# How Alzheimer's Disease Works

> A new study links the APOE4 gene variant to a protein that weakens the brain's blood vessel barrier, in mice and human tissue. To see why that matters, this film explains Alzheimer's disease from the start: Alois Alzheimer's first patient in 1906, how neurons and synapses hold memories, how amyloid plaques and tau tangles form, how damage spreads through the brain over decades, why age and APOE4 raise the risk, and how the disease is diagnosed and treated today. Add amyloid and tau, step through the Braak stages, choose APOE versions and open the blood–brain barrier yourself. Education, not medical advice.

Interactive film: https://www.planetpast.com/stories/how-alzheimers-disease-works/  
Publisher: PlanetPast (https://www.planetpast.com/) · d => T('readPublished', l, { d: dateIn(d, l) }) 2026-10-20 · Biology, Chemistry

## Prologue

### The slow unravelling
*Plaques, tangles and decades of silence*

Why some people with a risky gene stay sharp.

Some people carry a gene that makes Alzheimer's far more likely, yet stay sharp into their eighties. Why? In 2026, a Columbia University team linked that gene, APOE e4, to a protein called fibronectin that weakens the wall between blood and brain. First, though: what does Alzheimer's do to a brain?

- **~1 in 5**: people carry at least one copy (Columbia team)

- Bhattarai, Yilmaz, Kizil and colleagues, Columbia University; reported 19 Oct 2026
- e4 mice: nearly twice the fibronectin of e3 mice
- their blood–brain barrier leaked
- mice, zebrafish, human tissue; no treatment tested

![Carrying e4 raises the odds; it does not decide them. AI-generated still.](https://assets.planetpast.com/a/22/226b7df53d2027b0.jpg)

Prologue · The news

#### APOE4, fibronectin and a leaky barrier

A study in Nature Aging by Prabesh Bhattarai, Elanur Yilmaz, Caghan Kizil and colleagues at Columbia University Irving Medical Center, reported by ScienceDaily on 19 October 2026 (ScienceAlert covered it on 18 September), found that APOE4 promotes fibronectin build-up around brain blood vessels. In mice carrying human APOE4, brain fibronectin was nearly double that in APOE3 mice and the blood–brain barrier appeared leaky; raising fibronectin in astrocytes made the barrier more permeable and reducing it improved barrier function.

This is one preclinical study: the mechanism comes from cells, zebrafish and mice, the human findings are correlational, and no treatment has been tested. This film is education, not medical advice; questions about your own health belong with a doctor.

How to use: pick a chapter or press ← →; drag to rotate. Nine steps have buttons you can press.

Sources: [ScienceDaily / Columbia University Irving Medical Center: why some people escape Alzheimer’s despite carrying a high-risk gene (19 Oct 2026)](https://www.sciencedaily.com/releases/2026/10/261018205044.htm); [ScienceAlert: fibronectin and blood–brain barrier leakage in APOE4 models (2026)](https://www.sciencealert.com/?p=219531)

## Chapter I · “I have lost myself”

### Auguste’s brain
*Chapter I · “I have lost myself”*

Two strange deposits, seen for the first time.

In November 1901, a fifty-one-year-old woman was admitted to an asylum in Frankfurt. Confused and forgetful, she told her doctor again and again: I have lost myself. After she died in 1906, her doctor, Alois Alzheimer, examined her brain. Between the nerve cells were clumps, now called plaques. Inside the cells were twisted fibres, now called tangles. Today, dementia means a decline in memory and thinking, and Alzheimer's is its most common cause, behind sixty to seventy per cent of cases.

![The patient was Auguste Deter, admitted on 25 November 1901. AI-generated still.](https://assets.planetpast.com/a/16/16353e84cf67c6fc.jpg)

- Nov 1901: Auguste Deter admitted, aged 51
- Apr 1906: she dies, aged 55
- Nov 1906: Alzheimer presents her case in Tübingen
- 1910: Emil Kraepelin names it “Alzheimer’s disease”

- **57 million+**: people living with it
- **~10 million**: new diagnoses a year
- **60–70%**: of cases are Alzheimer’s

Chapter I · “I have lost myself”

#### Auguste Deter

Auguste Deter was admitted to the Frankfurt asylum on 25 November 1901, aged 51, and repeated “Ich habe mich verloren” (“I have lost myself”) during Alois Alzheimer’s examinations. She died on 8 April 1906. Examining her brain, Alzheimer found plaques and neurofibrillary tangles; he presented the case in Tübingen on 3 November 1906, and Emil Kraepelin named the disease in 1910.

WHO estimates that more than 57 million people live with dementia, with nearly 10 million new diagnoses a year, and that Alzheimer’s accounts for 60–70% of cases. Mayo Clinic calls Alzheimer’s the most common cause of dementia.

The 3D models are schematic and not to scale.

Sources: [Wikipedia: Auguste Deter](https://en.wikipedia.org/wiki/Auguste_Deter); [Wikipedia: Alois Alzheimer](https://en.wikipedia.org/wiki/Alois_Alzheimer); [WHO Thailand: new WHO guidelines, up to 45% of dementia risk could be prevented or delayed (21 Jul 2026)](https://www.who.int/thailand/news/detail/21-07-2026-new-who-guidelines--up-to-45--of-dementia-risk-could-be-prevented-or-delayed); [Mayo Clinic: Alzheimer’s disease, symptoms and causes](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447)

## Chapter II · The wiring of memory

### Eighty-six billion cells
*Chapter II · The wiring of memory*

Memories live in connections.

Start with the brain's wiring: about eighty-six billion nerve cells, or neurons, joined at roughly a hundred trillion contact points called synapses. At a synapse, one neuron releases chemical messengers that tell the next whether to fire. Memories live in patterns of these connections. Deep in each side of the brain sits a seahorse-shaped structure, the hippocampus, which turns new experiences into lasting memories. Alzheimer's damage usually begins near it.

- **~86 billion**: neurons
- **~100 trillion**: synapses: thousands per neuron

- electrical: a pulse runs down the cell’s fibre
- chemical: messengers cross a tiny gap
- first mapped by Golgi and Cajal: Nobel Prize, 1906

![One in each temporal lobe; its name comes from the Greek for seahorse. AI-generated illustration.](https://assets.planetpast.com/a/83/83e99547ba4d92fb.jpg)

Chapter II · The wiring of memory

#### Neurons, synapses and the hippocampus

The human brain has about 86 billion neurons and an estimated 100 trillion synapses, since each neuron makes thousands of connections. Golgi and Ramón y Cajal shared the 1906 Nobel Prize “in recognition of their work on the structure of the nervous system”. The hippocampus, deep in the medial temporal lobe of each hemisphere, helps form new memories and turns short-term memories into long-term ones.

Mayo Clinic notes that Alzheimer’s damage most often starts in the region of the brain that manages memory.

The 3D models are schematic and not to scale.

Sources: [UCLA Brain Research Institute: billions of neurons, trillions of synapses](https://bri.ucla.edu/brain-fact/billions-of-neurons-trillions-of-synapses/); [Nobel Prize in Physiology or Medicine 1906 (Golgi and Ramón y Cajal)](https://www.nobelprize.org/prizes/medicine/1906/summary/); [Osmosis: hippocampus](https://www.osmosis.org/answers/hippocampus); [Mayo Clinic: Alzheimer’s disease, symptoms and causes](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447)

## Chapter III · Two proteins gone wrong

### Sticky fragments
*Chapter III · Two proteins gone wrong*

The plaques are made of amyloid beta.

The plaques are made of a protein fragment, amyloid beta. Neurons carry a longer protein, APP, in their outer membrane, and enzymes snip pieces off it all the time. Usually the cut is harmless. But when two other enzymes cut it in a different place, the leftover piece is sticky. It clumps into clusters, then fibres, then the plaques Alzheimer saw. Add amyloid and watch clumps grow between the cells, as nearby signals begin to falter.

- cut by α-secretase: harmless pieces that dissolve
- cut by β-, then γ-secretase: amyloid beta, 40 or 42 building blocks (amino acids) long

- 1: single fragments (monomers)
- 2: small clusters (oligomers)
- 3: fibres (fibrils)
- 4: plaques between neurons

![George Glenner’s team characterised the plaque protein in 1984. AI-generated illustration.](https://assets.planetpast.com/a/50/50f30db550f6843b.jpg)

Chapter III · Two proteins gone wrong

#### Amyloid beta

APP is a transmembrane protein. Cut by α-secretase it yields soluble fragments; cut first by β-secretase and then by γ-secretase it releases amyloid beta peptides of 40 or 42 amino acids, which are prone to form oligomers, then fibrils, then plaques. George Glenner’s team characterised the plaque protein in 1984.

Plaques are thought to impair synaptic transmission and trigger inflammation. McGill’s Brain from Top to Bottom notes that this “amyloid hypothesis” does not explain everything about the disease.

The 3D models are schematic and not to scale.

Sources: [Cell Signaling Technology: amyloid beta and APP processing](https://www.cellsignal.com/science-resources/amyloid-beta-protein); [McGill University, The Brain from Top to Bottom: plaques and tangles](https://thebrain.lecerveau.ca/flash/d/d_08/d_08_m/d_08_m_alz/d_08_m_alz.html); [Mayo Clinic: Alzheimer’s disease, symptoms and causes](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447)

### Broken tracks
*Chapter III · Two proteins gone wrong*

The tangles are made of tau.

The second protein is tau. Inside each neuron, tracks called microtubules carry supplies out to its far ends, and tau holds those tracks steady. In Alzheimer's, tau picks up too many chemical tags called phosphates. It is thought to let go of the tracks, which fall apart, while the loose tau knots into tangles. Add tau and the deliveries stop. A neuron that cannot supply its synapses loses them, and may die.

- binds the microtubule tracks
- keeps transport running down the fibre
- normal, healthy and essential

- **1985**: an antibody to tau was shown to mark the tangles (Jean-Pierre Brion)

![Under a stain, tangles fill the cell body like dark flames. AI-generated illustration.](https://assets.planetpast.com/a/ac/ac8935c7458c3a2f.jpg)

Chapter III · Two proteins gone wrong

#### Tau and tangles

Tau stabilises microtubules, supporting axonal transport and the integrity of the neuron. Neurofibrillary tangles consist of tau that has detached from microtubules and clumped together; excess phosphorylation is named as the main suspected cause. In 1985 Jean-Pierre Brion found an antibody that binds tau and marks the tangles, and other teams confirmed tau as their main component.

The 3D models are schematic and not to scale.

Sources: [McGill University, The Brain from Top to Bottom: plaques and tangles](https://thebrain.lecerveau.ca/flash/d/d_08/d_08_m/d_08_m_alz/d_08_m_alz.html); [Mayo Clinic: Alzheimer’s disease, symptoms and causes](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447)

## Chapter IV · A slow spread

### Six stages
*Chapter IV · A slow spread*

Tangles follow the same route in brain after brain.

Tangles do not appear everywhere at once. In 1991, two German anatomists, Heiko and Eva Braak, found that they follow the same route, in six stages. In stages one and two, tangles sit beside the hippocampus; in three and four they reach it and the deep circuits of memory and emotion; in five and six, the cortex, the wrinkled outer layer. Step through the stages. As neurons die, the brain itself shrinks: late in the disease its folds are thinner and the grooves between them wider.

- **6**: stages of tangle spread, seen after death

- I–II: a small area next to the hippocampus
- III–IV: the hippocampus and nearby memory and emotion circuits
- V–VI: most of the wrinkled outer cortex

![Models of a healthy brain and one in late Alzheimer’s: narrower folds, wider grooves. AI-generated still.](https://assets.planetpast.com/a/22/22d008595ae1fc74.jpg)

Chapter IV · A slow spread

#### Braak staging

Braak and Braak (1991) staged Alzheimer’s by neurofibrillary tangles: in stages I–II tangles are confined mainly to the transentorhinal region; in III–IV they also involve limbic regions such as the hippocampus; in V–VI they extensively involve the neocortex. Plaques spread in a different pattern. By the late stage of the disease, the brain has shrunk.

In the model the darkening is schematic: it shows where tangles are, in the order Braak described, on an illustrative brain.

Sources: [Wikipedia: Braak staging](https://en.wikipedia.org/wiki/Braak_staging); [Wikipedia: Heiko Braak](https://en.wikipedia.org/wiki/Heiko_Braak); [Mayo Clinic: Alzheimer’s disease, symptoms and causes](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447)

## Chapter V · Who is at risk

### Age, then genes
*Chapter V · Who is at risk*

A common gene that tilts the odds.

Why some people and not others? Age is the strongest known risk: most cases begin at sixty-five or older. Genes matter too. In 1993, researchers linked Alzheimer's to APOE, a gene whose protein carries cholesterol and other fats around the brain. It has three common versions, e2, e3 and e4, and we inherit one copy from each parent. Compared with e3, the most common, one copy of e4 roughly doubles or triples the risk, and two copies make it eight to twelve times higher. E2 lowers it. Yet many e4 carriers never get the disease.

- older age: the strongest known risk factor
- late-onset: 65 or older, the vast majority
- rare inherited forms (APP, PSEN1, PSEN2): 1% of cases or less

- **20–30%**: carry one or two copies
- **~2%**: carry two copies
- **40–65%**: of people diagnosed carry e4

- e3/e3 (two copies of e3): 1×
- one e4: 2–3×
- two e4: 8–12×

- e4 is a risk factor, not a direct cause
- many people with e4 never develop the disease
- many people without e4 do

Chapter V · Who is at risk

#### APOE and other genes

Older age is the strongest known risk factor. In 1993 Allen Roses’s team at Duke reported that the APOE e4 allele is more frequent in late-onset Alzheimer’s and that risk rises with the number of copies. Mayo Clinic: at least one e4 “doubles or triples the risk”, two copies make someone “8 to 12 times more likely”; e2 “reduces the risk”; e3 appears to have no effect. Rare variants in APP, PSEN1 and PSEN2 cause early-onset familial disease, 1% of cases or less.

These are population figures. Genetic testing and what it means for a person is a conversation for a doctor or genetic counsellor. In the model, the e2 column has no single published figure: its height only says “lower”.

Sources: [Mayo Clinic: Alzheimer’s genes, are you at risk?](https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552); [Alzheimer’s Association: is Alzheimer’s genetic?](https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors/genetics); [Alzforum: Allen Roses and the 1993 APOE4 papers](https://alzforum.org/node/692141); [Liu, Kanekiyo, Xu & Bu, Nature Reviews Neurology (2013): apolipoprotein E and Alzheimer disease](https://mayoclinic.elsevierpure.com/en/publications/apolipoprotein-e-and-alzheimer-disease-risk-mechanisms-and-therap-2); [MedlinePlus Genetics: Alzheimer disease](https://medlineplus.gov/genetics/condition/alzheimers-disease/)

### The cleaners
*Chapter V · Who is at risk*

Immune cells that help, and can harm.

Another risk gene works in the brain's cleaning crew, its immune cells: a rare variant of TREM2, found in 2013, roughly triples the odds. These cells, microglia, clear away debris. Early on they swallow amyloid and seem to help, but their inflammatory signals can also harm neurons. Send in the microglia. Whether they mostly protect the brain or worsen the damage may depend on the stage of the disease.

- **2.9**: odds ratio for the rare R47H variant (Icelandic study)
- **immune**: a receptor on microglia

![Its branches constantly reach out, sampling the tissue around it. AI-generated illustration.](https://assets.planetpast.com/a/5f/5fa0d55eae565e1f.jpg)

- help: engulf amyloid and debris
- harm: inflammation damages neurons
- in one mouse study, removing them did not cut amyloid, yet fewer neurons were lost

Chapter V · Who is at risk

#### Microglia and inflammation

Two studies in the New England Journal of Medicine (online 14 November 2012, in print January 2013) linked a rare TREM2 variant, R47H, to Alzheimer’s, with an odds ratio of about 2.9. In 2013 a variant of TREM2, a gene involved in inflammation and the immune response, was identified as a significant risk factor for late-onset Alzheimer’s (N Engl J Med 368:117–27). TREM2 is a receptor on microglia, the brain’s immune cells, which clean up debris and can consume plaques but also trigger inflammation that can damage nearby cells.

According to Scientific American, microglia appear protective in early stages and may become overwhelmed later; researchers are unsure whether they drive the disease or worsen a process amyloid starts.

The 3D models are schematic and not to scale.

Sources: [HealthDay: new genetic variant implicated in Alzheimer’s disease (two NEJM studies, Nov 2012)](https://consumer.healthday.com/internal-medicine-21/genetics-news-334/new-genetic-variant-implicated-in-alzheimer-s-disease-670642.html); [NIH Intramural Research Program: identifying an Alzheimer’s disease risk gene (TREM2, 2013)](https://irp.nih.gov/accomplishments/identifying-an-alzheimers-disease-risk-gene); [Scientific American: uncovering new players in the fight against Alzheimer’s (microglia)](https://www.scientificamerican.com/article/uncovering-new-players-in-the-fight-against-alzheimer-s)

### What else is linked
*Chapter V · Who is at risk*

Risk factors across whole populations.

Other things are linked to risk too. In 2024, the Lancet Commission on dementia estimated that up to forty-five per cent of dementia might be prevented or delayed by removing fourteen risk factors, from high blood pressure to hearing loss. That is a population estimate, not a promise for anyone. As countries age, this matters more: in Thailand, one person in five was sixty or older in 2024, about fourteen million people.

- **14**: modifiable risk factors
- **up to 45%**: of dementia potentially preventable or delayed

- less education · hearing loss · high LDL cholesterol · untreated vision loss
- high blood pressure · diabetes · obesity · smoking
- depression · inactivity · excess alcohol
- head injury · air pollution · social isolation

![Share aged 60+: 6.8% in 1994, 20% in 2024 (NSO survey of older persons). AI-generated still.](https://assets.planetpast.com/a/1d/1d325f42e85a4189.jpg)

Chapter V · Who is at risk

#### Modifiable risk

The 2024 Lancet Commission (published 31 July 2024) estimated that “45% of future dementia could potentially be prevented if all 14 risk factors were eliminated”: low education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol, traumatic brain injury, air pollution, social isolation, and two new ones, high LDL cholesterol and untreated vision loss. WHO guidelines in July 2026 likewise attribute up to 45% of dementia risk to modifiable factors.

These figures cover all dementia, not Alzheimer’s alone, and describe populations, not individuals. Nothing here is advice; for your own risk, talk to a doctor. Thai figures are from the National Statistical Office’s 2024 Survey of Older Persons, as presented by Chulalongkorn University’s Panthip Pruksacholavit.

Sources: [Alzheimer Europe: 2024 Lancet Commission identifies 14 modifiable risk factors](https://www.alzheimer-europe.org/news/2024-lancet-commission-underscores-potential-dementia-risk-reduction-identifying-14-modifiable); [WHO Thailand: new WHO guidelines, up to 45% of dementia risk could be prevented or delayed (21 Jul 2026)](https://www.who.int/thailand/news/detail/21-07-2026-new-who-guidelines--up-to-45--of-dementia-risk-could-be-prevented-or-delayed); [Japan Institute for Labour Policy and Training seminar: Thailand’s ageing population (citing NSO 2024 Survey of Older Persons)](https://www.jil.go.jp/english/events/seminar/20250326/documents/Thailand.pdf)

## Chapter VI · Finding and treating it

### Before the first symptom
*Chapter VI · Finding and treating it*

Amyloid, then tau, then shrinkage, then memory.

The cruel part is timing. Two long studies published in 2024 followed people who later developed the disease. Amyloid starts to build up first, roughly fifteen to nineteen years before symptoms. Tau changes follow about ten to fourteen years before. The hippocampus begins to shrink about seven years before diagnosis. Only then do memory problems appear. Tap through the years with the buttons and watch each change arrive in turn.

![One study followed 1,789 people for about 20 years. AI-generated illustration.](https://assets.planetpast.com/a/5a/5a7634d89db3c398.jpg)

- 15–19: amyloid markers change (US study; 14–18 in China)
- 10–14: tau markers change
- ~7: hippocampus starts to shrink (before diagnosis)
- ~6: thinking tests start to decline

- US: Washington University, Annals of Neurology
- China: COAST cohort, New England Journal of Medicine
- amyloid → tau → shrinkage → symptoms

Chapter VI · Finding and treating it

#### Biomarkers before symptoms

Two studies published in February 2024, of sporadic Alzheimer’s, found the same order. Schindler, Li and colleagues (Annals of Neurology) estimated amyloid changes 19 to 15 years before symptoms and plasma p-tau217 14 to 12 years before; Jia and colleagues (NEJM; 1,789 people, about 20 years of follow-up) found amyloid changes 18 and 14 years, tau 11 to 10 years, hippocampal shrinkage 7 years and cognitive decline 6 years before diagnosis.

The model compresses this sequence into a few neurons; the timings on its clock follow the ranges above.

The 3D models are schematic and not to scale.

Sources: [NIHR Dementia Researcher: Alzheimer’s biomarkers change in the same order before symptoms (2024 studies)](https://www.dementiaresearcher.nihr.ac.uk/ad-biomarkers-change-similarly-before-symptoms/)

### Seeing the proteins
*Chapter VI · Finding and treating it*

From memory tests to a blood test.

How is it found? Usually with a specialist's assessment and memory tests. But those measure symptoms, not proteins. For a PET scan, a slightly radioactive tracer injected into a vein sticks to amyloid or tau and shows where it gathers. Spinal fluid can be tested too. In May 2025, US regulators cleared the first blood test to help diagnose Alzheimer's, for adults fifty-five and over with symptoms.

- history and a specialist’s assessment
- memory and thinking tests
- scans or fluid tests for the proteins

![Amyloid PET was the standard against which the new blood test was judged. AI-generated still.](https://assets.planetpast.com/a/0d/0d7ff82069bdd08d.jpg)

- **91.7%**: of positives had plaques on PET or spinal fluid
- **97.3%**: of negatives had none
- **< 20%**: results indeterminate

![The cleared test compares two proteins in plasma: p-tau217 and amyloid beta 1-42. AI-generated still.](https://assets.planetpast.com/a/0a/0a9f9bc55a4b0f90.jpg)

Chapter VI · Finding and treating it

#### Diagnosis

On 16 May 2025 the FDA cleared the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio for adults aged 55 and older with signs and symptoms of Alzheimer’s. In a study of 499 plasma samples from cognitively impaired adults, compared with amyloid PET or spinal fluid results, about 91.7% of positive results had amyloid plaques and 97.3% of negatives did not; fewer than 20% were indeterminate.

False positives and negatives occur, and the test shows whether plaques are present now, not what will happen. In the model, the amyloid and tau PET colours are schematic. Testing decisions belong with a doctor.

Sources: [AJMC: FDA clears first blood test for Alzheimer-linked amyloid plaques (May 2025)](https://ajmc.com/view/fda-clears-first-blood-test-for-early-detection-of-alzheimer-linked-amyloid-plaques); [I-MED Radiology: amyloid PET scan](https://i-med.com.au/procedures/pet/amyloid-pet)

### Slowing, not curing
*Chapter VI · Finding and treating it*

Clearing amyloid, at a modest pace and a cost.

There is still no cure. Older medicines such as donepezil can ease symptoms for a time, but they do not stop the disease. Newer drugs are antibodies that tag amyloid for clearing. Compared with a placebo, lecanemab slowed the worsening by about twenty-seven per cent over eighteen months; donanemab works similarly. That is slower decline, not improvement. The benefit is modest, and both can cause brain swelling or small bleeds, called ARIA, most often with two copies of e4.

- donepezil, galantamine, rivastigmine: boost a chemical messenger neurons use to signal (acetylcholine)
- memantine: damps an excess of another messenger (glutamate)
- ease some symptoms for a time; no cure

- Jul 2023: lecanemab: full US approval (decline 27% slower than placebo over 18 months)
- Jul 2024: donanemab: US approval
- 2025: EU approves both, not for people with two e4 copies

![Treatment needs confirmed amyloid and regular MRI scans to watch for ARIA. AI-generated still.](https://assets.planetpast.com/a/18/186c376cdea9fa90.jpg)

- **0.7%**: of participants had severe ARIA
- **MRI**: scans before and during treatment

Chapter VI · Finding and treating it

#### Treatments

The NHS lists acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine, which can temporarily reduce some symptoms; there is no cure. Lecanemab received full FDA approval on 6 July 2023 after the Clarity AD trial showed 27% less clinical decline than placebo at 18 months; donanemab was approved on 2 July 2024. The EU approved lecanemab in April 2025 and donanemab on 25 September 2025, for people with confirmed amyloid who carry no more than one e4 copy.

ARIA (amyloid-related imaging abnormalities) means temporary brain swelling or small bleeds seen on MRI; it is usually without symptoms but can be serious, and the risk is higher with two e4 copies. NICE, the cost watchdog for England and Wales, did not recommend either drug for routine NHS use in June 2025, judging the benefit too modest for the cost. After appeals it consulted on a third draft from 31 March to 28 April 2026, and its committee met again on 8 July 2026; at the end of July no new decision had been published, no deadline was set, and price talks with NHS England were under way. Whether a treatment is suitable is a decision for a doctor.

The 3D models are schematic and not to scale.

Sources: [NHS: Alzheimer’s disease, treatment](https://www.nhs.uk/conditions/alzheimers-disease/treatment/); [Alzheimer Europe: FDA grants traditional approval for lecanemab (July 2023)](https://www.alzheimer-europe.org/news/fda-grants-traditional-approval-lecanemab-treatment-early-alzheimers-disease); [University of Washington: FDA approves donanemab (July 2024)](https://depts.washington.edu/mbwc/news/article/donanemab-approval); [Nordic Life Science: EU approves Leqembi for early Alzheimer’s disease (April 2025)](https://nordiclifescience.org/eu-approves-leqembi-for-treatment-of-early-alzheimers-disease/); [Eli Lilly: European Commission approves Kisunla (25 Sep 2025)](https://investor.lilly.com/node/52961); [Alzheimer Europe: NICE to reconsider lecanemab and donanemab after appeals (20 Mar 2026)](https://www.alzheimer-europe.org/news/nice-reconsider-lecanemab-and-donanemab-following-successful-appeals); [Pharmaceutical Journal: NICE opens consultation on donanemab and lecanemab (1 Apr 2026)](https://pharmaceutical-journal.com/article/news/nice-opens-consultation-on-previously-rejected-alzheimers-treatments-donanemab-and-lecanemab); [Pharmaceutical Journal: companies in talks with NICE about access to Alzheimer’s drugs (30 Jul 2026)](https://pharmaceutical-journal.com/article/news/pharmaceutical-companies-in-talks-with-nice-about-access-to-alzheimers-drugs)

## Chapter VII · Back to the news

### A leaky wall
*Chapter VII · Back to the news*

Where APOE e4 may do some of its harm.

Back to the news. The brain's smallest blood vessels are sealed by their lining and wrapped by support cells called astrocytes. This blood–brain barrier keeps most blood proteins and immune cells out. When it leaks, they get in and can fuel inflammation that harms neurons. In mice with the human e4 gene, the Columbia team found nearly twice the fibronectin seen with e3, and a leaky barrier. Try it: switch to e4, then reduce fibronectin. That may be part of the answer to our first question: some healthy e4 carriers have a rare protective change in the fibronectin gene. But this is one study in animals and tissue, and fibronectin also helps wounds heal.

- lining cells joined by tight junctions
- astrocyte “end-feet” wrap the vessel
- when it leaks: blood proteins such as fibrinogen and immune cells get in

![In the study, excess fibronectin upset the growth signals that keep the barrier sealed. AI-generated illustration.](https://assets.planetpast.com/a/5c/5cc6fad42d354934.jpg)

- **~2×**: brain fibronectin in e4 mice compared with e3 mice

- shown: a mechanism in cells, zebrafish and mice
- human tissue: an association, not proof
- not shown: any benefit for memory
- no treatment tested

> Reducing fibronectin itself rescues the barrier defects. (Caghan Kizil, Columbia University, to ScienceAlert (in animal models))

Chapter VII · Back to the news

#### Fibronectin and the barrier

The blood–brain barrier is made of endothelial cells joined by tight junctions, supported by a basement membrane, pericytes and astrocyte end-feet; it limits what passes from the blood into the brain. A 2023 review (Chen et al.) describes how, when it is disrupted in Alzheimer’s, plasma proteins such as fibrinogen and immune cells enter, inflammation increases, and barrier damage and disease may drive each other; APOE4 carriers show more barrier dysfunction. Kizil’s team found that APOE4 promotes fibronectin around brain vessels; excess fibronectin activated abnormal integrin and focal adhesion kinase signalling and disrupted VEGF, HBEGF and IGF1 signals that maintain the barrier.

The team’s earlier work found a rare protective FN1 variant in some APOE4 carriers. Fibronectin has essential roles in tissue support and healing, so any future treatment would have to target only its harmful build-up. The model is schematic; “nearly twice” is the mouse measurement.

Sources: [ScienceDaily / Columbia University Irving Medical Center: why some people escape Alzheimer’s despite carrying a high-risk gene (19 Oct 2026)](https://www.sciencedaily.com/releases/2026/10/261018205044.htm); [ScienceAlert: fibronectin and blood–brain barrier leakage in APOE4 models (2026)](https://www.sciencealert.com/?p=219531); [Chen et al., Frontiers in Aging Neuroscience (2023): blood–brain barrier dysfunction and Alzheimer’s disease](https://frontiersin.org/articles/10.3389/fnagi.2023.1258640/full)

## Epilogue

### The long silence
*Epilogue*

If you notice memory changes, talk to a doctor.

Alzheimer could only look at his patient's brain after she died. Today the same proteins show up in a living brain, and in blood, years before the first forgotten name. That silent stretch is where research now looks: earlier treatment, the brain's immune cells, and its blood vessels. And for the sharp eighty-year-olds we began with, part of the answer may lie in those vessels. Researchers are now exploring that idea in the lab.

- 1906: Alzheimer describes plaques and tangles
- 1984–85: amyloid beta and tau identified
- 1991: Braak stages of tangle spread
- 1993: APOE e4 linked to risk
- 2023–25: anti-amyloid drugs; first blood test
- 2026: fibronectin and the barrier (mice)

- why some e4 carriers stay healthy
- how amyloid, tau and inflammation drive each other
- whether treating earlier helps more
- memory changes? talk to a doctor; sources are in the panel

![All stills and illustrations in this film are AI-generated.](https://assets.planetpast.com/a/0b/0b808ac6f28275ed.jpg)

Epilogue · Sources

#### How Alzheimer’s disease works

Alzheimer’s disease is defined by amyloid plaques between neurons and tau tangles inside them. The changes begin one to two decades before symptoms, spread through the brain in a regular order, and end in the loss of synapses and neurons. Age is the strongest risk factor; APOE e4 raises risk; diagnosis can now detect the proteins in life, and anti-amyloid antibodies modestly slow early disease.

This film is general education, not medical advice, diagnosis or a guide to treatment. If you are worried about memory changes, talk to a doctor. All interactive models are schematic and all images are AI-generated.

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