Fixing the Aging Brain

The number one thing most people fear as they age is developing dementia. As the world’s population becomes increasingly older, this is a growing public health issue too. The World Health Organization estimates that 55 million people already have dementia worldwide. With a global market estimated to reach $13 billion over the next few years, drug developers are eager to get a bite of this market, but until recently, it has proved to be one of the toughest fields to enter.

Now, Leqembi, the first drug that treats Alzheimer’s underlying biology is finally fully approved and being covered by Medicare. Alzheimer’s is the leading cause of dementia. There are also new data sources, and insights on root causes of this and other forms of cognitive decline, as well as new tests to guide treatment. Plus, we are hearing lots of discussion about whether prominent elderly political figures, such as U.S. president Biden and former U.S. president Trump, have the mental stamina required for public offices.

The aging brain is in the spotlight.

Studying the human brain is always a challenge, and in this case there have been a few detours. “Mouse models just recapitulate certain phenotypes, but even though it looks like Alzheimer’s it really isn’t a good model,” says Ulrich Hengst, PhD, associate professor of Pathology and Cell Biology at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain.

As a result, it has been extremely difficult to develop drugs for this condition. In the last decade, more than 200 drug discovery programs for Alzheimer’s have failed or been abandoned. The field was a wasteland, and still researchers persisted.

So, how did things change and start to look more hopeful?

Rethinking the amyloid hypothesis

An important step forward, says Hengst, has been a shift in how we think about the famous “amyloid hypothesis,” which is about 30 years old. This hypothesis suggested the accumulation of the peptide amyloid beta, 10-20 years before there are signs of the disease, was the starting point of the disease. After all, this leads to harmful plaques that are a hallmark of Alzheimer’s. Mopping up that molecule, the reasoning went, should help slow or even reverse cognitive decline.

“The idea used to be that it was a straight line from amyloid beta to neurodegeneration,” Hengst says. “But now we think its much more complicated than that, with on and off ramps,”

Even if clearing amyloid beta was sufficient, it occurs in different ways, Hengst points out—inside and outside of cells. “We had to figure out what amyloid to target and which are the best antibodies” he says. Also, importantly, amyloid beta is more easily cleared from the rodent brain than humans.

“How the monoclonal binds and what it binds to is key,” says Seth Alan Gale, MD, co-director of the Brain Health Program at Harvard Medical School. What triggers the cascade is still not known, but it’s clear it involves more than amyloid beta. “From lab research and studying families with genetic mutations we know they first develop amyloid beta, but there are also tau tangles and inflammation,” he adds.

Both Hengst and Gale agree that Leqembi, (Biogen and Eisai’s lecanemab-irmb), is not the breakthrough drug we were waiting for. But it is the first fully approved treatment shown to reduce the rate of detectable Alzheimer’s progression and slow cognitive and functional decline.

For one thing, Hengst says, the drug only works in about 30% of patients: “It’s a case where the glass is half full and half empty.”

Says Gale, “The cognitive benefits of the drug are modest, sometimes it is hard to even see them. It’s just a beginning. It proves there is something we can do with amyloid beta.”

They both anticipate a future where a combination of therapies will target more than amyloid beta. They may even personalized, according to specific mutations or other factors.

New data and approaches

Among the new targets for Alzheimer’s drugs are tau, apolipoprotein E (APOE)/lipids and lipoprotein receptors, neurotransmitter receptors, neurogenesis, inflammation, growth factors, and more. But how will drug developers pick among these targets?

Hengst’s group recently identified a new amyloid beta-triggered pathway in Alzheimer’s that points to a potential drug for the disease. The team used datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors.

They showed amyloid beta promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. This process activates a transcription network that interacts with roughly half of the genes differentially expressed in Alzheimer’s. Further, the team determined that the drug dovitinib, Allarity’s pan-tyrosine kinase inhibitor, could be a candidate against this target.

Another recent study, from INSERM, involved a two-stage genome-wide association study of more than 110,000 people with Alzheimer’s. This team found 75 risk loci, 42 of which were new. Genome-wide summary statistics were deposited to the European Bioinformatics Institute GWAS Catalog.

Another new tool is a spatiotemporal RNA sequencing atlas of the mouse brain recently constructed by the lab of Tony Wyss-Coray, PhD, professor of Neurology and Neurological Sciences, and director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford University. The team looked at 1,076 samples from 15 regions across seven ages and two rejuvenation interventions. They are planning to repeat this with human samples.

But the mouse data has given them a good start. “We made a number of discoveries,” says Wyss-Coray. “For one thing, these regions do not age in synchrony, a gene’s activity can go up several fold in one region but not in another. Also, the white matter is the connection between regions that show most of the changes.”

There are also other causes than Alzheimer’s of cognitive decline, such as vascular disease.

Women, for example, are more likely than men to develop dementia, and that has long been assumed that to be due to the fact that they live longer. But new evidence suggests that pregnancy complications may also lead to higher risk of earlier cognitive decline.

Among these findings, a Swedish team recently found that risk of later dementia increases for women who experienced pregnancy-induced hypertension, spontaneous preterm labor, or preterm rupture of membranes (placental bed disorders). Such disorders, the team concluded, are associated with vascular dementia even after adjusting for cardiovascular disease.

New tests and clinical protocols are being developed to protect pregnant women from these conditions.

Keys to graceful aging

Lifestyle also has a role in cognitive decline. “It seems to have modest benefits, but people who adopt healthy lifestyles can modify their risk of dementia,” says Gale. He thinks that along with new therapies, lifestyle changes will be a help.

There is also widespread agreement that earlier detection could help clinical care and drug development. So, a priority is improving diagnosis of Alzheimer’s and other conditions that affect cognitive function.

“Amyloid deposition is not strongly correlated with cognition, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss,” says Valentina Garibotto, of the Laboratory of Neuroimaging and Innovative Molecular Tracers at Geneva University.

She points out that better selection of patients is crucial to optimal trial design and she sees the measurement of Tau as being an important step forward. “Tau is routinely measured in CSF, and several new blood tests are in development to measure phosphorylated tau,” she says.

Only one tau PET radiopharmaceutical, [18F]-flortaucipir, has FDA approval, also though this test is routinely used in clinical trials. In fact, Garibotto says, “Crucially, participants in TRAILBLAZER-ALZ 2 [a trial of Eli Lilly’s donanemab] were stratified by their level of tau, as assessed by tau PET,

Gale notes that new diagnostic criteria will soon be available from the National Institute on Aging and the Alzheimer’s Association (NIA-AA) The criteria were posted for final review at the end of August this year. Medicare is also planning to expand its coverage of PET scans, which are one of the best means of detecting amyloid beta on the brain.

Former president Trump famously said that he had to remember the words: “Person. Woman. Man. Camera. TV,” as part of a test to demonstrate his mental acuity. The test, the Montreal Cognitive Assessment, is designed to detect signs of Alzheimer’s or other types of dementia.

With advances in precision medicine, we are poised to have much more sophisticated tests in hand. That should make old age much easier for many people.

Read More

Atlas of the aging mouse brain reveals white matter as vulnerable foci—Cell, 2023.

Can precision pregnancy save more mothers?—Inside Precision Medicine, 2023.

CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology—Science Advances, 2023.

New insights into the genetic etiology of Alzheimer’s disease and related dementias—Nature Genetics, 2022.

Montreal Cognitive Assessment (MoCA) website, 2023.

‘Person. Woman. Man. Camera. TV,’ didn’t mean what Trump hoped it did—The New York Times, 2020.

Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort study—BJOG, 2020.

Reasons for failed trials of disease-modifying treatments for Alzheimer Disease and their contribution in recent research—Biomedicines, 2019.

The Alzheimer’s disease drug development landscape—BMC. 2021.

The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline—Alzheimer’s & Dementia, 2023.

Malorye Branca is a contributing editor at Inside Precision Medicine and a freelance medical science journalist. She has written hundreds of articles, as well as managed and launched health and science magazines, newsletters, and market research report businesses. She has also co-authored two books: “Moneyball Medicine” and “Walmart’s Second Opinion.”

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