Introduction Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non‐steroidal anti‐inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short‐term treatment of transgenic AD mice with the pro‐inflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM‐CSF/sargramostim to safely ameliorate AD symptoms/pathology. Methods A randomized, double‐blind, placebo‐controlled trial was conducted in mild‐to‐moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow‐up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. Results Sargramostim treatment expectedly changed innate immune system markers, with no drug‐related serious adverse events or amyloid‐related imaging abnormalities. At end of treatment (EOT), the Mini‐Mental State Examination score of the sargramostim group increased compared to baseline ( P = .0074) and compared to placebo ( P = .0370); the treatment effect persisted at FU1 ( P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% ( P = .0105); plasma markers of neurodegeneration (total tau and UCH‐L1) decreased 24% ( P = .0174) and 42% ( P = .0019), respectively, after sargramostim treatment compared to placebo. Discussion The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long‐term safety and efficacy of GM‐CSF/sargramostim in AD is warranted.

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SummaryResponding to requests from attorneys concerning patients or providing independent consultations in the legal process may present unique challenges, particularly if special reports are needed or if there is to be testimony under oath. While the legal process is adversarial, the role of the physician consultant, whether acting as treating physician or independent expert, is not to advocate for one side or the other, or to persuade the trier of fact, but to state his or her professional opinion clearly and concisely. The American Academy of Neurology published a position statement on "Qualifications and Guidelines for the Physician Expert Witness" in 2005. Following professional practice guidelines allows the neurologist to participate in the legal process effectively and ethically. The larger the pool of neurologists available for consultation in legal matters, the more access the legal system will have to balanced expertise.

Background Rheumatoid arthritis (RA) patients have a reduced risk of developing Alzheimer’s disease (AD), originally hypothesized to be attributable to their use of non‐steroidal anti‐inflammatory drugs (NSAIDs). However, clinical trials with NSAIDs were unsuccessful in both AD and Mild Cognitive Impairment (MCI) subjects. We hypothesized that intrinsic innate immune system factors associated with RA itself may underlie the AD protective effect(s). We tested several cytokines upregulated in RA blood and found that 20 daily injections of 5 μg granulocyte‐macrophage colony stimulating factor (GM‐CSF) reduced cerebral amyloidosis by greater than 50% and completely reversed the cognitive impairment of transgenic AD mice. In a retrospective study, we found that short‐term treatment with sargramostim/Leukine® (recombinant human GM‐CSF) plus G‐CSF improved cognition of leukemia patients following bone marrow chemoablation/hematopoietic cell transplant compared to patients who received G‐CSF alone. Method A double blind Phase II safety and efficacy trial of sargramostim in 40 mild‐to‐moderate AD subjects, half receiving placebo and half receiving 250 μg/m2/day sargramostim by subcutaneous injection five days/week for three weeks with follow‐up visits at 45 and 90 days post‐treatment is complete (NCT01409915). Neurological and neuropsychological assessments and MRI and amyloid‐PET scans were performed to assess the safety and efficacy of treatment. Result Clinical and imaging analyses showed no drug‐related serious adverse events, including no amyloid‐related imaging abnormalities (ARIAs; micro‐hemorrhage or vasogenic edema). At the end of treatment, the mean Mini‐Mental State Examination (MMSE) score in the sargramostim group was improved relative to baseline (p=0.0074) and to the placebo group (p=0.037) by repeated measures mixed model analysis. The beneficial effect of sargramostim on MMSE, compared to placebo, was retained at the first follow‐up visit at 45 days after the end of treatment (p=0.0272). In contrast, there was a single poorer ADAS‐Cog‐13 (Alzheimer’s Disease Assessment Scale‐Cognitive Subscale‐13) mean score in the sargramostim group compared to placebo–at the first follow‐up visit 45 days after the end of treatment. Amyloid and volumetric brain scans are being analyzed. Conclusion These results indicate that GM‐CSF/sargramostim shows promise as a potential treatment for AD and that our Alzheimer’s Association “Part the Cloud”‐funded 24‐week treatment trial is warranted.

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Background: Mild cognitive impairment ("MCI") is defined as the "symptomatic pre-dementia stage" on the continuum of cognitive decline. Currently, no medications have proven effective for MCI. Preclinical experiments indicate that NA-831 is an endogenous small molecule that exhibits neuroprotection, neurogenesis, and cognitive protective properties across a range of disease models. NA-831 has been shown to be safe and well tolerated in healthy volunteers. Methods: A randomized Phase 2A clinical trial of NA-831 was performed in Alzheimer patients with mild cognitive impairment of vascular origin. Inclusion criteria included: (a) male or female, at 55-80 years of age at screening, (b) Mini-Mental State Exam (MMSE) score !20 (primary school) or !24 (high school or above) (d) Center for Epidemiological Studies-Depression (CES-D) score <27. A total of 56 Patients were randomly assigned to NA-831 at a daily dosage of 10 mg or matched placebo (1:1) for 24 weeks. The primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), brief cognitive rating scale (BCRS) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and per protocol population. Results: The effects of NA-831 on Alzheimer patients with mild cognitive impairment were measured as statistically significant reductions in scores on the BCSR, and ADAS-cog scales. Based on the BCRS, the effects of NA-831 were apparent after 8 weeks of treatment (p¼0.001), with the significant improvement in the following areas: fatigue, anxiety, irritability, affective lability, disturbance to waking, daytime drowsiness, headache, and nocturnal sleep. NA-831 showed significant improvement with the ADAS-cog score changed 3.21 points (NA-831 change À4.47 vs. placebo À1.26; P ¼ 0.001; ITT). CIBIC-Plus showed (23 [82.1%] vs. 5 [17.9%]) patients improved; P ¼ 0.01; ITT). NA-831 was well-tolerated at high dosage up to 50 mg per day. No adverse effects were reported. Conclusions: Over the 6-month treatment period, NA-831 was effective for improving cognitive and global functioning in patients with mild cognitive impairment. As an endogenous compound, NA-831 is well-tolerated and has excellent safety profile.