global cognitive composite change (slope) by intervention arm group adjusted by site, baseline age, test version, number of cognitive assessments and a number of cognitive assessments × age interaction. STR=structured intervention arm; SG=self-guided intervention arm; Bl.=baseline; HC=hippocampal; WMH=white matter hyperintensities
Parent Trial Results in the POINTER Imaging Subsample
The US POINTER parent trial reported that participants randomized to the STR intervention arm had significantly more global cognitive improvement over 2 years compared to the SG arm and that this effect was similar across pre-specified subgroups.3 We repeated parent trial analyses in the POINTER Imaging subsample and found that effect sizes and directions were largely consistent but findings were not statistically significant due to a reduction in sample size of more than 50% (eTable 13, eFigure 2).
Discussion
The POINTER Imaging ancillary study showed that brain biomarker trajectories were not significantly affected by intervention arm, and intervention arm effects on cognition were not associated with or moderated by Aβ burden. While observational studies have frequently reported that individuals with lower-risk brain characteristics have better cognitive trajectories compared to those with higher-risk characteristics16–19, the STR intervention reversed this effect, showing the greatest cognitive benefit among those with specific higher-risk brain characteristics. In particular, individuals with lower HC volume at baseline and more medial temporal lobe tau accumulation showed a significantly greater cognitive benefit from the STR compared to SG multidomain lifestyle intervention. In these at-risk individuals, the high-intensity, more rigorous STR intervention supported better-than-expected cognitive performance compared to similar at-risk individuals in the SG arm, suggesting the STR intervention was associated with greater cognitive reserve, as defined as a variable that moderates the effect between a brain insult and cognition.20,21
A topic of great interest to stakeholders involved in testing and implementing lifestyle interventions in older adults is whether their non-pharmacologic strategies have primary effects on the brain.5,22–24 We did not observe intervention effects on any brain imaging biomarker change over time. This may have been due to lack of influence of the STR intervention on the specific biomarkers we selected, a similar influence of both interventions on the outcomes, lack of power to observe brain changes underlying the STR effects, or the STR>SG baseline difference in tau among Aβ+ individuals, indicating that the STR group was more progressed on AD biomarkers prior to the start of the intervention. Another explanation is that the 2-year imaging follow-up time which occurred contemporaneously to the administration of the intervention may have been too proximal and too short to detect changes in brain biomarkers that might be revealed with longer follow-up, particularly because the intervention included a 5-month ramp-up period.1
Individuals in the STR arm with lower baseline HC volume and higher rate of atrophy showed disproportionate cognitive improvement. The 0.077 SD STR vs SG difference in global cognitive trajectories in the HC N+ group is 2.7x larger than the STR vs SG effect size in global cognitive trajectories reported in the parent trial (0.029 SD). Our interpretation is that the STR intervention enhanced global cognitive reserve in specific at-risk groups, including those with lower HC volume. Further, there was evidence, supported by sensitivity analyses, that among individuals with higher WMH volume, the STR intervention was more beneficial compared to SG. Our findings suggest that relatively standard MRI-based cross-sectional biomarkers, HC and WMH volumes, could be used to stratify people into lifestyle interventions with those at-risk requiring more support.
Baseline AD biomarkers (PET measures of Aβ and tau) did not significantly predict intervention response, and Aβ status was not an important moderator in any of our primary analyses. This is a critical finding that suggests that effects of the intervention did not differ in individuals with and without evidence of AD7, and that supports future approaches where AD-modifying therapies25 and lifestyle interventions could be combined to maximally protect against cognitive decline. The association between ERC tau accumulation and cognitive change significantly differed by intervention arm, when we explicitly adjusted for baseline ERC tau. In models where baseline ERC tau was a primary predictor, it is likely that the notable difference in baseline AD-related ERC tau across intervention arms influenced our results. Another factor may be the relatively lower cognitive variance explained by tau biomarkers in POINTER participants, recruited using a community engagement strategy, compared to a matched cohort of ADNI participants recruited primarily from memory clinics.26 Given these factors, we believe our reported findings with ERC tau are likely to be conservative.
Limitations
The POINTER Imaging study had several limitations. First, the parent trial topline finding of a global cognitive benefit of the STR intervention did not replicate in the POINTER Imaging ancillary study subsample (n=983) making the STR-related cognitive benefits we identified more difficult to interpret. Second, a 2-year follow-up time may not be sufficient for detecting intervention effects on brain biomarker changes. Third, our significant prespecified findings would not survive correction for multiple comparisons and require replication. Fourth, AD-related ERC tau was meaningfully higher in the STR arm compared to SG at baseline, presenting a challenge in the prespecified tau analyses. Finally, generalizability may be limited by the recruitment sites, selective enrollment criteria and participant willingness to complete time-intensive intervention and undergo serial MRI and PET scanning sessions.
Conclusions
The POINTER Imaging study successfully collected and measured brain biomarkers of AD, cerebrovascular disease and neurodegeneration in participants enrolled in a multidomain lifestyle intervention clinical trial to delay or prevent cognitive decline. There were no primary effects of the intervention on brain biomarker changes over the course of the 2-year study. Specific brain characteristics generally related to worse cognitive performance -- lower HC volume at baseline, greater HC atrophy, higher WMH volume at baseline and greater medial temporal tau accumulation -- were associated with a benefit of the STR intervention compared to SG. These findings are congruent with the parent trial subgroup findings which also showed that an at-risk group, those with lower baseline global cognitive performance, significantly benefitted from the STR intervention. Further work and longitudinal follow-up will further define profiles of older adults who require differing levels of intervention support and intensity to avoid cognitive decline.
Supplementary Material
Key Points.
Question:
How does a structured, high-intensity multidomain lifestyle intervention affect brain imaging biomarkers of Alzheimer’s disease (AD), cerebrovascular disease and neurodegeneration or their associations with global cognition, and do relationships differ by specific subgroups?
Findings:
In 983 participants, the structured (vs. self-guided) multidomain intervention was not associated with simultaneous change in brain imaging biomarkers, but was associated with better-than-expected cognitive outcomes in older adults with certain brain imaging characteristics that confer risk for cognitive decline, including lower hippocampal volume and greater medial temporal tau accumulation over time.
Meaning:
A multidomain lifestyle intervention did not affect brain imaging biomarker trajectories. Certain at-risk, but non-AD specific brain imaging characteristics predicted greater cognitive benefit from the more intensive, structured intervention compared to self-guided.
Conflict of Interest Disclosures
TMH reports grants from the National Institutes of Health (NIH). DJH is on the Statistical Advisory Board for PLOS One has served as a consultant for NervGen Pharma Corp and received grants from the NIH. SNL is a full-time employee at Perceptive Inc. but was an employee of Wake Forest University at the time of this work. AWT is on the advisory board of the San Antonio ADRC and receives grants from the NIH Fox Foundation and the Alzheimer’s Association. WJJ has served as a consultant to Lilly and has grants from NIH. RAW reports grants from the NIH. HMS and MCC are full-time employees of the Alzheimer’s Association. MAE reported receipt of grants from the NIH and personal fees from Annovis Bio, Acumen Pharma, and Nestlé. CD has served as a consultant to Eisai and Novo Nordisk outside the submitted work. SM Landau is on advisory boards for KeifeRX and the NIH IPAT study, has consulted for Banner Health, is on the Editorial Board for JAMA Neurology, has received speaking honoraria from Eisai, Johnson & Johnson, and the Alzheimer’s Therapeutic Research Institute, and has grants from NIH. TC, YC, JT, PM, LL, STF, KVP, RAK, YJ, LDB and PV have no conflicts to report.
Funding/Support
This study was supported by the National Institute on Aging (R01 AG062689) and the Alzheimer’s Association (POINTER-19-611541).
Role of the Funders/Sponsors
The National Institute on Aging (NIA) funded the POINTER Imaging study as an ancillary study of the US POINTER parent trial, but had no role in study design, conduct, nor collection, management, and analysis and interpretation of the data. The NIA had no role in preparation, review or approval of this manuscript. The US POINTER parent trial was conceived and developed in partnership with the Alzheimer’s Association. Drs. Snyder and Carrillo, full-time employees of the Alzheimer’s Association, participated in the design and conduct of the parent trial; collection, management, analysis, and interpretation of the data as well as review and approval of the parent trial manuscript. For the current manuscript, Drs. Snyder and Carrillo are co-authors whose contributions can be found in the Author Contributions section.
Additional Contributions
We thank the US POINTER parent trial participants, especially those who co-enrolled in the POINTER Imaging ancillary study, and their study partners. We would also like to acknowledge the many contributions of the POINTER Imaging investigators and staff across institutions (eAppendix 2 in Supplement 3).
Footnotes
US POINTER Parent Trial Registration:
ClinicalTrials.gov Identifier: NCT03688126
Data Sharing Statement
Data from the US POINTER main trial and the POINTER Imaging ancillary study will be shared with qualified investigators once primary analyses are complete. Publicly available neuroimaging data will be accessible via the Laboratory of Neuroimaging (LONI; https://ida.loni.usc.edu) by any qualified investigator that has formally agreed to the POINTER Imaging Data Use Agreement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data from the US POINTER main trial and the POINTER Imaging ancillary study will be shared with qualified investigators once primary analyses are complete. Publicly available neuroimaging data will be accessible via the Laboratory of Neuroimaging (LONI; https://ida.loni.usc.edu) by any qualified investigator that has formally agreed to the POINTER Imaging Data Use Agreement.