Just reminders, all covered before in this thread and elsewhere…
The midlife habits that could make or break your brain health long-term
Researchers increasingly believe the 40s, 50s and 60s represent a critical window for protecting cognitive health later in life.
Neuroscientist Miia Kivipelto’s life’s work has been about preventing dementia. Now, at 52, she has begun thinking more about her own vulnerability.
“Midlife is the time,” said Kivipelto, a neuroscientist who recently joined the Yale School of Nursing as the inaugural director of its Center for Aging Well in New Haven, Connecticut. “It’s the last best chance to lower risk.”
The idea that dementia prevention may hinge on what people do in their mid-30s to their 60s is rapidly reshaping the field. Scientists increasingly believe the disease is driven not only by changes in the aging brain, but also by years of metabolic stress, inflammation and vascular damage accumulating across the body. Many researchers now think the biological process that leads to dementia begins 15 to 20 years before the first memory problems emerge. By the time symptoms become noticeable, the disease likely will already be well established.
Neuroscientists now see midlife as a critical window when the brain becomes especially vulnerable to aging — but also more responsive to intervention.
The implications are profound: The ordinary habits of middle age may matter far more than scientists once realized, and cognitive decline may not be inevitable.
Last year, a large study in JAMA Network Open found that people who remained physically active during midlife had a 40 to 45 percent lower risk of dementia later in life. A meta-analysis of more than 3 million people published in April in PLOS One found that the greatest reductions in dementia risk came from how people behaved in midlife and were associated with seven to eight hours of sleep, at least 150 minutes of aerobic activity a week, and fewer than eight sedentary hours a day.
Taken together, the findings suggest a new pathway for addressing a growing societal problem. More than 57 million people worldwide are living with dementia, and researchers predict that number will nearly triple to more than 150 million by 2050, according to estimates published in the Lancet. Scientists now estimate that roughly 45 percent of cases could potentially be delayed or prevented through changes to modifiable risk factors.
“The younger you are, the greater the bang for the buck in terms of these behaviors and lowering your risk,” said Akinkunle Oye-Somefun, a research associate at York University in Toronto and a co-author of the PLOS One study.
These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI. Such an approach would prioritize established neuroprotective mechanisms while potentially mitigating the kidney and thyroid risks associated with higher-dose carbonate formulations. If low-dose lithium can indeed meaningfully alter disease trajectory, it would represent a much-needed, accessible, and inexpensive treatment that may be especially relevant in low- and middle-income countries.
“In addition, extensive evidence demonstrates that low-dose lithium (approximately 0.3mM)—significantly lower than traditional psychiatric doses (0.6-1.0mM)—exerts robust neurotrophic and neuroprotective effects.”
Is there a formula to convert this to mg? The “low dose” here looks like about half of customary psychiatric dose? I assume psychiatric means carbonate? I’m trying to get a sense of what “low” dose for orotate would be here if possible.
Higher blood glucose levels linked to faster brain aging
Faster brain aging has been linked to various neurological and psychiatric disorders, as well as some neurodegenerative diseases. The factors that influence the speed at which the brain ages, however, have not yet been clearly and comprehensively elucidated.
Researchers at Jilin University and China Medical University recently analyzed available neuroimaging, genomic and biological data to better understand the contribution of metabolic processes (i.e., the chemical reactions that transform food into energy) to brain aging. Their findings, published in Molecular Psychiatry, suggest that higher levels of glucose in the blood are associated with accelerated brain aging.
Uncovering metabolic signatures of brain aging with AI
To explore the biological underpinnings of brain aging, the researchers analyzed data from the UK Biobank, a large biomedical database that contains health-related, genetic and imaging data collected from thousands of people living in the U.K. By analyzing these people’s brain scans, they derived measurable brain features, such as the size of specific brain regions, tissue characteristics and structural changes.
Subsequently, they trained machine learning algorithms to predict the age of people based on the brain features they identified. They found that a specific statistical method, known as a least absolute shrinkage and selection operator (LASSO) regression model, was best at predicting the age of people’s brains, with an average error rate of 3.26 years.
Mr Stallard has been working for a decade to corroborate this revelation. His findings have, if anything, become even more striking. Last year he and some colleagues published research in the Journal of the American Medical Association showing that, whereas 40 years ago three in every ten Americans aged 85-89 had dementia, by 2024 just one in ten had it (see chart 1). What is more, America is not the only beneficiary of this trend. Between 1988 and 2015 the share of older people being diagnosed with dementia fell by 13% a decade across six countries in North America and Europe, according to a study of almost 50,000 people by Frank Wolters of the Erasmus Medical Centre in Rotterdam, and colleagues.
chart: the economist
Some smaller studies have also found big declines. Data from the Framingham Heart Study, which has tracked three generations in an American town, show an average drop in new dementia cases of 20% per decade over almost 40 years between the late 1970s and early 2010s. Those who were entering their dotage when Daft Punk’s “Get Lucky” was topping the charts (2013) were 44% less likely to have dementia than those who were doing so when Sting was urging Roxanne to switch off her red light (1978).
Whereas most earlier studies had simply pooled elderly people and then applied a statistical adjustment for age, Mr Stallard looked at narrow bands of ages to compare different cohorts of people over 50 years. By examining the changes between each successive cohort, he calculates that dementia rates have been declining by 2.5-3% for each calendar-year cohort. “In my view it was the Copernican revolution in the field,” he says, turning assumptions about dementia’s spread upside down. Similar cohort studies in various European countries and Japan have found comparable trends there, too.
An anti-inflammatory diet may prevent dementia, even in people at higher risk, new study suggests
About the latest research
The new study, published in June in JAMA Network Open, sought to determine whether healthy eating patterns could modify dementia risk in older adults with blood biomarkers indicating Alzheimer’s-related brain changes or other signs of brain cell damage.
To do so, the researchers analyzed data from adults without dementia, ages 60 and older, who took part in the Swedish National Study on Aging and Care. A total of 1,865 participants, with an average age of 70, were followed for up to 15 years.
At the start of the study, researchers measured three blood biomarkers linked to Alzheimer’s disease and other signs of damage or stress in the brain. They also assessed participants’ diets, lifestyle habits and health status, updating this information at follow-up visits three and six years later.
Participants’ diet information was used to assess adherence to three dietary patterns: a Mediterranean-style diet, the Alternative Healthy Eating Index and the Reverse Empirical Dietary Inflammatory Index, which measures the inflammatory potential of a person’s diet (a higher score denotes a more anti-inflammatory diet). Higher adherence scores for each dietary pattern indicate a higher quality diet.
Each diet pattern highlights different aspects of diet quality, and they all emphasize vegetables, fruits, nuts and whole grains while limiting more inflammatory foods such as red and processed meats and sugary drinks.
Better diets, especially less inflammatory ones, tied to lower dementia risk
Across all participants, healthier diet patterns were associated with a lower likelihood of developing dementia.
When the researchers analyzed participants according to their levels of blood biomarkers, however, they found striking results.
Greater adherence to all three diet patterns was generally associated with a lower risk of dementia among people with lower levels of blood biomarkers.
Inhaling high-dose CO2 clears Alzheimer’s proteins from the brain
Intermittently inhaling a high dose of carbon dioxide seems to remove the proteins amyloid and tau, which are implicated in Alzheimer’s disease, from the brain by boosting its glymphatic system.
Guanfacine may aid in improving sleep caused by amyloid beta induced disruption of Alzheimer’s disease:“5xFAD mice displayed dark phase-specific hyperarousal and impaired brain state transitions by 2 months of age. LC neurons exhibited increased tonic firing due to impaired Kv4 and Kv7 potassium channel conductance, resulting from soluble amyloid beta (Aβ)-induced disruption of α2A adrenergic receptor regulation. Pharmacological activation of α2A adrenergic receptors restored Kv4/7 function and normalized LC excitability. Local administration of guanfacine (α2A agonist) or retigabine (Kv7 modulator) significantly rescued sleep-wake disturbances.”Impaired adrenergic regulation of Kv channels underlies LC hyperactivity and early-onset sleep disruption in AD-like amyloidogenic micepubmed.ncbi.nlm.nih.gov
Alzheimer’s may start with inflammation in the skin, lungs or gut
The Alzheimer’s field is being turned on its head as mounting evidence points to the disease beginning outside the brain many years before symptoms start. This may mean we have to totally rethink how we approach preventing and treating the condition
Alzheimer’s disease has long been viewed as something that originates inside the brain, but an in-depth genomic analysis suggests it may initially be triggered by inflammation in distant organs like the skin, lungs or gut – perhaps decades before a person’s memory starts to decline. This radical reframing of the disease may explain why Alzheimer’s drugs have been disappointing to date, because they act too late in the disease process. Instead, we may need to redirect our efforts towards addressing inflammation in other parts of the body.
“As neuroscientists, we tend to be very brain-centric, but this study really shines a spotlight on the fact that the brain is not disconnected from the rest of the body, and when changes happen in the rest of the body, it affects how the brain functions,” says Donna Wilcock at Indiana University, who wasn’t involved in the research. “Even though Alzheimer’s is a brain disease, we need to think about the whole body when we think about how it begins.”
To explore the genetic underpinnings of Alzheimer’s disease, César Cunha at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark and his colleagues studied genetic data from more than 85,000 people with the condition and 485,000 people without it from the European Alzheimer and Dementia Biobank. They also analysed gene activity in 5 million single cells from 40 areas of the body and 100 brain regions.
As part of this deep dive, the researchers examined 1000 genes with variants that increase the risk of Alzheimer’s disease. To their surprise, these seemed to show up far less in the brain than in other organs like the skin, lungs, digestive system and spleen, as well as in various types of immune cells circulating in the blood. “I kept looking at the graph and it seemed wrong because the expression of these genes in single cells in the brain was extremely low,” says Cunha. “But we ran more analyses and the more we looked at it, the more we realised they really weren’t in the brain, they were mostly in other parts of the body.”
If so, then this might explain, at least in part, the persistent findings that agents which do not cross the BBB or barely do, (like rapamycin), nonetheless often seem very impactful in various brain NDDs including dementias like Alzheimer’s. Those agents might act against inflammatory and other pathological processes in those tissues where AD might have etiological triggers. Food for thought - literally… if we posit that diet is associated with dementia, it need not affect the brain directly, just through a proxy like gut microbiome. It might all be connected, the body being an interconnected biological system.
This also keeps GLP1s very much in play, even with the disapointing results from the Novo trial that showed semaglutide did not slow down the disease once it set.
