Introduction There is an urgent need to develop effective interventional treatments for people with Alzheimer's disease (AD). AD results from a complex multi‐decade interplay of multiple interacting dysfunctional biological systems that have not yet been fully elucidated. Epidemiological studies have linked several modifiable lifestyle factors with increased incidence for AD. Because monotherapies have failed to prevent or ameliorate AD, interventional studies should deploy multiple, targeted interventions that address the dysfunctional systems that give rise to AD. Methods This randomized controlled trial (RCT) will examine the efficacy of a 12‐month personalized, multimodal, lifestyle intervention in 60 mild cognitive impairment (MCI) and early stage AD patients (aged 50+, amyloid positivity). Both groups receive data‐driven, lifestyle recommendations designed to target multiple systemic pathways implicated in AD. One group receives these personalized recommendations without coaching. The other group receives personalized recommendations with health coaching, dietary counseling, exercise training, cognitive stimulation, and nutritional supplements. We collect clinical, proteomic, metabolomic, neuroimaging, and genetic data to fuel systems‐biology analyses. We will examine effects on cognition and hippocampal volume. The overarching goal of the study is to longitudinally track biological systems implicated in AD to reveal the dynamics between these systems during the intervention to understand differences in treatment response. Results We have developed and implemented a protocol for a personalized, multimodal intervention program for early AD patients. We began enrollment in September 2019; we have enrolled a third of our target (20 of 60) with a 95% retention and 86% compliance rate. Discussion This study presents a paradigm shift in designing multimodal, lifestyle interventions to reduce cognitive decline, and how to elucidate the biological systems being targeted. Analytical efforts to explain mechanistic or causal underpinnings of individual trajectories and the interplay between multi‐omic variables will inform the design of future hypotheses and development of effective precision medicine trials.

Objectives: The feasibility and safety of the use of neurorehabilitation technology (SMARTfit® Trainer system) by physical therapists in implementing a gamified physical-cognitive dual-task training (DTT) paradigm for individuals with Parkinson disease (IWPD) was examined. Additionally, the efficacy of this gamified DTT was compared to physical single-task training (STT), both of which were optimized using physio-motivational factors, on changes in motor and cognitive outcomes, and self-assessed disability in activities of daily living. Methods: Using a cross-over study design, eight participants with mild-to-moderate idiopathic PD (including one with mild cognitive impairment) completed both training conditions (i.e., gamified DTT and STT). For each training condition, the participants attended 2–3 sessions per week over 8.8 weeks on average, with the total amount of training being equivalent to 24 1 h sessions. A washout period averaging 11.5 weeks was inserted between training conditions. STT consisted of task-oriented training involving the practice of functional tasks, whereas for gamified DTT, the same task-oriented training was implemented simultaneously with varied cognitive games using an interactive training system (SMARTfit®). Both training conditions were optimized through continual adaptation to ensure the use of challenging tasks and to provide autonomy support. Training hours, heart rate, and adverse events were measured to assess the feasibility and safety of the gamified DTT protocol. Motor and cognitive function as well as perceived disability were assessed before and after each training condition. Results: Gamified DTT was feasible and safe for this cohort. Across participants, significant improvements were achieved in more outcome measures after gamified DTT than they were after STT. Individually, participants with specific demographic and clinical characteristics responded differently to the two training conditions. Conclusion: Physical therapists’ utilization of technology with versatile hardware configurations and customizable software application selections was feasible and safe for implementing a tailor-made intervention and for adapting it in real-time to meet the individualized, evolving training needs of IWPD. Specifically in comparison to optimized STT, there was a preliminary signal of efficacy for gamified DTT in improving motor and cognitive function as well as perceived disability in IWPD.

Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. Objective: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox ® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader ® by Brainreader). Methods: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models. Results: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87). Conclusion: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia.

Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry. Methods: We selected 38 participants with Alzheimer’s disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

BackgroundMaintaining healthy lifestyle behaviors and optimizing health may slow cognitive decline through risk reduction in older adults with cognitive impairments. Curriculum‐based health coaching, weekly psychosocial support, and use of biomarkers to guide health optimization may aid in establishing effective behavior change centered around multiple reversible dementia risk factors.MethodWe piloted combined use of a six‐month online Cognitive Health Program (www.amosinstitute.com) with a telehealth lifestyle support group in six patients with subjective cognitive complaints receiving ongoing outpatient memory care. These patients were given lab‐guided personalized health recommendations for dementia risk reduction throughout the pilot intervention during monthly individual appointments with the study physician overseeing the group. A registered dietician was invited to lead the weekly telehealth lifestyle support group, which was delivered in partnership with the Center’s memory clinicians and health coaches. Highlights of the online Cognitive Health Program were reviewed by the dietician each week followed by group discussion on topics including diet, exercise, sleep, stress, and cognitive training. Cognition was assessed at baseline and post‐intervention using a computerized battery (www.cambridgebrainsciences.com). The significance of cognitive changes was estimated with nonparametric tests and effect sizes (Cohen’s d). The participants were also queried qualitatively on adherence and satisfaction.ResultCompared to baseline, the participants improved significantly in the global cognition score (p<.02, d = 1.6), and had significant improvements in spatial planning (p<.01, d = 2.3) and visuospatial processing (p<.05, d = 1.1). There was a borderline improvement in verbal reasoning (p<.06, d = 1.0). Subjective reports indicated that participants were able to successfully adhere to multiple lifestyle habits in the areas of sleep, nutrition, and exercise. Participants reported high levels of satisfaction with the virtual group format, the online curriculum, and access to the additional online resources.ConclusionA virtually administered, six‐month, weekly health coaching group that addresses multiple lifestyle factors associated with brain health, supplemented by self‐paced online health education and lab‐based health optimization by a physician, is feasible and potentially efficacious for improving cognition in participants with subjective cognitive impairment. This format may facilitate behavior change to slow cognitive decline. Future studies will include neuroimaging, formal neuropsychological testing, controls, and larger sample sizes.

BackgroundHandgrip strength is important for performing activities of daily living[1]. In older adults, weaker handgrip strength and asymmetry are associated with poorer cognition. o better understand mechanisms, we sought to quantify the relationship between handgrip strength and regional volumes quantified on brain MR imaging.MethodWe selected 32 participants (mean age=70.8±7.3 [range 57‐89] years, 53.1% female, 90.6% right‐handed, mean body mass index BMI=23.9±4.1) from the Pacific Brain Health Center at Providence St. John’s Health Center, with Alzheimer dementia biomarker evidence of amyloidosis[2]. Mean Montreal Cognitive Assessment score for all participants was 21.3±3.8 points. Handgrip strength on dominant and non‐dominant hands was measured using the NIH Motor Toolbox[3] as part of a cognitive fitness assessment using a hydraulic hand dynamometer. The resulting scores included handgrip strength and percentile comparisons to normative data. Asymmetry scores were calculated. Regional brain volumes, including lobar structures and the hippocampus, were measured from T1‐weighted MR images using Neuroreader[4]. Partial correlations (rp), adjusting for age, sex, BMI and total intracranial volume modeled handgrip strength, asymmetry, and brain volumes with a significance threshold of p<0.05.ResultIn the dominant hand, higher handgrip strength scores and percentiles were associated with larger volumes in the left frontal lobe (rp=+0.51, p=0.007; rp =+0.47, p=0.01) and right parietal lobe (rp=+0.40, p=0.03; rp=+0.39, p=0.04). In the non‐dominant hand, higher handgrip strength score and percentiles were associated with smaller total cerebral spinal fluid (CSF) volume (rp =‐0.55, p=0.004; rp =‐0.52, p =0.006) and larger volumes within the left hippocampus (rp=+0.45, p=0.01; rp=+.43, p=0.02), right hippocampus (rp=+0.47, p=0.01; rp=+0.43, p=0.02), and right parietal lobe (rp=+0.39, p=0.04; rp=+0.44, p=0.02). Handgrip strength asymmetry was inversely related to right hippocampal volume (rp=‐0.58, p=0.002) and positively correlated to CSF volume (rp=+0.39, p=0.04).ConclusionGreater handgrip strength was related to larger regional brain volumes. A higher number of brain regions were related to the non‐dominant hand. Asymmetry was associated with lower right hippocampal volume and higher CSF volume. Interventions focused on improving handgrip strength may seek to include quantified brain volumes on MR imaging as endpoints.

BackgroundPersonalized multi‐modal interventions for Alzheimer dementia hold promise to slow progression of symptoms yet related quantitative neuroimaging biomarkers have not been investigated[1,2].MethodWe selected 16 participants (mean age 68.6±5.9 [range 57‐77] years, 50% female) from the Pacific Brain Health Center at Providence St. John’s Health Center, with biomarker evidence of Alzheimer dementia amyloidosis. All participants received data‐supported clinical recommendations (DSCR), [3–7] which included a modified SHIELD program[8] recommending a low carbohydrate diet. DSCRs were personalized based on clinical evaluations and laboratory values and closely overseen by a dementia specialist (DM, CW). T1‐weighted MR images were acquired at baseline and with a 1‐year average follow up. Total gray and white matter, hippocampal, lateral ventricle, temporal, parietal, occipital and frontal lobe volumes were quantified using Neuroreader[9]. Global cognition was tested using the Montreal Cognitive Assessment (MoCA). Paired t‐tests were done for these metrics.ResultChanges in hippocampal volumes (t=+1.6, p=0.11), temporal (t=+0.03, p=0.97) and frontal lobes (t=‐0.63, p=0.53) were not significant. There was a marginally significant decline in the parietal lobes (t=+2.1, p=.048) and statistically significant increased lateral ventricles (t=‐4.9, p<0.01). White matter volume declined significantly (t=‐2.8, p=0.01) while gray matter did not change significantly (t=+1.2, p=0.21). Table 1 shows annualized percent changes for these regions. These changes were attenuated compared to literature values for the following regions: gray matter at ‐2%/year [10], hippocampus at ‐3.5%/year [11], temporal lobes at ‐3.23%/year, parietal lobes at ‐3.62%/year and frontal lobes at ‐2.88%/year [12]. Total gray matter and frontal lobe volumes showed increased average annualized changes at +1.97%/year and +0.87%/year respectively. Over the same time period as the brain‐volume trajectory measurements, there was an average decline in MoCA (‐1.5 from 22.06±4.1 to 20.56±6.1, p=0.06) that trended towards but was not statistically significant.ConclusionRegional volume loss, while present, was moderated compared to literature derived rates. Increased ventricular volumes appear driven by white matter volume loss. These preliminary data suggest that efforts to track and report on clinical outcomes in settings providing close medical management and multimodal lifestyle recommendations may be a worthwhile step towards validating research findings.

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