This is an interesting area:

Researchers have identified a new form of dementia that is often mistaken for Alzheimers but is less severe and doesn’t have the signature amyloid protein. Called LATE, for Limbic-predominant age-related encephalopathy, it affects about a third of people over 85. A mild condition on its own, when combined with Alzheimers it ravages the brain.

https://www.nytimes.com/2025/11/28/health/late-dementia-alzheimers.html

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@adssx , you’ve probably already looked at this, but it seems like this might have potential in Parkinson’s also…

The Effect of Exogenous Ketone Bodies on Cognition in Patients with Mild Cognitive Impairment, Alzheimer’s Disease and in Healthy Adults: A Systematic Review and Meta-Analysis

Open access Paper:

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The owner of KetoneAid had me excited about this a couple of years ago. Their KE4 product is a great source of exogenous ketones. Their “Hard Ketones” can be a beer substitute (doesn’t taste that great though).
He has lots of reports of individuals with dementia symptoms who reportedly had marked improvement with this product.
As with many other things I’ve tried utilizing, my patient population didn’t seem to have any response to this treatment - however, I was utilizing it on individuals with a vague sense of mental sharpness decline, often in the setting of having an ApoE4 and being older.

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Yes ketone drinks look interesting. There’s an ongoing trial in PD in the UK. I wonder if SGLT2i could achieve the same result as they shift the brain metabolism towards ketone use: Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022

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Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

CAUTION: Chinese paper.

Pioglitazone reduces serum ketone bodies in sodium-glucose cotransporter-2 inhibitor-treated non-obese type 2 diabetes: A single-centre, randomized, crossover trial

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Couln’t find the full paper but here is the main figure.
The effect is real but mild it seems.

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From New Scientist:

Your brain undergoes four dramatic periods of change from age 0 to 90

Our brain wiring seems to undergo four major turning points at ages 9, 32, 66 and 83, which could influence our capacity to learn and our risk of certain

The brain has distinct regions that exchange information via white matter tracts – wiry structures made of spindly projections, called axons, that project from neurons, or brain cells. These connections influence our cognition, such as our memory. But it was unknown whether major shifts in this wiring occur throughout life. “No one has combined multiple metrics together to characterise phases of brain wiring,” says Alexa Mousley at the University of Cambridge.

To fill this knowledge gap, Mousley and her colleagues analysed MRI brain scans from around 3800 people in the UK and US, who were mostly white, and ranged in age from newborns to 90. These scans were previously taken as part of various brain imaging projects, most of which excluded people with neurodegenerative or mental health conditions.

The researchers found that among people who reach 90, the brain’s wiring has generally undergone five main phases, separated by four key turning points.

In the first phase, which occurs between birth and 9 years old, white matter tracts between brain regions seem to become longer, or more convoluted, making them less efficient. “It takes longer for information to pass between regions,” says Mousley.

This could be because our brain is packed with lots of connections as infants, but as we grow and experience things, the ones we don’t use are gradually pruned away. The brain seems to prioritise making a broad range of connections that are useful for things like learning to play the piano, at the cost of them being less efficient, says Mousley.

But during the second phase, between 9 and 32 years old, this pattern seems to flip, which is potentially driven by the onset of puberty and its hormonal changes influencing brain development, says Mousley. “Suddenly, the brain is increasing the efficiency of the connections – they become shorter, so information gets from one place to another more quickly.” This may support the development of skills like planning and decision-making, and improvements in cognitive performance, such as working memory, says Mousley.

Read full story: Your brain undergoes four dramatic periods of change from age 0 to 90

Open access paper:

Topological turning points across the human lifespan

https://www.nature.com/articles/s41467-025-65974-8

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Liraglutide might have succeeded where semaglutide failed?

Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial 2025

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer’s disease syndrome. ‘Evaluating liraglutide in Alzheimer’s disease’ (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer’s disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = −0.17; 95% confidence interval: −0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome—score on the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec)—performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03−0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (−0.58; 95% confidence interval: −3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (−0.06; 95% confidence interval: −0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer’s disease. ClinicalTrials.gov identifier: NCT01843075.

Liraglutide crosses the BBB better than semaglutide.

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Not sure if discussed already, if not might be worth a discussion

Looks promising?

The age-specific incidence of dementia has dropped sizably over the last few decades:

Today’s 90-year-olds have less than half the risk of dementia that ones in 1980s did!

https://x.com/drsamuelbhume/status/1999873122540171747?

https://www.alzforum.org/news/research-news/dementia-incidence-still-dropping-birth-cohort-data-say-yes

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I think it’s the same reason why people are not dying from CVD in their 50’s anymore (see CVD mortality graph over the past 100 yrs), better fat consumption of more unsaturated fats compared to saturated, even if it’s from processed food, better and more treatment, awareness of risk factors for CVD.

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We know about half of the risk factors for dementia:

image

Most have improved over time (better education, earlier and better treatments for hearing loss, cholesterol, diabetes, hypertension, and obesity), people drink and smoke less and air pollution has improved. So the lower incidence is expected. But how low can it go with those preventive measures only?

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