Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer's Disease Risk.

BACKGROUND: The Comparative Effectiveness Dementia and Alzheimer's Registry (CEDAR) trial demonstrated that individualized, multi-domain interventions improved cognition and reduced the risk of Alzheimer's disease (AD). As biological sex is a significant risk factor for AD, it is essential to explore the differential effectiveness of targeted clinical interventions in women vs. men. METHODS: Patients were recruited from an Alzheimer's Prevention Clinic. Subjects with normal cognition, subjective cognitive decline, or asymptomatic preclinical AD were classified as "Prevention". Subjects with mild cognitive impairment due to AD or mild AD were classified as "Early Treatment." The primary outcome was the change from baseline to 18-months on the modified-Alzheimer's Prevention Cognitive Composite. Secondary outcomes included a cognitive aging composite, AD and cardiovascular (CV) risk scales, and serum biomarkers. Subjects who adhered to > 60% of recommendations in the CEDAR trial were included in this a priori sub-group analysis to examine whether individualized intervention effects were modified by sex (n=80). RESULTS: In the Prevention group, both women (p=0.0205) and men (p=0.0044) demonstrated improvements in cognition with no sex differences (p=0.5244). In the Early Treatment group, there were also no significant sex differences in cognition (p=0.3299). In the Prevention group, women demonstrated greater improvements in the Multi-Ethnic Study of Atherosclerosis risk score (MESA-RS) than men (difference=1.5, p=0.0013). Women in the Early Treatment group demonstrated greater improvements in CV Risk Factors, Aging and Incidence of Dementia (CAIDE) risk score (difference=2.3, p=0.0067), and the MESA-RS (difference=4.1, p<0.001). CONCLUSIONS: Individualized multi-domain interventions are equally effective at improving cognition in women and men. However, personally-tailored interventions led to greater improvements in calculated AD and CV risk, and CV blood biomarkers, in women compared to men. Future study in larger cohorts is necessary to further define sex differences in AD risk reduction in clinical practice.

Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021.

Alzheimer's disease is a progressive, irreversible neurodegenerative disease impacting cognition, function, and behavior. Alzheimer's disease progresses along a continuum from preclinical disease, to mild cognitive and/or behavioral impairment and then Alzheimer's disease dementia. Recently, clinicians have been encouraged to diagnose Alzheimer's earlier, before patients have progressed to Alzheimer's disease dementia. The early and accurate detection of Alzheimer's disease-associated symptoms and underlying disease pathology by clinicians is fundamental for the screening, diagnosis, and subsequent management of Alzheimer's disease patients. It also enables patients and their caregivers to plan for the future and make appropriate lifestyle changes that could help maintain their quality of life for longer. Unfortunately, detecting early-stage Alzheimer's disease in clinical practice can be challenging and is hindered by several barriers including constraints on clinicians' time, difficulty accurately diagnosing Alzheimer's pathology, and that patients and healthcare providers often dismiss symptoms as part of the normal aging process. As the prevalence of this disease continues to grow, the current model for Alzheimer's disease diagnosis and patient management will need to evolve to integrate care across clinical disciplines and the disease continuum, beginning with primary care. This review summarizes the importance of establishing an early diagnosis of Alzheimer's disease, related practical 'how-to' guidance and considerations, and tools that can be used by healthcare providers throughout the diagnostic journey.

Feasibility of Using a Wearable Biosensor Device in Patients at Risk for Alzheimer's Disease Dementia.

BACKGROUND: Alzheimer's disease (AD) is the most common and most costly chronic neurodegenerative disease globally. AD develops over an extended period prior to cognitive symptoms, leaving a "window of opportunity" for targeted risk-reduction interventions. Further, this pre-dementia phase includes early physiological changes in sleep and autonomic regulation, for which wearable biosensor devices may offer a convenient and cost-effective method to assess AD-risk. METHODS: Patients with a family history of AD and no or minimal cognitive complaints were recruited from the Alzheimer's Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian. Of the 40 consecutive patients screened, 34 (85%) agreed to wear a wearable biosensor device (WHOOP). One subject (2.5%) lost the device prior to data collection. Of the remaining subjects, 24 were classified as normal cognition and were asymptomatic, 6 were classified as subjective cognitive decline, and 3 were amyloid-positive (one with pre-clinical AD, one with pre-clinical Lewy-Body Dementia, and one with mild cognitive impairment due to AD). Sleep-cycle, autonomic (heart rate variability [HRV]) and activity measures were collected via WHOOP. Blood biomarkers and neuropsychological testing sensitive to cognitive changes in pre-clinical AD were obtained. Participants completed surveys assessing their sleep-patterns, exercise habits, and attitudes towards WHOOP. The goal of this prospective observational study was to determine the feasibility of using a wrist-worn biosensor device in patients at-risk for AD dementia. Unsupervised machine learning was performed to first separate participants into distinct phenotypic groups using the multivariate biometric data. Additional statistical analyses were conducted to examine correlations between individual biometric measures and cognitive performance. RESULTS: 27 (81.8%) participants completed the follow-up surveys. Twenty-four participants (88.9%) were satisfied with WHOOP after six months, and twenty-three (85.2%) wanted to continue wearing WHOOP. K-means clustering separated participants into two groups. Group 1 was older, had lower HRV, and spent more time in slow-wave sleep (SWS) than Group 2. Group 1 performed better on two cognitive tests assessing executive function: Flanker Inhibitory Attention/Control (FIAC) (p=.031), and Dimensional Change Card Sort (DCCS) (p=.061). In Group 1, DCCS was correlated with SWS (ρ=.68, p=0.024) and HRV (ρ=.6, p=0.019). In Group 2, DCCS was correlated with HRV (ρ=.55, p=0.018). There were no significant differences in blood biomarkers between the two groups. CONCLUSIONS: Wearable biosensor devices may be a feasible tool to assess AD-related physiological changes. Longitudinal collection of sleep and HRV data may potentially be a non-invasive method for monitoring cognitive changes related to pre-clinical AD. Further study is warranted in larger populations.

Female Sex and Alzheimer's Risk: The Menopause Connection.

Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer's disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.

Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

Alzheimer's Prevention Education: If We Build It, Will They Come? www.AlzU.org.

BACKGROUND: Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. OBJECTIVES: Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). DESIGN: Observational. SETTING: Online. PARTICIPANTS: Men/Women, aged 25+, recruited via facebook.com. INTERVENTION: Alzheimer's Universe (www.AlzU.org) education research platform. MEASUREMENTS: Pre/post-test performance, self-reported Likert-scale ratings, completion rates. RESULTS: Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. CONCLUSIONS: Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.