12 Jan 2024

After decades of effort, setbacks, and dogged steps forward, Alzheimerologists breathed a collective sigh of relief last year with the U.S. FDA’s thumbs-up for Leqembi, the first traditional approval for a disease-modifying immunotherapy for this disease. Finally, a hurdle was cleared—without much contest, no less. Building on this breakthrough, scientists across academia and industry are off to the races, it seems. They are energized far beyond this one drug. As systemic biology is being deployed in longitudinal cohort studies, producing some converging results, progress appears to be accelerating across the field. Before you fully turn your gaze forward to the work of 2024, look back one more time at the main developments that brought us all to this point.

Therapeutics

**Clarity on Clearance.** In the Clarity clinical trial, amyloid accumulated slowly over 18 months in people on placebo (top panel). Lecanemab (bottom panel) reduced plaque load over the same period. *[Courtesy of Eisai.]*

Alzforum's raison d'etre, it could be said, is to facilitate the search for treatments for Alzheimer's and related diseases. The year 2023 was a good year for this, as the U.S. FDA approved several drugs, compared to none in 2022. Last July saw the first traditional approval in the U.S. of a disease-modifying therapy for Alzheimer's disease—the anti-amyloid antibody Leqembi, aka lecanemab. Boston's Brigham and Women's Hospital, New York's Columbia University, St. Louis's Washington University, the Mayo Clinic, and LA's University of Southern California started administering the therapeutic right away. The number of centers grew throughout the second half of the year, helped along in October by news that the Centers for Medicare & Medicaid Services was now covering amyloid PET scans. The Japanese health authorities greenlighted Leqembi last September. In December, they gave it clinical use guidelines and added it to the nation's health insurance drugs list. Hospitals started infusions days later (Japan Times; Pharmaforum; NHK World News Japan). Approval in China came on January 9, 2024 (see Eisai/Biogen press release). In Europe and elsewhere, the wait is still on.

Clinicians the world over are watching closely, hoping that catastrophic side effects can be avoided as more people in more settings get treated (Solopova et al., 2023). Next up for the FDA to decide: donanemab. This antibody posted a clinical benefit in Phase 3, despite a niggling question about not having budged tau PET.

Throughout 2023, scientists studied the entire crop of anti-amyloid antibodies to learn more about when to treat (before amyloid “bothers” tau) and how much plaque to remove (all of it). A tantalizing foreshadowing of potential Alzheimer's prevention with anti-amyloid therapy came from the Dominantly Inherited Alzheimer's Network (DIAN). Analysis of long-term extension data from its first treatment trial hinted that eight years on the now-discontinued antibody gantenerumab indeed staved off both amyloid deposition and symptoms in autosomal-dominant mutation carriers destined to develop Alzheimer's dementia. In the wake of Leqembi's approval, research interest in ARIA, CAA, and complement as a potential mechanism has surged.

Tangle Load Is Key. People with few tangles at baseline, below 1.10 tau PET SUVR, were reported to have fared better on amyloid immunotherapy than did those with intermediate and high tangle loads. [Courtesy of Eisai.]

Controversy remains. Asking whether de facto unblinding by ARIA, abetted by the CDR-SB's subjectivity, may have skewed results, scientists are calling for companies to release patient-level data linking a person's amyloid removal to their clinical outcome, or to show spaghetti plots. More hotly debated in 2023 was the question of how to measure when a treatment effect becomes meaningful and outweighs the risk.

Complement, the Hatchet Man? According to this hypothesis, anti-amyloid antibodies (light blue) bind to vascular amyloid and trigger the complement cascade, prompting formation of the membrane attack complex (dark blue), which damages blood vessels. [Courtesy of Cynthia Lemere and Maria Tzousi Papavergi.]

Meanwhile, next-generation antibodies are on their way. Among those that advanced in 2023: formulations people self-inject under the skin, and brain shuttle versions that circumvent the larger blood vessels where ARIA seems to originate and instead enter the parenchyma via capillaries. Leqembi's approval also revived interest in anti-amyloid approaches that had been pronounced dead. A γ-secretase modulator moved into Phase 2; for low-dose BACE inhibitors, there is talk but no discernable action yet.

Conventional versus Shuttle. In mouse brain, conventional antibodies (green, left) linger in the choroid plexus and ventricles five days after infusion. A brain shuttle (right) delivers them evenly throughout brain parenchyma. [Courtesy of Roche.]

April brought a win for patients with SOD1-mutant ALS, when the FDA granted accelerated approval to the anti-SOD1 anti-sense oligonucleotide (ASO) Qalsody, aka Tofersen. The decision rested on biomarkers, i.e., lower CSF SOD1 and—importantly—neurofilament light. NfL reduction is thought to predict a clinical benefit that may manifest months after this neurodegeneration marker has changed. Does NfL reduction after a given drug has hit its target presage clinical improvement? In 2023, this became a closely watched question across the ADRD field, especially following anecdotal observations that the anti-FUS ASO ION363 may be doing exactly that. Hence an ongoing trial of the anti-ataxin ASO BIIB105 added plasma NfL as an outcome measure. In Alzheimer's, the anti-tau ASO BIIB080 sailed past Phase 1, initially based on reducing tau in the CSF and tangles on PET, and subsequently buoyed by hints of a clinical benefit.

Tantalizing Trend? Volunteers with mild AD in two high-dose BIIB080 groups (top and bottom) appear to have declined less on the CDR-SB (left), MMSE (middle), and FAQ (right) than external controls. [Courtesy of Biogen.]

Moreover, 2023 saw FDA approval for Lamzede, Elfabrio, Pombiliti. These enzyme-replacement therapies treat rare lysosomal disorders, namely alpha-mannosidosis, Fabry, and Pompe diseases. These drugs do not reach the CNS, yet they give ADRD scientists hope because they confirm that rectifying specific enzyme deficiencies in cellular proteostasis helps patients. The race is on to define lysosomal targets in the brain, and to deliver drugs to them in neurologic illnesses. One such treatment, using brain shuttle technology, was uplifted by none other than CSF NfL reduction (see above). In June 2023, Denali reported that DNL301, an enzyme replacement therapy for Hunter syndrome, a pediatric lysosomal storage disease, halved CSF NfL in an open-label Phase 1/2 study. Subsequent hints of a clinical benefit advanced DNL301 to Phase 2/3. A brain shuttle version of progranulin replacement therapy called DNL593 was reported to increase CSF progranulin but no NfL or clinical data are reported yet. DNL593 is being developed to treat FTD.

Synthetic peptides rarely succeed, so it is worth mentioning that 2023 saw one such winner, in a brain disease no less. The FDA approved Daybue, aka trofinetide, for Rett Syndrome. In AD research, a synthetic peptide against Aβ oligomers moved into Phase 2 last year.

After Long Wait, Aβ Oligomer Detangler Poised for Phase 2

Last but not least, the FDA's approval, in May 2023, of brexpiprazole /therapeutics/brexpiprazole formally handed doctors another tool to help them manage the agitation that can make the middle stages of Alzheimer's dementia so very difficult for patients and their care partners.

FDA Approves Rexulti for Agitation in Alzheimer’s

In general, drug evaluation in ADRD is expanding, meaning the number of people needed to fill trials is growing, as well. The 2023 version of an annual survey of AD clinical trials noted that 57,000 participants were required for the 187 Phase 1, 2, and 3 trials that were active last year. Of those trials, 19 percent target the amyloid hypothesis. Most others fell into these mechanistic buckets: neurotransmitter receptors, inflammation, synaptic plasticity, tau, bioenergetics, proteostasis, oxidation. Small but hopefully up and coming: ApoE/lipids (Cummings et al., 2023).

Biomarkers

For the goal of diagnosing Alzheimer's disease in routine clinical care, some forms of phospho-tau now look better than ever. Plasma p-tau217 led the pack in a round-robin comparison of 26 different assays, distinguishing people with AD from controls accurately and reproducibly (image below). Even so, it is not quite sharp enough to be a stand-alone test. One option: set a high cutoff to identify people who are surely positive, a low cutoff to identify people who are surely negative, and send anyone who falls in between for further testing. Another option: measure the fraction of serine 217 residues with a phosphate group, since the p-tau217/217 ratio better correlates with plaques and tangles than does p-tau217 alone. Last year, C2N began selling PrecivityAD2, a new plasma test that combines this ratio with the Aβ42/40 ratio. This test is not yet FDA approved, unlike Roche’s Aβ42/total-tau cerebrospinal fluid (CSF) test, which got the agency's green light last June, joining Roche's CSF Aβ42/p-tau181 approved in 2022. To the dismay of many in the field, Quest Diagnostics in 2023 began selling its Aβ42/40 blood test directly to consumers, sans any peer-reviewed data.

Round 1: P-tau217. In a round-robin analysis of 40 plasma samples, p-tau217 assays best distinguished people with AD from healthy controls (left). They also record the biggest fold differences (right). [Courtesy of Nick Ashton, University of Gothenburg.]

The NIA-AA working group on AD diagnostic criteria proposed to split tau markers into those that measure soluble phospho-tau, which is seen as more a correlate of "amyloid pathology bothering tau," versus those that measure fibrillar tau. For the latter, a fragment of tau's microtubule-binding domain containing leucine 243 currently looks like the best option. Amid controversy, the NIA took its name off the criteria.

Beyond Aβ and tau fragments, other proteins will eventually add depth to a person's AD diagnosis. In 2023, a panel of 48 CSF proteins distinguished people with AD 94 percent of the time, beating out the core markers. Extracellular matrix proteins found in CSF predicted autosomal-dominant Alzheimer's 30 years prior to symptoms. Others distinguished sporadic from familial AD and from people carrying TREM2 risk variants. Likewise, proteome signals from TREM2 or progranulin knockout mice suggest markers of microglial activation that correlate with amyloid burden in people.

**Synuclein PET?** Cryo-EM reveals F0502B (orange) binding within a groove formed by stacked pairs of α-synuclein protofibrils. *[Courtesy of Xiang et al., Cell, 2023.]*

Biomarkers for other neurodegenerative diseases are on the horizon. After decades of effort, α-synuclein PET tracers look promising. 18F-ACI-12589, previously shown to detect synuclein deposits only in people with multiple system atrophy, lit up in people with PD or DLB who have a duplication of the synuclein gene, implying that the tracer works best when synuclein burden is high. Other candidate tracers bound α-synuclein in brain samples or in macaques. CryoEM helps scientists understand the binding chemistry of their ligand (image above). For fluid markers, high levels of dopa decarboxylase in the blood or CSF picked out people with Lewy body disease from within a research cohort. α-Synuclein seed amplification assays detected PD with high sensitivity, and are starting to see use in some clinics. In November 2023, a specialty meeting convened groups seeking biomarkers for ALS/FTD. They still have a ways to go. Among the leads: 4R non-AD tauopathies such as corticobasal syndrome may become identifiable via the MTBR-275 and -282 fragments of tau in CSF. Strange “cryptic peptides” turned up in the CSF of patients. This discovery raised hope that there will soon be a marker for TDP-43 proteinopathies, diseases in which this RNA-binding protein abandons its post in the nucleus and exposes RNA to mis-splicing events that form translatable “cryptic exons.”

Lipids

If you haven’t already gotten the whiff: Fats started to sizzle last year. Among the thousands of lipids and hundreds of lipoproteins in the brain, scientists have begun to identify modulators of neurodegeneration. They described triglyceride-laden droplets that nix microglial phagocytosis of Aβ, long-chain fatty acids that spur α-synuclein aggregation, and the astrocyte receptor TMEM164 tempering synthesis and release of neurotoxic fatty acids. TMEM106b, a transmembrane protein linked to FTD and AD, supports axonal myelin sheaths by keeping them stocked with the fatty acid derivative galactosylceramide. Microglia also support myelin by regulating oligodendrocyte lipid metabolism, keeping cholesterol esters from building up.

Lives of Lipids. Long-chain fatty acids give rise to a plethora of inflammatory lipids (red) and pro-resolving mediators (blue). A “class switch” could cool inflammation. [Courtesy of Oliver Werz.]

Cholesterol itself oils microglial phagocytosis of Aβ, but its metabolite, 25-hydroxycholesterol, fuels inflammation, hastening neurodegeneration. That's in a tauopathy model. Astrocytes and oligodendrocytes accumulate cholesterol and other lipids if they express ApoE4, linking it to lipid biology.

Beyond fatty acids and cholesterol lies a land of lipids that regulate inflammation. Prostaglandins and leukotrienes can evoke acute inflammation; structurally related “specialized pro-resolving mediators” can calm it (image above). In 2023 scientists merely scratched the surface of this field. Even so, they hope shifting the balance toward resolving lipids could prove beneficial. Also ripe for study are the hundreds of lipoproteins that turn up in the cerebrospinal fluid, many with links to inflammation and immune responses.

For the first time, the International Conference on Alzheimer’s and Parkinson’s Diseases held a symposium on lipid dyshomeostasis in neurodegenerative disease, while the conference Lipids in Brain Diseases, held for the second time in 2023, plans to be biannual.

Meninges/Immune Cells

For decades, scientists lived by the textbook tenet that three meningeal membranes surround the brain. Last year, a controversial paper claimed that in addition to the dura, arachnoid, and pia membranes, a fourth, dubbed the subarachnoid lymphatic-like membrane (SLYM), lies between the arachnoid and pia, separating the space. SLYM chance, countered others, who believe the cells of this purported fourth membrane are instead part of the arachnoid membrane (image below). Resolving this debate is important, because these border tissues not only protect the brain, but the fluid spaces they create affect the flow of CSF and some of the membranes produce brain-specific immune cells that may play a role in AD. In a separate development in 2023, infiltrating T cells accelerated neurodegeneration caused by tau or APP/PS1 mutations in mouse and three-dimensional cells models.

Arachnoid Architecture. The barrier cells of the outer layer (magenta) are in close contact with cells that express both Prox1 (white) and VE-cadherin (green, yellow arrowhead), proteins claimed to be markers of a fourth meningeal layer. VE-cadherin is expressed more strongly by vascular endothelial cells (white arrowhead). Asterisk marks blood vessel lumen, nuclei are blue. [Courtesy of Mapunda et al., Nature Commun, 2023.]

Fibrils

At the heart of every proteinopathy lies a fibril. Their makeup eluded scientists. Then along came cryo-electron microscopy and now, three-dimensional structures of Aβ, tau, α-synuclein, and TMEM106b fibrils are mapped at high resolution. Last year saw fibrils of Aβ40, TDP-43, and the RNA-binding protein TAF15 join the club (image below). Obtained from people with cerebral amyloid angiopathy and two different types of frontotemporal dementia, these new structures could enable the development of PET ligands or even therapeutics. Indeed, cryo-EM revealed what makes MK6240 such a good PET ligand for neurofibrillary tangles. So many amyloid structures are now solved that scientists began an atlas to keep track. At time of publication, it contained 261 structures, many being different polymorphs of the same protein.

Stacked Scooters. A TAF15 filament comprises a single protofilament stack of molecules twisting left around its helical axis (left). Perpendicular to the filament axis, the protofilament core comprises 13 β-strands folded into the shape of a scooter (right).

While cryo-EM captures the contours of individual fibrils extracted from tissue, cryo-electron tomography can map fibril structure in situ. In tissue from APP knock-in mice, this method showed amyloid plaques to be a meshwork of fibrils intermingled with plasma membrane, lipid droplets, and a variety of membrane-bound vesicles—perhaps products of autophagy (image below). Plaques from AD brain had a strikingly similar menagerie. Different fibrils of tau were seen in different cellular compartments, implying multiple forms exist in the same AD brain. Cryo-ET even spotted tau fibrils inside extracellular vesicles.

Innards of a Plaque. Bundles of Aβ fibrils (blue) mingle with round (red), C-shaped (orange), and ellipsoid (purple) vesicles, as well as membrane-less droplets (yellow). Plasma membrane from intact neighboring cells, or from cellular remnants (green) interdigitate. [Courtesy of Leistner et al., Nature Communications, 2023.]

But how do fibrils form? And spread? In 2023, scientists found out that tau forms dozens of fibrillar intermediates before finally morphing into a common protofibrillar precursor present in AD and in chronic traumatic encephalopathy. Whether tau undergoes a similar metamorphosis in other diseases is unknown. For a decade, cell-based sensors have helped scientists identify and quantify fibrillogenic species of tau, and last year cryoEM validated these assays by showing that the fluorescent chimeras do form fibrils. As for why tau forms fibrils, acetylation, aberrant ubiquitin, and RNA-binding proteins might all nudge it. Brain imaging showed in 2023 that plaques in the default mode network make tau fibrils spread faster in the medial temporal lobe, and fibrillogenic tau might even travel retrogradely, scientists reported. Tau tethered to exosomes or in synapses was said to promote spread. So may retroviral proteins, explaining links between activation of latent viruses in the genome and AD. Curiously, by activating dormant retrotransposons or damaging mitochondria, toxic tau may unleash double-stranded nucleic acids, setting off the cGAS-STING DNA sensor and a toxic immune response.

Microglia

Quite on their own, without needling from tau, microglia can unleash the cGAS-STING inflammatory response as mice age, damaging neurons. Other regulators of microglia that emerged last year include variants of the MS4A4A and PLCγ2 genes. The former push the cell's transition to an inflammatory state, while the latter modulate their plaque clearance. The AD risk genes clusterin and CD33 conspire to suppress microglial phagocytosis of Aβ, as does the 22-nucleotide mRNA miR155.

Curiously, other work suggested that microglia can clear extracellular Aβ. They dispatch lysosomes to their cell surfaces, where the organelles disgorge digestive juice onto nearby plaques. (Gross.) These lysosomes apparently can be a breeding ground for Aβ and tau aggregation, and releasing this brew into the extracellular space may spread pathology, not curtail it. Other work suggested that when microglia don't clear plaque, they enter a senescent state.

Lysosomal Synapses. A microglial cell (gray) sits underneath an Aβ aggregate (red). At the point of contact, it released acidic contents of its lysosomes, as detected by pH-sensitive dye (green, arrowhead). [Courtesy of Santiago Sole-Domenech, Weill Cornell Medical College.]

While corralling or clearing plaques may help protect against cognitive decline, overzealous microglia may achieve the opposite by pruning too many synapses. Last year, scientists reported that perivascular macrophages instigate this cull by spewing out inflammatory cytokines. The macrophages react to Aβ being cleared through the blood vessels. On the other side of the coin, the pruning might not be all bad because it can temper networks that become hyperactive in AD.

Omics

Single-cell omics continue to produce high-resolution snapshots of what goes on in healthy and diseased brains. In October, NIH’s Brain Research through Advancing Innovative Neurotechnologies initiative, aka “BRAIN,” published the most detailed cellular atlas to date of the healthy human brain. Using a variety of techniques, it mapped millions of cells of 3,300 types. In December, they followed with a higher-resolution map of the mouse brain that identified 5,300 cell types. In AD, a single-cell transcriptomic and epigenomic analysis of postmortem prefrontal cortex uncovered damaged DNA amid collapsed cell identity. Spatial transcriptomics-cum-histopathology identified a gradient of cellular responses around plaques, while single-nucleus transcriptomics studies pointed out abnormal cells in the AD vasculature. A transcriptomic and chromatin accessibility analysis of the same cells pinpointed two transcription factors— ZEB1 and MAFB—that might explain the dysregulated gene expression in AD neurons and microglia. All told, scientists are beginning to get a clearer picture of single cell pathology in AD.

What do scientists need to move beyond one-off studies with human postmortem materials? Standardized brain biopsy tissue from deeply phenotyped and genotyped participants in longitudinal studies. Last year, Alzforum reported a five-part series on such an endeavor in Kuopio, Finland. Every week, aging patients undergoing routine shunt-placement surgery to ameliorate symptoms of their normal-pressure hydrocephalus donate a teeny piece of frontal cortex from where the shunt catheter enters the brain. It is suitable for electrophysiology, single-cell analysis, genomics, spatial transcriptomics, disease modeling, immunohistochemistry and electron microscopy studies. Dura, intracerebroventricular and lumbar CSF, blood, skin, and fat samples taken during both the surgery and pre- and post-op care enable unprecedented data integration in this cohort. Nearly half of them have AD pathology; some carry ADRD mutations.

From Brain to Vibratome in a Hurry. Within an hour of coming out, a tiny pyramid-shaped piece of frontal cortex is sliced, recorded from, and preserved for other methods of study. [Courtesy of Henna Jäntti.]

Burrowing deeply into cells, scientists in 2023 developed a method to analyze mRNA in single synapses. In a mouse model of amyloidosis, this identified transcripts of inflammatory genes and complement components that tick up in synapses. At the population level, last year also saw the first study comparing single-cell findings across different tauopathies. For the most part, it seems, gene expression undergoes similar changes in AD, behavioral variant frontotemporal dementia, and progressive supranuclear palsy; that said, microglial expression changes are more likely in AD, while neurons and astrocytes bear a larger burden in bvFTD and PSP.

Last but not least, spatial proteomics in 2023 came into its own. Though technically trickier than transcriptomics, this cutting-edge methodology has become tractable thanks to antibodies tagged with unique tags that localize proteins at single-cell resolution. This identified microglial subtypes around plaques, and neurons that may resist tau pathology. Single-cell proteomics could help scientists learn which cells release biomarkers into the cerebrospinal fluid or blood. On that note, last year saw the first publications from the Plasma Proteomics Project, which matches genetic variants with plasma proteomes of more than 50,000 people in the U.K. Biobank. The pharmaceutical companies sponsoring this study hope it will generate new plasma markers or drug targets.

Cell Biology

After decades of singling out APP, presenilin 1 and presenilin 2, scientists have built a case that SORL1 is the fourth autosomal-dominant AD gene. Of more than 500 variants in this gene, those predicted to scupper protein folding, dimerization, or trafficking in the endosome dramatically raise a person’s risk of AD. Multigenerational pedigrees are being described. The Alzforum curation team placed all known variants on an interactive map of this 2,214-amino-acid behemoth (Mutations database).

Without SORL1 dimers, APP-laden retromers bog down in endosomes, and Aβ production runs amok. The retromer also keeps lysosomes running smoothly. Without SORL1, these mini recycling plants swell with undigested cargo, including APP. Sliced by β-secretase, APPs C-terminal fragment makes matters worse, scientists found, blocking the proton pump that acidifies the lysosome and hobbling them further. All told, 2023 evidence strengthens the idea that bad recycling through the endosome-lysosome-autophagy system spells trouble for neurons in AD. Possibly helpful: toning down ryanodine receptors, which release calcium that slows autophagy. In a twist on cell models of AD, neurons differentiated directly from adult fibroblasts seem to better capture lysosomal dysfunction in AD brain than do iPSCs.

Behold the Beast. SORL1's myriad component pieces include 10 VPS10p domains (green), six YWTD domains (gray), one EGF domain (orange), 11 CR domains (turquoise), six 3Fn domains (blue), a transmembrane domain, and a cytoplasmic tail. [Courtesy of Andersen et al., bioRxiv, 2023.]

ApoE

Unlike the “bad” ApoE4 isoform, ApoE3 is considered neutral with respect to risk for AD. How surprising then, when scientists reported that two copies of the R136S “Christchurch” variant of ApoE3 seemed to shield a woman with autosomal-dominant AD from neurofibrillary tangles. That was in 2019. Last year, they added that even one copy of Christchurch slowed AD progression in 12 carriers of said mutation and that they, too, had fewer tangles than expected for their amyloid burden (image below). These cases buttressed the claim that Christchurch is protective. So did animal studies on this variant. In amyloidosis mice, ApoE3 Christchurch slowed the spread of tau fibrils injected into the brain, and gliosis. In ApoE4 tauopathy mice, R136S slowed tangles, gliosis, and neurodegeneration. In the same ADAD kindred, a man carrying the H3447R variant in the Reelin gene also staved off dementia for 20 years after his expected symptom onset. Whether it explains his escape remains to be seen.

In related news, scientists reported that two men, one 79, the other in his 90s, who were ApoE4 positive but cognitively healthy had loss-of-function variants that might have protected them. This might bode well for therapies aiming to knock down ApoE4.

On ApoE's functional front, scientists reported that it draws microglia to clear amyloid plaques. Glia expressing the cell adhesion molecule VCAM1 sense ApoE, then switch gene expression to a disease-associated phenotype. The apolipoprotein has been thought to seed or stabilize plaques, but this work suggests the opposite. Maybe not for ApoE4, though. Another study suggests this isoform locks microglia in a homeostatic state, allowing plaques and tangles to grow unimpeded. Similarly, neurons that express ApoE4 worsen pathology, but conditionally deleting ApoE4 from them slowed accumulation of tangles, astro- and microgliosis, and neuron loss in a model of tauopathy.

It's a big field. It was a busy year. What did we miss? Nominate important advances, or critiques, of 2023 by sending a comment to contact@alzforum.org.—Tom Fagan and Gabrielle Strobel

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References

Therapeutics Citations

News Citations

Conference Coverage Series Citations

Alzpedia Citations

Mutation Interactive Images Citations

Paper Citations

Solopova E, Romero-Fernandez W, Harmsen H, Ventura-Antunes L, Wang E, Shostak A, Maldonado J, Donahue MJ, Schultz D, Coyne TM, Charidimou A, Schrag M. Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer's disease. Nat Commun. 2023 Dec 12;14(1):8220. PubMed.
Digma LA, Winer JR, Greicius MD. Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies. arXiv:2310.15456 [q-bio.TO], November 19, 2023 Cornell University, Quantitative Biology
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385. Epub 2023 May 25 PubMed. Correction.

2023—A Bumper Year for the Treatment and Science of Alzheimer's

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