Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI Metrics in Cognitive Decline.

BACKGROUND: Advanced diffusion-based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline. PURPOSE: To assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups. STUDY TYPE: Prospective/longitudinal. POPULATION: Twelve CI patients (75% female) and 13 HC subjects (69% female). FIELD STRENGTH/SEQUENCE: 3 T; Spin-Echo-IVIM-DWI. ASSESSMENT: Two MRI scans were performed with a 12-month interval. ADC and IVIM-DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel-based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters. STATISTICAL TESTS: Analysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial-η2 and Hedges' g were used for effect-size analysis. Spearman's correlations (FDR corrected) were used for the relationship between ΔMoCA score and imaging. P < 0.05 was considered statistically significant. RESULTS: Significant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM-D, and IVIM-f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08. 10-3 vs. 1.09 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.82 ± 0.01. 10-3 vs. 0.73 ± 0.01. 10-3  mm2 /sec; and IVIM-f: 0.317 ± 0.008 vs. 0.253 ± 0.009). Significantly higher ADC, IVIM-D, and IVIM-f values were observed in the CI group after 12 months (ADC: 1.45 ± 0.05. 10-3 vs. 1.50 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.87 ± 0.01. 10-3 vs. 0.94 ± 0.02. 10-3  mm2 /sec; and IVIM-f: 0.303 ± 0.007 vs. 0.332 ± 0.008), but not in the HC group at large effect size. ADC, IVIM-D, and IVIM-f negatively correlated with ΔMoCA score (ρ = -0.49, -0.51, and -0.50, respectively). DATA CONCLUSION: These findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM-based metrics. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Mapping autonomic, mood and cognitive effects of hypothalamic region deep brain stimulation.

Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied-at multiple international centres-58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation-including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear-were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.

Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease.

INTRODUCTION: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. METHODS: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients' implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning-based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. RESULTS: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. DISCUSSION: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.

Preliminary Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI (IVIM-DWI) Metrics in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects aging populations. Current MRI techniques are often limited in their sensitivity to underlying neuropathological changes. PURPOSE: To characterize differences in voxel-based morphometry (VBM), apparent diffusion coefficient (ADC), and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) metrics in aging populations. Additionally, to investigate the connection between cognitive assessments and neuroimaging metrics. STUDY TYPE: Prospective/cross-sectional. POPULATION: In all, 49 subjects, including 13 with AD dementia, 12 with mild cognitive impairment (MCI), and 24 healthy controls (HC). FIELD STRENGTH/SEQUENCE: 3T/magnetization-prepared rapid acquisition gradient echo (MP-RAGE) and IVIM-DWI ASSESSMENT: All participants completed a cognitive screening battery prior to MRI. IVIM-DWI maps (pure diffusion coefficient [D], pseudodiffusion coefficient [D*], and perfusion fraction [f]) were generated from a biexponential fit of diffusion MRI data. VBM was performed on the standard T1 -weighted MP-RAGE structural images. Group-wise templates were used to compare across groups. STATISTICAL TESTS: Analysis of covariance (ANCOVA) with gender and age as covariates (familywise error [FWE] corrected, post-hoc comparisons using Bonferroni correction) for group comparisons. Partial-η2 and Hedges' g were used for effect-size analysis. Spearman's correlations (false discovery rate [FDR]-corrected) for the relationship between cognitive scores and imaging. RESULTS: Clusters of significant group-wise differences were found mainly in the temporal lobe, hippocampus, and amygdala using all VBM and IVIM methods (P < 0.05 FWE). While VBM showed significant changes between MCI and AD groups and between HC and AD groups, no significant clusters were observed between HC and MCI using VBM. ADC and IVIM-D demonstrated significant changes, at P < 0.05 FWE, between HC and MCI, notably in the amygdala and hippocampus. Several voxel-based correlations were observed between neuroimaging metrics and cognitive tests within the cognitively impaired groups (P < 0.05 FDR). DATA CONCLUSION: These findings suggest that IVIM-DWI metrics may be earlier biomarkers for AD-related changes than VBM. The use of these techniques may provide novel insight into subvoxel neurodegenerative processes. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2 J. MAGN. RESON. IMAGING 2020;52:1811-1826.

Added value and limitations of amyloid-PET imaging: review and analysis of selected cases of mild cognitive impairment and dementia.

Amyloid-positron emission tomography (PET) imaging of the brain detects elevated amyloid-beta (amyloid-ß) neuritic plaques in vivo, which can be helpful in appropriately selected cases of mild cognitive impairment (MCI) and dementia, when Alzheimer's disease remains a possible etiology, after a comprehensive clinical evaluation. We reviewed cases of cognitively impaired patients who underwent amyloid-PET imaging because of diagnostic uncertainty. Pre- and post-PET elements of diagnosis and management were first compared, to assess impact of scan results on clinical decision-making, and then an analysis of those decisions was undertaken in appropriate clinical situations, to delineate the added value and limitations of amyloid-PET imaging. The potential benefits and limitations of this diagnostic tool are important to understand in an era when the utility of such scans in clinical practice is evolving.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

The landscape of fear: the missing link to understand top-down and bottom-up controls of prey abundance?

Identifying factors that may be responsible for regulating the size of animal populations is a cornerstone in understanding population ecology. The main factors that are thought to influence population size are either resources (bottom-up), or predation (top-down), or interspecific competition (parallel). However, there are highly variable and often contradictory results regarding their relative strengths and influence. These varied results are often interpreted as indicating "shifting control" among the three main factors, or a complex, nonlinear relationship among environmental variables, resource availability, predation, and competition. We argue here that there is a "missing link" in our understanding of predator-prey dynamics. We explore whether the landscape-of-fear model can help us clarify the inconsistencies and increase our understanding of the roles, extent, and possible interactions of top-down, bottom-up, and parallel factors on prey population abundance. We propose two main predictions derived from the landscape-of-fear model: (1) for a single species, we suggest that as the makeup of the landscape of fear changes from relatively safe to relatively risky, bottom-up impacts switch from strong to weak as top-down impacts go from weak to strong; (2) for two or more species, interspecific competitive interactions produce various combinations of bottom-up, top-down, and parallel impacts depending on the dominant competing species and whether the landscapes of fear are shared or distinctive among competing species. We contend that these predictions could successfully explain many of the complex and contradictory results of current research. We test some of these predictions based on long-term data for small mammals from the Chihuahuan Desert in the United States, and Mexico. We conclude that the landscape-of-fear model does provide reasonable explanations for many of the reported studies and should be tested further to better understand the effects of bottom-up, top-down, and parallel factors on population dynamics.

White Matter Microstructure Analysis in Subjective Memory Complaints and Cognitive Impairment: Insights from Diffusion Kurtosis Imaging and Free-Water DTI.

Background: Dementia is characterized by a cognitive decline in memory and other domains that lead to functional impairments. As people age, subjective memory complaints (SMC) become common, where individuals perceive cognitive decline without objective deficits on assessments. SMC can be an early sign and may precede amnestic mild cognitive impairment (MCI), which frequently advances to Alzheimer's disease (AD). Objective: This study aims to investigate white matter microstructure in individuals with SMC, in cognitively impaired (CI) cohorts, and in cognitively normal individuals using diffusion kurtosis imaging (DKI) and free water imaging (FWI). The study also explores voxel-based correlations between DKI/FWI metrics and cognitive scores to understand the relationship between brain microstructure and cognitive function. Methods: Twelve healthy controls (HCs), ten individuals with SMC, and eleven CI individuals (MCI or AD) were enrolled in this study. All participants underwent MRI 3T scan and the BNI Screen (BNIS) for Higher Cerebral Functions. Results: The mean kurtosis tensor and anisotropy of the kurtosis tensor showed significant differences across the three groups, indicating altered white matter microstructure in CI and SMC individuals. The free water volume fraction (f) also revealed group differences, suggesting changes in extracellular water content. Notably, these metrics effectively discriminated between the CI and HC/SMC groups. Additionally, correlations between imaging metrics and BNIS scores were found for CI and SMC groups. Conclusions: These imaging metrics hold promise in discriminating between individuals with CI and SMC. The observed differences indicate their potential as sensitive and specific biomarkers for early detection and differentiation of cognitive decline.

Altered resting-state functional connectivity and dynamic network properties in cognitive impairment: an independent component and dominant-coactivation pattern analyses study.

Introduction: Cognitive impairment (CI) due to Alzheimer's disease (AD) encompasses a decline in cognitive abilities and can significantly impact an individual's quality of life. Early detection and intervention are crucial in managing CI, both in the preclinical and prodromal stages of AD prior to dementia. Methods: In this preliminary study, we investigated differences in resting-state functional connectivity and dynamic network properties between 23 individual with CI due to AD based on clinical assessment and 15 healthy controls (HC) using Independent Component Analysis (ICA) and Dominant-Coactivation Pattern (d-CAP) analysis. The cognitive status of the two groups was also compared, and correlations between cognitive scores and d-CAP switching probability were examined. Results: Results showed comparable numbers of d-CAPs in the Default Mode Network (DMN), Executive Control Network (ECN), and Frontoparietal Network (FPN) between HC and CI groups. However, the Visual Network (VN) exhibited fewer d-CAPs in the CI group, suggesting altered dynamic properties of this network for the CI group. Additionally, ICA revealed significant connectivity differences for all networks. Spatial maps and effect size analyses indicated increased coactivation and more synchronized activity within the DMN in HC compared to CI. Furthermore, reduced switching probabilities were observed for the CI group in DMN, VN, and FPN networks, indicating less dynamic and flexible functional interactions. Discussion: The findings highlight altered connectivity patterns within the DMN, VN, ECN, and FPN, suggesting the involvement of multiple functional networks in CI. Understanding these brain processes may contribute to developing targeted diagnostic and therapeutic strategies for CI due to AD.

WarpDrive: Improving spatial normalization using manual refinements.

Spatial normalization-the process of mapping subject brain images to an average template brain-has evolved over the last 20+ years into a reliable method that facilitates the comparison of brain imaging results across patients, centers & modalities. While overall successful, sometimes, this automatic process yields suboptimal results, especially when dealing with brains with extensive neurodegeneration and atrophy patterns, or when high accuracy in specific regions is needed. Here we introduce WarpDrive, a novel tool for manual refinements of image alignment after automated registration. We show that the tool applied in a cohort of patients with Alzheimer's disease who underwent deep brain stimulation surgery helps create more accurate representations of the data as well as meaningful models to explain patient outcomes. The tool is built to handle any type of 3D imaging data, also allowing refinements in high-resolution imaging, including histology and multiple modalities to precisely aggregate multiple data sources together.

Diagnosing and Treating Alzheimer Disease During the Early Stage.

Recent advances in technology can lead to earlier detection of Alzheimer disease (AD) in patients and therefore opportunities for early diagnosis and treatment. In addition, novel agents can slow disease progression and improve symptoms. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Early detection and intervention are crucial to slow symptom progression, and these advances provide a window of opportunity to diagnose the disease early and even prevent it from becoming symptomatic. Clinicians need education on early recognition of AD and on sharing the diagnosis of AD with patients and families as well as guidance for providing patients and families with information on next steps and facilitating early treatment initiation for AD. Partnering with clinicians in the primary care setting and providing them with the necessary tools can change the trajectory of the disease for patients and caregivers.

Timely Diagnosis of Alzheimer Disease.

Diagnosing early-stage Alzheimer disease can lead to prompt initiation of treatment and slow down symptom progression. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Tests for biomarkers, new symptomatic treatments and disease-modifying agents, and the addition of the preclinical stage to the diagnostic criteria for AD can aid in earlier disease recognition and developing treatment plans. Communicating diagnosis and information on next steps with patients and caregivers can lead to patient and caregiver involvement in decision-making and planning as well as participation in clinical trials and maximizing benefits and lifestyle interventions.

Facilitating Treatment Initiation in Early-Stage Alzheimer Disease.

Once a diagnosis of Alzheimer disease is established, a wide variety of therapy options are available to treat different stages of the disease. Patients have the opportunity to delay onset of the disease or delay its progression if diagnosed early enough through new FDA-approved disease-modifying treatments. For mild to moderate stages, new symptomatic treatments can slow the progression of the disease and improve symptoms. A multi-component approach is recommended in order to tailor treatments to each patient's needs.

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-ß (Aß). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aß pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aß immunoglobulin G titers. Design, Setting, and Participants: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 µg or 1000 µg, or placebo. Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers. Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aß immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 µg and 2 receiving 1000 µg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aß1-40 and Aß1-42 levels among individuals receiving ACI-24. Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aß antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-Stage Alzheimer Disease?

While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.

Talking With Patients and Care Partners About Treatment Goals and Challenges in Early-Stage Alzheimer Disease.

Alzheimer disease (AD) requires timely diagnosis and treatment initiation as early as possible to delay further loss of functioning. Clinicians must attempt to answer patients' and care partners' questions about treatment goals and expected challenges. In this webcast, Drs Burke and Apostolova address topics critical to the care of patients with early-stage AD. They highlight barriers to diagnosis, describe genetic risk factors, and emphasize the role of neuropsychologic testing. Drs Burke and Apostolova agree that, although current medications slow symptom progression associated with AD, emerging therapies offer hope for disease modification. These experts also talk about important conversations to have with patients and their care partners, such as about diet, exercise, driving, and plans for the later stage of illness.

Treatment Challenges and the Hope of Emerging Therapies in Early-Stage Alzheimer Disease.

Alzheimer disease (AD), the most common cause of dementia, is a degenerative brain disease with no cure. In the United States alone, an estimated 5.8 million people are living with AD. More than half of individuals living with AD and other dementias are not getting an accurate diagnosis and, when they do receive one, clinicians are not effectively communicating with patients and care partners regarding the illness and next steps. Additionally, prompt treatment initiation does not occur in a substantial number of newly diagnosed patients. This Academic Highlights addresses best practices for identifying patients with early-stage AD, discussing treatment goals and challenges with patients who have AD and their care partners, employing current medications approved by the U.S. Food and Drug Administration to slow symptom progression, and staying informed about emerging therapies that offer new hope for disease modification.

Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease.

BACKGROUND: Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD). OBJECTIVE: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. METHODS: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation ("on") or sham DBS-f ("off") for 12 months. RESULTS: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the "on" and "off" groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer's Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f "off" versus "on" over 12 months in the < 65 age group but favored DBS-f "on" versus "off" in the≥65 age group on all clinical metrics. On the integrated Alzheimer's Disease rating scale (iADRS), the effect size contrasting DBS-f "on" versus "off" changed from +0.2 (favoring "off") in the < 65 group to -0.52 (favoring "on") in the≥65 age group. CONCLUSION: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.