Research Highlights from Padmaja Genesh (October 2020)

Published: Oct 30, 2020

Research Blog for the month of October

Systolic blood pressure postural changes variability is associated with greater dementia risk 

The objective of the study was to determine whether orthostatic hypotension (drop in blood pressure on standing) (OHYPO) and visit-to-visit blood pressure (BP) postural changes variability are associated with incident dementia. 

The researchers studied 2,131 older adults from the Health, Aging, and Body Composition cohort study. Orthostatic BP was repeatedly assessed over a 5-year baseline period. OHYPO was defined as a fall ≥15 mm Hg in systolic or ≥7 mm Hg in diastolic BP after standing from a sitting position for one-third or more of the visits.

Results: Of 2,131 participants (mean age 73 years, 53% female, 39% Black), 309 (14.5%) had OHYPO, 192 (9.0%) had systolic OHYPO, 132 (6.2%) had diastolic OHYPO, and 462 (21.7%) developed dementia. After adjustment for demographics, seated systolic BP (SBP), antihypertensive drugs, cerebrovascular disease, diabetes mellitus, depressive symptoms, smoking, alcohol, body mass index, and presence of 1 or 2 APOE ε4 alleles, systolic OHYPO was associated with greater dementia risk, unlike diastolic OHYPO and OHYPO. SBP postural changes variability was also associated with higher dementia risk. 

Conclusion Systolic OHYPO and visit-to-visit SBP postural changes variability were associated with greater dementia risk. These findings raise the question of potential preventive interventions to control orthostatic SBP and its fluctuations. 

Source: https://n.neurology.org/content/95/14/e1932 ; First published July 20, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010420 

 

Sleep, major depressive disorder, and Alzheimer disease- A Mendelian randomization study 

The objective of the study was to explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). 

The researchers  conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). 
 

The researchers found that higher risk of AD was significantly associated with being a “morning person”, shorter sleep duration, less likely to report long sleep, earlier timing of the least active 5 hours, and a smaller number of sleep episodes,  after adjustment for multiple comparisons.
 

The researchers also found that higher risk of AD was associated with lower risk of insomnia. However, the researchers did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. 
 

Conclusion: The researchers found that AD may causally influence sleep patterns. However, they did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD. 

Source: https://n.neurology.org/content/95/14/e1963; First published August 19, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010463

 

Dosing Starts in Phase 2/3 Trial of Athira’s ATH-1017 for Alzheimer’s 

Dosing of patients has begun in a Phase 2/3 clinical trial evaluating ATH-1017, Athira Pharma‘s investigational candidate for the treatment of mild to moderate Alzheimer’s disease. 
 

Called LIFT-AD, the randomized trial (NCT04488419) will evaluate the safety and efficacy of ATH-1017 (previously known as NDX-1017), compared with a placebo, for the treatment of mild to moderate Alzheimer’s disease. 

ATH-1017 is a small molecule specifically designed to increase the activity of the hepatocyte growth factor, and its receptor protein MET.  Several studies have reported that HGF-MET can regulate various brain functions, including axonal growth,  neuronal survival, and transmission of information between cells (synapses).  Designed to slow or stop disease progression or even reverse it, ATH-1017 was shown to be able to regenerate nerve cells and improve cognitive function in preclinical studies.

Results from a previous Phase 1a/b trial (NCT0329872) showed that the treatment was safe and well tolerated at multiple dose levels in healthy individuals as well as those with amnestic mild cognitive impairment or Alzheimer’s disease. 

Moreover, ATH-1017 was capable of crossing the blood-brain barrier,  activating its targets across a range of doses. Increasing doses of ATH-1017 correlated with improvements in learning and memory as well as cognitive processes.

An estimated 300 individuals are currently being recruited for the trial in Florida and Washington. Participants will be randomly assigned to receive either a low or high dose of ATH-1017 or a placebo, delivered subcutaneously (under the skin) daily for 26 weeks. Clinical efficacy will be demonstrated by improvement in cognition and functional assessments compared with the placebo. 

Source: https://alzheimersnewstoday.com/2020/10/12/dosing-starts-in-phase-2-3-trial-of-athiras-ath-1017-for-alzheimers/

 

Semorinemab Fails to Show Efficacy in Early Alzheimer’s Phase 2 Trial 

Semorinemab, a monoclonal antibody against tau, failed to significantly alter dementia progression in people with early Alzheimer’s disease (AD) taking part in a Phase 2 clinical trial.  The investigational therapy is being jointly developed by AC Immune and Genentech (a Roche company). 


Semorinemab, an antibody that targets phosphorylated and non-phosphorylated forms of tau, was designed to lessen the extent of these tangles in the brain, thereby easing disease progression. 


The experimental antibody was evaluated in a Phase 2 clinical trial called TAURIEL (NCT03289143), which enrolled 457 people with early (prodromal to mild) Alzheimer’s across 97 global sites. For 73 weeks, patient were given either semorinemab (three different doses) or a placebo, administered intravenously (by injection directly into the bloodstream). 

No significant difference was found between those given semorinemab and those on a placebo. As such, the trial failed to meet its primary efficacy endpoint. 

The trial similarly failed to meet two secondary goals: scores on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13), which measures cognitive function in Alzheimer’s, and on the Alzheimer’s Disease Cooperative Study Group – Activities of Daily Living Inventory (ADCS-ADL), which assesses the difficulty people with Alzheimer’s have handling day-to-day activities. 

A separate Phase 2 trial evaluating semorinemab in people with moderate Alzheimer’s, called LAURIET (NCT03828747), is ongoing. The Genentech-sponsored trial is currently enrolling up to 260 patients at locations in the U.S. and Europe. 

Source: https://alzheimersnewstoday.com/2020/10/07/semorinemab-fails-to-show-efficacy-phase-2-early-alzheimers-trial/ 

 

First Patient Dosed in Phase 2 Trial of Bryostatin-1 in Long-term Use 

The first patient has been dosed in a Phase 2 trial investigating the safety and long-term efficacy of bryostatin-1 in treating moderate and moderately severe Alzheimer’s disease, the therapy’s developer, Neurotrope, announced. 

The trial (NCT04538066), which is recruiting patients at several sites across the U.S., will build on data from previous studies assessing bryostatin-1.

The study, which opened this year, aims to enroll about 100 patients with moderate and moderately severe Alzheimer’s. Those enrolled will be randomly assigned to either bryostatin-1 or a placebo — both in the absence of Namenda — for two 11-week dosing cycles, given over six months. 

Its main goal will be to assess the long-term effects of bryostatin-1 on patients’ cognitive function, as measured by the Severe Impairment Battery (SIB), a test used to assess cognition in people with advanced dementia who are unable to complete other psychological tests. 

Bryostatin-1 is a molecule that is designed to cross the blood-brain barrier  and to increase the activity of the enzyme protein kinase C (PKC) in brain cells. Evidence suggests PKC activity is linked to cognitive function, and required for the maintenance of healthy synapses — the sites where nerve cells come into contact and communicate with each other. 

previous Phase 2 trial (NCT02431468), assessing the efficacy of two doses of bryostatin-1 in 147 patients with moderate to severe Alzheimer’s, showed the therapy’s lowest dose (20 micrograms, mcg) was safe and led to improvements in cognitive function. This benefit was seen to be more pronounced in a subgroup of patients not taking Namenda. In those with moderately severe disease, improvements in cognition were sustained for four weeks after the end of treatment. 

A follow-up Phase 2 trial (NCT03560245), assessing an 11-week treatment course of 20 mcg of bryostatin-1 without Namenda, showed treatment led to similar cognitive improvements in patients with moderately severe disease, but failed to meet its primary efficacy goal of demonstrating bryostatin-1’s superiority over a placebo at improving cognitive function in those with more severe disease. 

Source: https://alzheimersnewstoday.com/2020/10/19/first-alzheimers-patient-dosed-phase-2-trial-assessing-long-term-bryostatin-1-efficacy/

 

RetiSpec and Gentex Developing Technology to Detect Early Alzheimer’s 

RetiSpec and Gentex are partnering to develop a technology to detect Alzheimer’s disease — potentially years before symptom onset — using a non-invasive and cost-effective eye scan technique. 

RetiSpec’s technology uses a device to perform a simple eye scan, which then can be used to identify the presence of certain disease biomarkers in the eye. This technology also uses hyperspectral imaging techniques and artificial intelligence (AI)-driven algorithmic methods to analyze biomarker data. 

According to RetiSpec, preclinical and feasibility studies showed its patented technology was effective at detecting changes in biomarkers that are associated with high levels of amyloid beta, a protein that is thought to contribute to the onset of Alzheimer’s, in the brain. The technology also was effective at detecting biomarker changes in patients who did not yet show symptoms of the disease. 

To further advance the development of this technology, RetiSpec has partnered with Gentex, a technology company focused mainly on the development of electro-optical devices with a wide range of applications. 

RetiSpec already partnered with clinical sites in the U.S. and Canada, to make its technology available for research purposes. The test can be performed on site at these locations. 

Source: https://alzheimersnewstoday.com/2020/10/21/retispec-gentex-developing-technology-detect-early-alzheimers/ 

 

Association between APOE ε2 and Aβ burden in patients with Alzheimer- and vascular-type cognitive impairment 

The objective of the study was to investigate the association between APOE genotype and β-amyloid (Aβ) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease–related cognitive impairment (ADCI). 

This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aβ positivity,  the researchers performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach.

In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aβ positivity, while in the SVCI group, ε2 carriers showed a higher frequency of Aβ positivity. In particular, the researchers observed an interaction effect of ε2 carrier status and diagnostic group on Aβ positivity, in that relative to ε3 homozygotes, there were more Aβ-positive ε2 carriers in the SVCI group than in the ADCI group. The researchers also identified latent subgroups of Aβ-positive APOE ε2 carriers with SVCI and Aβ-positive APOE ε4 carriers with ADCI. 

These findings suggest that APOE ε2 is distinctly associated with Aβ deposition in patients with SVCI and those with ADCI. The findings further suggest that there is a distinctive subgroup of Aβ-positive APOE ε2 carriers with SVCI among patients with cognitive impairment. 

Source: https://n.neurology.org/content/95/17/e2354 

 

Decline in kidney function over the course of adulthood and cognitive function in midlife 

The objective of the study was to test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife. 

 The researchers included 2,604 participants from the population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30.

At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate <60 mL/min/1.73 m2 or albumin-to-creatinine ratio >30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. 

Over the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function, psychomotor speed, and executive function. All these associations were independent of sociodemographic status and cardiovascular risk factors. 

In this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife. 

Source: https://n.neurology.org/content/95/17/e2389 ; First published September 2, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010631 

 

Evaluation of a novel immunoassay to detect p-Tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias
First published September 24, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010814 

 

The objective of the study was to investigate whether p-tau T217 assay in cerebrospinal fluid (CSF) can distinguish Alzheimer’s disease from other dementias and healthy controls. 

The researchers developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from three cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy subjects (n = 44). 

The p-tau T217 assay (cut-off 242 pg/ml) identified AD subjects with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, 88% specificity compared favorably with p-tau T181 ELISA (52 pg/ml) showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, 97% sensitivity. 

The assay distinguished AD patients from age-matched healthy subjects,  similarly to p-tau T181 ELISA. In AD patients, the researchers found a strong correlation between p-tau T217-tau and p-tau T181, t-tau and Aβ40 but not with Aβ42. 

This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggests that the new p-tau T217 assay has a potential as an AD diagnostic test in the clinical evaluation.

Classification of Evidence: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes AD from other dementias and healthy controls. 

Source: https://n.neurology.org/content/early/2020/10/26/WNL.0000000000010814 

 

Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype 

 The objective of the study is to evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. 

The study included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF β-amyloid1–42 (Aβ42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. 

The researchers found that within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD. 

Source: https://n.neurology.org/content/95/17/e2378 

First published August 11, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010629

 

Compiled by Padmaja Genesh, Learning Specialist