2019 Year in Review

[antimatter37]

Here is an article reviewing Alzheimer's research throughout 2019. It is a long, very interesting read covering a wide diversity of AD research topics and ideas that show some promise.

https://www.alzforum.org/news/research- ... s-research

[NF52]

Here is an article reviewing Alzheimer's research throughout 2019. It is a long, very interesting read covering a wide diversity of AD research topics and ideas that show some promise.
https://www.alzforum.org/news/research- ... s-research

Thanks for posting this! In an effort to help spread some of this news--and because who has time to read all this stuff--I've excerpted several topics.
Apologies in advance for the length--you may want to just browse the topic heading for ones of interest. It's helpful to see the breadth of research, which extends far beyond clinical trials, which tend to get the most media attention. [Bold emphases are my additions.]:

ApoE

2019 saw a resurgence of interest in ApoE...Mechanistically, ApoE4...was front and center in 2019. Alas, findings thus far are so complicated and sometimes contradictory that a clear story has not yet emerged. Over the last few years it became apparent that ApoE and TREM2 coordinate microglial responses in AD, switching them from homeostasis into a neurodegenerative state (Sep 2017 news; Feb 2015 conference news). Scientists learned that ApoE4 locks microglia into a homeostatic state, leaving the brain vulnerable to myriad pathologies. Others reported that while ApoE4 squelches microglial phagocytosis, it ramps up their inflammatory responses (May conference news; Sep news)... What, if anything, do microglia ablation experiments say about ApoE and human AD? People...accumulate more neurofibrillary tangles if they carry ApoE4, which also seems to hasten tangle-related memory loss (Nov news). Could this explain gender differences in AD? Among people with plaques who are cognitively healthy, women accumulate more tangles in the entorhinal cortex than do men, and ApoE4 exacerbates this sex difference (Feb news). Whether this revolves around microglia remains to be seen... In P301S-tau/ApoE4 mice, eliminating microglia prevented the spread of tau pathology and spared neurons from degenerating

Blood tests for Amyloid Beta positivity:

Blood is a more complex mixture than CSF; its Aβ42 concentration is 10-fold lower, and peripheral cells release their own Aβ into blood...Inconsistencies across assays—which have to perform near their detection limit to pick up a solute that also rises and falls on the tides of biological parameters such as blood pressure, diabetes, diet, or exercise—prompt leaders in the field to urge a thoughtful stepwise deployment of these tests, first with limited applications such as clinical trials and population-based studies.

Microglia

2019 was the year of the microglia...researchers got a better handle on how variants in ApoE, TREM2, CD33, Bin1, the MS4A gene cluster, and progranulin either soothe microglia into a homeostatic state, or aggravate them into a cytokine-spewing one...Bolstering the idea that TREM2 shedding is protective, people with plaques were sharper if their CSF [cerebral spinal fluid] sTREM2 was high

Exercise

New evidence from large observational studies further cemented the well-accepted idea that physical activity protects against all-cause dementia...Among people older than 50, more physical activity associated with reduced AD biomarker and markedly less dementia over five to14 years in U.S., U.K., and Chinese cohorts...In a long-standing observational cohort in New York City, people who had exercised vigorously since their teenage years were 60 percent less likely to develop dementia decades later.

Sleep

Rhythms from without the brain might help, too. Rocking like a baby deepens sleep in adults, as well, extending time in non-rapid eye movement sleep and improving memory ...Longer waves, in the 40 Hz range, may be important during waking hours...In 2019, sound was reported to achieve the same synchronicity in the auditory cortex and hippocampus, and sound and light together reportedly caused synchronicity deep in the sensory cortex, where it stimulated microglia to remove Aβ.

Transcriptomics [per wikipedia, the study of an organism's transcriptome, the sum of all of its RNA transcripts]

Spatial transcriptomics emerged as a way to correlate changes in gene expression at the cellular level with neuropathology, perhaps offering an answer to the old question about why specific regions of the brain are more vulnerable in specific age-related neurodegenerative diseases. This method uncovered an upregulated network... The network includes known AD genes, such as TREM2 and APOE, but also 36 not previously linked to plaques.

Vascular Risk and Prevention

In the British Birth Cohort, a group of people studied since they were born in 1947, vascular problems as early as their 30s put them at risk for dementia late in life. They are now 72. Importantly, their vascular risk did not correlate with brain amyloid deposition, reinforcing separate etiologies for AD and other types of dementia

The Sprint MIND hypertension control trial results were published, and a two-year follow-up study started...lowering systolic blood pressure to 120 mmHg for three years in people over 50 nudged down their subsequent rate of MCI by 20 percent. The follow-up will look for a longer-lasting effect on dementia.

Aducanumab (amyloid beta antibody)

Midway through the trials, Biogen had introduced protocol changes. One allowed ApoE4 carriers to now receive the highest dose of 10 mg/kg, whereas initially they had been capped at 6 mg/kg over concerns about ARIA; another allowed ApoE4 carriers to resume their original aducanumab dose after their ARIA had resolved. Essentially, these changes increased drug exposure over time in some of the later enrollees, but not earlier enrollees, especially in EMERGE, which started after ENGAGE did. In the former, Biogen reported a slowing of cognitive decline by a quarter and functional decline by 40 percent in people on the highest dose. This was not seen in ENGAGE, however.

Amyloid beta immunotherapies:

Other Aβ immunotherapies, especially the antibodies BAN2401, gantenerumab, and donanemab, all appear to push brain amyloid below the threshold of positivity, as well, and possibly even keep it there for a few years after antibody treatment is stopped... Scientists uniformly welcomed the current trend of calling immunotherapy trial participants back for open-label extensions to watch how their amyloid load, disease progression, and potential side effects unfold over several years.

Inhibition of cytokines:

The epigenetic drug apabetalone, on the other hand, may quell brain inflammation indirectly, by acting not in the brain but in the blood. By blocking transcriptional machinery, this drug shuts down hundreds of genes, including pro-inflammatory cytokines made by endothelial cells (see image below). It is being tested primarily in cardiovascular disease, but in a cognitive sub-study seemed to help people with mild cognitive impairment or early dementia.

Novel therapeutic targets:

[T]he past year saw innovation in the form of NDX-1017, a small molecule that induces the neuroprotective HGF/MET receptor, and gemfibrozil, a cheap old fibrate drug that activates the PPARα nuclear receptor. Both managed respectable results in well-designed Phase 1 trials and are moving forward...

Non-steroidal anti-inflammatory prevention

2019 brought ups and down for anti-inflammatory strategies. The coffin finally closed on the idea that nonsteroidal anti-inflammatory drugs can prevent Alzheimer’s disease, when the INTREPAD trial failed (Apr news). Two years of naproxen in asymptomatic people at high risk for AD made no difference on cognition, structural or functional brain imaging, or CSF Aβ, total or phospho-tau, all the while causing significant gastrointestinal and cardiovascular side effects.

Reduction of hallucinations and delusions in AD

Acadia Pharmaceuticals’ Phase 3 trial for the selective serotonin inverse agonist pimavanserin wrapped up early when the drug reached its primary endpoint of delaying relapse to hallucinations and delusions in people with dementia ...This study used an unusual design, testing how well patients did when they came off pimavanserin rather than when they went on it. After a 12-week open-label phase, patients who responded to the drug either continued it or were switched to placebo. At CTAD, Acadia reported that 75 percent of patients responded to the drug in the open-label phase of the trial...Those randomized to [continue the drug after 12 weeks] were three times less likely to relapse than were those switched to placebo.

Genetics

Scientists are combining genetics, genomics, transcriptomics, and expression network analyses to pin down the functional effects of risk variants. Time and again, they find genes expressed primarily in microglia. For example,...researchers mapped known GWAS variants in enhancer regions to gene expression in myeloid cells, uncovering nine genes not previously linked to AD,...implying coordinated expression of AD-related genes in these cells. Other groups create their own atlases of active regulatory regions specific to human neurons, astrocytes, oligodendrocytes, and microglia. They too, see AD GWAS hits cluster in regulatory regions of the microglial genome

[Plumster]

Thank you, NF52!!

[Fiver]

Thanks antimatter37 and NF52, that was really helpful!