Good news, pandemic aside, Alzheimer and dementia (AD) research continues. Bad news: there is no miracle drug, no FDA-approved drugs for years. As always, families can look skyward and hope! (the image above is a tribute to the Part the Cloud funding group, and their exciting, specific focus on therapy).
Scientific meetings are a way to learn about how close we might be to treating patients. The Alzheimer’s Assn International Conference (AAIC>20), scheduled for July in Amsterdam, was held online instead; their online vendor created a “fun” way to access the lectures (free sessions now closed), but if you could ever find what you were looking for, there were hundreds of presentations. Screenshot:
The AAIC2020 Highlights Press Release doesn’t say much; there may be a new “early diagnosis” blood test (again), flu shots may help prevent AD, and general good health seems to ward off AD, but nothing about therapy for people now living with dementia; last year, the press release mentioned nasal insulin, but sadly that therapy failed, documented in the paper published this year.
The release doesn’t mention the presentation of results from the DIAN study (two amyloid meds, neither positive for cognitive improvement), the presentation of the GV-971 / oligomannate agent approved in China (no specific cognitive outcome data shared), or the IDEAS study of the economic and care impact of expensive PET biomarker scans (evidently no cost savings in overall patient care, reported in the media). A few other things caught our attention:
“Inflammaging” was a new word to AlzGadfly, used by Dr. H. Fillit of the Alz Drug Discovery Foundation; it’s a combination of inflammation and aging. He explained that everyone aging is thought to have more inflammation, a trending buzzword concept. This is evidently not the age-old inflammation taught in med schools of the last century, with Latin words (dolor, rubor, etc), mobile effector cells and chemical mediator release, but brain astrocytes and microglia doing their own “innate immunity” duty in their own peculiar way. It seems that the defining evidence for this kind of neuroinflammation is finding a transcript of a putative inflammatory or cytokine gene, not the tissue level inflammation associated with the classic “brain fevers” of meningitis or encephalitis.
Tau, a protein that is part of abnormal tangles in many diseased neurons, seems to be emerging from behind amyloid’s shadow. Dr. R. Tanzi, a long-time amyloid champion, surprised AlzGadfly by making “tauopathy” the initial topic of his presentation, even calling Alzheimer’s Disease itself an amyloid-induced tauopathy, comparing it to other tauopathies including Chronic Traumatic Encephalopathy (CTE), associated with head trauma in athletes.
Resistance and Resilience to putative tau and amyloid effects, found in some remarkable individuals, was discussed. Dr. Y. Quiroz presented her work on a unique patient who carries a known familial gene mutation and heavy amyloid burden but has only mild cognitive issues [discussed here last year]. Dr. T. Gomez-Isla presented her work on neuropathology in this arena. Dr. T. Montine and colleagues had proposed some definitions well before last year’s meeting: “resistance” is aging with normal cognition and not much neuropathology, whereas “resilience” is having some neuropathology, but still maintaining fairly normal cognition anyway….hm, does Lancet-style dementia prevention (see below) mechanistically promote resistance or resilience somehow?
Early Onset AD , <age 65, was the subject of an excellent (IMHO) clinical summary, given with clarity and empathy by Dr. N. Fox, an AAIC Plenary Presentation. Even with ~240,000 afflicted in the US and UK combined, it is considered “rare,” about 5-7% of all ADRD. Perhaps 40% of those afflicted are sporadic and do not have an easily identified gene issue (from another speaker’s slide).
Dr. Fox pointed out how those afflicted have less common presentations, a usual delay in diagnosis, differences in biomarkers and natural history, while trying to maintain a “social facade” at work and home. He discusses the devastation the condition creates for patients and their families in their prime. In the Q&A, he mentioned that most afflicted with EOAD have none of the Lancet risk factors like diabetes, obesity, hypertension, etc, making it more puzzling and frustrating. Perhaps AAIC can make his talk more available.
The ambitious LEADS (longitudinal EOAD) study, emphasizing imaging and neuropath issues, basically compares it to Late Onset AD. The presentations of preliminary findings shows pattern differences; tau seem prominent. In a separate session, Dr. B. Boon described “novel coarse-grained” amyloid-40 plaques associated with EOAD.
Repurposing Drugs, utilizing agents already approved for other diseases, trying them for dementia, was given it’s own live session with several speakers, including Dr. H. Fillit mentioned above. He described the funding of a second trial using dasatinib and quercetin to slow cellular aging and inflammation. The idea is that these medications may be “senolytic,” i.e. anti-aging in general.
Another presentation, more lab-based and preclinical, was by Dr. C. Ballard, who discussed repurposed drug screening strategies. He mentioned a few diabetes drugs, for example, and an Asian agent fasudil, used there for pulmonary hypertension but evidently not approved elsewhere. Their “hits” would still need further development to even get to clinical trials.
There was an intriguing poster by J. Stacey that showed indirect evidence that the use of anti-TNF drugs (like Enbrel TM) , used in severe rheumatoid arthritis, was associated with fewer later insurance claims for dementia, and fewer cases of a subsequent dementia diagnosis in electronic medical records (EMR).
The Seattle “Adult Changes in Thought” (ACT) Study held their annual research conference in August. Now running over 25 years, started by Dr. E. Larson and colleagues, the volunteer subjects at an HMO with a fairly robust EMR has been a rich source of data for this longitudinal study. Many subjects also gave consent for brain autopsies after death; detailed clinicopathologic correlations have been made.
Back in 2018, Dr. C. Latimer also presented concepts of AD resistance and resilience in the context of neuropathology at the ACT meeting. This year, Dr. CD Keene discussed some of the on-going work on the neuropath overlap. Dr. M. Albert gave a keynote presentation of the work studying how best to “maintain cognitive function;” she was part of a committee at the National Academy of Medicine summarizing those studies.
The online meeting this year focused on the pandemic’s impact on subjects and the remote running of current physical activity and cognitive monitoring studies; a collaboration with the Paul Allen Brain Institute, looking at various aspects of the transcriptome; and data mining the EMR for AD correlations with diabetes, along with examining specific drug prescriptions in hypertension management and subsequent AD.
The Lancet provided, this July, a 2020 update of their massive dementia review from 2017 (cited here), produced by Prof. G. Livingston and her international group of colleagues, including two from Seattle. They write there are now even more non-drug issues in preventing or delaying AD; they currently cite >300 papers, mostly dated 2017 on.
Given the evidence of drug failures in AD, it’s interesting that the Lancet paper group of researchers still finds good science for things each individual might do to reduce the risk of eventual cognitive decline:
“New evidence supports adding three modifiable risk factors—excessive alcohol consumption, head injury, and air pollution—to our 2017 Lancet Commission on dementia prevention, intervention, and care life-course model of nine factors (less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and infrequent social contact). Modifying 12 risk factors might prevent or delay up to 40% of dementias… Be ambitious about prevention.”
So that leaves at least 60% of dementias that might benefit from disease-modifying therapy. Late last year, Drs. J. Long and D. Holtzman wrote an AD review in the eminent journal Cell [paywall link here]. They review the current science and hypotheses, then document the frustrating trail and hard work of failed clinical trials; among things with which to move forward, they mention immune modulation, and champion combination trials.
Last December, the annual Clinical Trials AD (CTAD) meeting had few positive results. A CTAD Task Force led by Dr. S. Gauthier subsequently published “non-amyloid” approaches for disease modification, this April. The authors also discuss current ideas, including “geroscience” (about aging), and propose a “general strategy.” Last year the CTAD Task Force championed combination trials.
Rational pronouncements aside, AlzGadfly still senses a lack of operational leadership and a comprehensive concrete strategy to really broaden the scope of clinical trials. This blog has encouraged an oncology-like approach to AD therapeutics [based on experience with the prioritized approach of the Children’s Oncology Group], and readers here know that combination trials were started in pediatric leukemia over 60 years ago, by Dr. J. Burchenal and colleagues. Combination therapy still remains critical for many cancer cures.
Let’s hope that the Part the Cloud group, started by Michaela Hoag in memory of her father, raising $60M for therapy related research through the Alzheimer’s Association, can provide a catalyst to improve the lives of people living with dementia, ASAP.