GLADIATOR was a prospective, randomized, open-label, phase 3 study of lasmiditan 100 mg or 200 mg dosed intermittently for up to 1 year in patients with episodic migraine. Most patients had completed one of two single-attack studies before participation. A total of 2030 patients received ≥1 lasmiditan dose and 19,879 migraine attacks were treated. Safety results were similar to the previously reported interim analysis. The most frequently reported treatment-emergent adverse events (TEAEs) included dizziness (18.5%), somnolence (8.5%), and paresthesia (6.8%), with frequency of adverse events appearing to decrease with subsequently treated attacks. At 2 h post-dose, 26.7% and 32.2% of all attacks treated with lasmiditan 100 mg and 200 mg, respectively, were pain free. This pattern was generally consistent across study quarters and treated attacks. In conclusion, during a 1-year treatment period, intermittent lasmiditan for episodic migraine treatment was associated with generally decreasing TEAEs and consistent efficacy.

Background Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. Methods Subgroups of patients reporting an overall response of “good” or “poor/none” to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). Results Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. Conclusions Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. Trial Registration SAMURAI (NCT02439320); SPARTAN (NCT02605174).

May 8, 2019April 9, 2019Free AccessResponse to Lasmiditan for Acute Treatment of Migraine Based on Prior Response to Triptan Therapy (P4.10-022)Kerry Knievel, Louise Lombard, Andrew Buchanan, Simin K. Baygani, Joel Raskin, and Joshua TobinAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P4.10-022 Letters to the Editor

Trial DesignSAMURAI and SPARTAN were double‐blind, placebo‐controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment.MethodsData from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug.ResultsDizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non‐Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30‐40 minutes, and the median duration was 1.5‐2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 (<0.1%).ConclusionThe incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy.

Background Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose. Study design and methods Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3–8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications. Results Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p < 0.001). Sustained pain freedom was significantly higher in patients treated with lasmiditan versus placebo at 24 hours: 200 mg: 21.2%; 100 mg: 16.9%; 50 mg: 17.4%; placebo: 10.3% (all p < 0.01); and at 48 hours: 200 mg: 18.4%; 100 mg: 15.2%; 50 mg: 14.9%; placebo: 9.6% (all p < 0.05). Similar sustained benefits of lasmiditan versus placebo at 24 and 48 hours were noted for most bothersome symptom-free, total migraine-free and disability-free responses. Modified sustained pain freedom at 24 hours was also observed in significantly higher proportions of lasmiditan-treated patients versus placebo: 200 mg: 27.0%; 100 mg: 21.7%; 50 mg: 21.7%; placebo: 12.9% (all p < 0.01). Conclusion Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses. Clinicaltrials.gov identifier numbers SAMURAI: NCT02439320; SPARTAN: NCT02605174.

May 5, 2019April 9, 2019Free AccessLong-term Safety and Efficacy of Lasmiditan for Acute Treatment of Migraine Over a One-Year Period: Interim Results of an Open-Label Phase 3 Study (GLADIATOR) (P1.10-021)Jan Brandes, David Kudrow, Suzanne Klise, John H. Krege, Michael Case, Joel Raskin, Rashna Khanna, and Raghavendra VasudevaAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P1.10-021 Letters to the Editor

Objectives To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. Methods In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. Results As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received >= 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period.

Randomized placebo-controlled trials in the development of disease-modifying treatments for Alzheimer’s disease are typically of short duration (12–18 months), and health economic modeling requires extrapolation of treatment effects beyond the trial period.

BackgroundWe studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.MethodsSAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was to be taken within 4 hours (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2h and took a second dose 2-24h post-first dose) or recurrence (patient pain-free at 2h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan.ResultsThe proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p>0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p>0.05); MBS free, 71% vs 41% (p=0.02); pain relief, 77% vs 52% (p=0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo.ConclusionsA second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo.

Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer’s disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study.

INTRODUCTION:Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1-40 and Aβ1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.METHODS:CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3.RESULTS:Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low.DISCUSSION:Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer’s disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

Solanezumab is a monoclonal antibody that binds to a mid-domain epitope of soluble Aβ. Efficacy of solanezumab (400mg i.v. every four weeks for 80 weeks) was assessed in EXPEDITION3 (NCT01900665), a phase 3, randomized, placebo-controlled, double-blind trial in patients with mild Alzheimer disease (AD) and evidence of amyloid pathology. Solanezumab efficacy in EXPEDITION3 was less than that in a pooled mild AD patient population enrolled in two previous phase 3 trials without regard to amyloid status, (EXPEDITION, NCT00905372; EXPEDITION2, NCT00904683). The present investigation examines central drug target engagement (TE) and pharmacodynamic (PD) activity of solanezumab in EXPEDITION3 and compares both to that in the pooled mild AD population from EXPEDITION/EXPEDITION2. Cerebrospinal fluid (CSF) was obtained at baseline and after 80 weeks of treatment from patients enrolled in an EXPEDITION3 Lumbar Puncture Addendum. Central TE was assessed by treatment effects on CSF total (free plus drug bound) Aβ1–40 and Aβ1–42. Central PD activity was assessed by treatment effects on CSF free (non-drug bound) Aβ1–40 and Aβ1–42. Concentrations of all biomarkers and solanezumab were measured in CSF by validated assays. An ANCOVA analysis of each biomarker compared the 80-week least squares mean change ± S.E. in placebo and solanezumab groups. CSF total Aβ1–40 decreased 1256.4±470.2 pg/mL in the placebo arm (N=120) and increased 3285.6±460.6 pg/mL in the solanezumab arm (N=127) (p<0.001). Total Aβ1–42 decreased 63.2±31.3 pg/mL in the placebo arm (n=123) and increased 459.6±31.1 pg/mL in the solanezumab arm (N=131) (p<0.001). CSF free Aβ1–40 decreased 320.0±182.5 pg/mL in the placebo arm (N=123) and decreased 714.6±177.8 pg/mL in the solanezumab arm (N=131) (p=0.07). Free Aβ1–42 decreased 9.3±8.2 pg/mL in the placebo arm (N=103) and decreased 37.3±7.5 pg/mL in the solanezumab arm (N=116) (p=0.005). In EXPEDITION3, solanezumab central TE was demonstrated with respect to both total Aβ1–40 and Aβ1–42. These effects were consistent with those observed in EXPEDITION/EXPEDITION2 and correlated with CSF solanezumab exposure. Solanezumab central target-related PD activity was significant as assessed by CSF free Aβ1–42 but not free Aβ1–40. The differences observed for free Aβ1–40 and Aβ1–42 between EXPEDITION/EXPXPEDITION2 and EXPEDITION3 are complex and will be further discussed.

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer’s disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

The number of people diagnosed with Alzheimer's disease (AD) is expected to increase substantially in the near future. In the recent Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the terminology related to AD has shifted from "dementia" to major or mild "neurocognitive disorder", emphasizing the cognitive impairment that occurs relatively early in the disease process. The concept of "mild neurocognitive disorder" or "mild cognitive impairment" promotes early detection and diagnosis of AD, particularly by psychiatrists, who often consult the DSM-5. This narrative review describes the current and future role of psychiatrists in the diagnosis and management of AD, focusing on the DSM-5 criteria for mild and major neurocognitive disorder. We summarize some of the key instruments used to assess cognition and the neuropsychiatric and behavioral symptoms that often accompany early AD, neuroimaging diagnostic tools, and newly available AD-specific biomarkers that enhance the ability of clinicians to diagnose early AD. We also briefly describe current and emerging pharmacological treatments for AD that target amyloid and tau and that may modify disease progression. Finally, we provide our clinical opinion on the future role of psychiatrists in AD, the education and training necessary to fulfil this role, interactions between psychiatrists and other specialists as part of a multidisciplinary team, and the potential for routine screening of cognitive function among elderly people.

In two solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status.Quantile regression was used to examine solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively.In mild patients, solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, solanezumab did not show effects across most percentiles.Results are compatible with design of the ongoing solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.

Background: The burden on caregivers of patients with Alzheimer's disease (AD) is associated with the patient's functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed.Methods: Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed.Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression.Results: Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p < 0.05), compared with caregivers of patients without diabetes (n = 1307). Analyses showed caregivers of patients with diabetes spent significantly more time on iADL (+16 %; p = 0.03; increases were also observed for basic ADL and total caregiver time but did not reach statistical significance) and had a trend towards increased ZBI score. Patients with diabetes had a 63 % increase in the odds of requiring supervision versus those without diabetes (p = 0.01). Caregiver and patient HCRU did not differ according to patient diabetes.Caregivers with diabetes (n = 127) did not differ from those without diabetes (n = 1367) regarding burden/time, but caregivers with diabetes had a 91 % increase in the odds of having outpatient visits (p = 0.01).Conclusions: This cross-sectional analysis found caregiver time on iADL and supervision was higher for caregivers of patients with AD and diabetes versus without diabetes, while HCRU was unaffected by patient diabetes. Longitudinal analyses assessing change in caregiver burden over time by patient diabetes status may help clarify the cumulative impact of diabetes and AD dementia on caregiver burden.

The global impact of Alzheimer's disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

BACKGROUND:Both cognitive and functional deterioration are characteristic of the clinical progression of Alzheimer's disease (AD).OBJECTIVES:To systematically assess correlations between widely used measures of cognition and function across the spectrum of AD.DESIGN:Spearman rank correlations were calculated for cognitive and functional measures across datasets from various AD patient populations.SETTING:Post-hoc analysis from existing databases.PARTICIPANTS:Pooled data from placebo-treated patients with mild (MMSE score ≥20 and ≤26) and moderate (MMSE score ≥16 and ≤19) AD dementia from two Phase 3 solanezumab (EXPEDITION/2) and two semagecesatat (IDENTITY/2) studies and normal, late mild cognitive impairment (LMCI) and mild AD patients from the Alzheimer's Disease Neuroimaging Initiative 2-Grand Opportunity (ADNI-2/GO). Intervention (if any): Placebo (EXPEDITION/2 and IDENTITY/2 subjects).MEASUREMENTS:Cognitive and functional abilities were measured in all datasets. Data were collected at baseline and every three months for 18 months in EXPEDITION and IDENTITY studies; and at baseline, 6, 12, and 24 months in the ADNI dataset.RESULTS:The relationship of cognition and function became stronger over time as AD patients progressed from preclinical to moderate dementia disease stages, with the magnitude of correlations dependent on disease stage and the complexity of functional task. The correlations were minimal in the normal control population, but became stronger with disease progression.CONCLUSIONS:This analysis found that measures of cognition and function become more strongly correlated with disease progression from preclinical to moderate dementia across multiple datasets. These findings improve the understanding of the relationship between cognitive and functional clinical measures during the course of AD progression and how cognition and function measures relate to each other in AD clinical trials.