The Simplified Biological Timeline of Alzheimer’s

Think of Alzheimer’s disease as unfolding in three major biological phases.

1. Amyloid deposition (earliest phase)

This begins 10–20 years before symptoms.

What happens biologically
• Amyloid beta accumulates in plaques in the brain
• Soluble Aβ42 in blood and CSF decreases because it is being trapped in plaques

Biomarkers that detect this stage:

MarkerWhat it measuresAβ42/40 ratioEarly amyloid pathologyAmyloid PETDirect plaque imagingPET centiloidsStandardized plaque burden scale

Interpretation example from your table:

• Aβ42/40 ≤ ~0.15 → higher likelihood of amyloid plaques

• PET centiloid >20 → amyloid positive

• ~50+ CL → clearly abnormal plaque burden

This is the first gate for Leqembi eligibility.

2. Tau pathology (middle phase)

After amyloid accumulates, abnormal tau begins to spread.

What happens biologically
• Tau becomes phosphorylated
• Neurofibrillary tangles develop
• Tau pathology spreads through brain networks

Biomarkers detecting this stage:

MarkerMeaningp-tau217Highly specific AD tau pathologyp-tau181Earlier tau biomarkerTau PETImaging of tau deposition

Your table thresholds reflect this stage:

• p-tau217 > 0.15 pg/mL → abnormal

• p-tau181 > ~1.07 pg/mL → abnormal

These markers strongly predict amyloid PET positivity and future cognitive decline.

Many programs now use blood p-tau tests to triage who should get PET scans.

3. Neurodegeneration (later phase)

This is when brain injury and cognitive decline become measurable.

What happens biologically
• synaptic loss
• neuronal death
• brain atrophy

Markers here include:

MarkerWhat it showsMRIhippocampal atrophyFDG PETreduced brain metabolismNeuropsych testingcognitive impairment

This is where patients start showing symptoms.

How This Relates to Leqembi Eligibility

Leqembi works by removing amyloid plaques, so treatment must begin before extensive neurodegeneration occurs.

Programs therefore look for patients in the “early symptomatic” window:

Amyloid present
        +
Early symptoms
(MCI or mild dementia)
        +
Acceptable MRI safety
        ↓
Eligible for anti-amyloid therapy

If treatment occurs too late, removing amyloid may not reverse the downstream damage.

Where Each Marker in Your Table Fits

MarkerPhase of diseaseRole in screeningAβ42/40 ratioEarly amyloidblood screeningAmyloid PET centiloidsAmyloid plaque burdenconfirm pathologyp-tau217Tau pathologystrong AD predictorp-tau181Tau pathologyearlier tau biomarkerAPOE genotypeRisk modifierARIA safety risk

So your table essentially combines three types of information:

1️⃣ Amyloid detection
2️⃣ Tau pathology detection
3️⃣ Treatment safety risk

Why Blood Biomarkers Are Becoming Important

Historically the pathway was:

Symptoms
→ cognitive testing
→ amyloid PET

Now many programs use:

Symptoms
→ blood biomarker panel
(Aβ42/40 + p-tau)
→ PET confirmation only if positive

This reduces cost and speeds triage.

A Useful Mental Model

You can think of the Alzheimer biomarker sequence like this:

Amyloid starts accumulating
        ↓
Tau pathology develops
        ↓
Neurodegeneration begins
        ↓
Cognitive symptoms appear

Leqembi is targeting the first step in that chain.

If you're building your Squarespace learning page

One helpful section could be titled:

Biological Markers of Alzheimer’s Disease

Subsections:

• Amyloid biomarkers
• Tau biomarkers
• Neurodegeneration markers
• Genetic risk modifiers

This structure mirrors the ATN research framework used in Alzheimer’s science.

If you'd like, I can also show you something that will be extremely useful for someone in your role:

A very clear table of what most real-world Leqembi programs require for eligibility, including typical cognitive scores, MRI findings, and exclusion criteria. It’s one of the things that tends to be surprisingly variable across programs.