Alzheimer's disease has traditionally been perceived as a condition characterized by diffuse cortical amyloid deposition, which spreads across the brain before symptoms emerge. This perspective affects everything from the interpretation of PET scans to the design of clinical trials, reinforcing a binary view: amyloid is either present or absent, positive or negative, diffuse or insignificant.

However, this model is incomplete.

Closer examination of the literature, focusing on early rather than late-stage disease, reveals a different narrative:

Early amyloid is not diffuse. It is regional, staged, asymmetric, and biologically predictive.

Moreover:

Low global amyloid does not equate to low disease relevance.

The "Gray Zone" Is Not Noise - It Is Biology

In early Alzheimer's disease, individuals often present with low global Centiloid levels, falling below traditional positivity thresholds. These scans are often labeled as:

• borderline
• indeterminate
• clinically insignificant

This interpretation overlooks a crucial point:

Global burden is low, but regional pathology may already be present and active.

Research shows that individuals who are globally amyloid-negative can still exhibit focal cortical deposition predictive of:

• future cognitive decline
• subsequent tau accumulation
• eventual conversion to global amyloid positivity

This isn't a pre-disease state; it represents the earliest detectable phase of disease expression.

Amyloid Follows a Structured Regional Sequence

Early amyloid deposition is not random; it follows a hierarchical and reproducible spatial trajectory. Across studies, initial accumulation occurs in:

• Posterior cingulate and precuneus
• Orbitofrontal cortex
• Temporobasal regions
• Default mode network hubs

Only later does it extend into:

• Broader associative cortex
• Then primary cortical regions

Despite methodological differences across studies, the central conclusion remains:

Amyloid deposition is regionally staged, not globally uniform from onset.

This aligns with network biology: regions with high connectivity and metabolic demand accumulate pathology first.

A Critical Signal: Early Regional Hotspots

One of the most compelling findings in the literature is the identification of early-vulnerable cortical regions with significant prognostic value. A key example:

Banks of the Superior Temporal Sulcus (BANKSSTS)

• Among the earliest regions to show amyloid deposition
• Detectable even when global PET remains negative
• Associated with:
  • ~2.5x faster memory decline
  • Increased likelihood of future tau deposition

This is not subtle statistical noise. It is a clinically meaningful early marker of disease trajectory.

Asymmetry: The Forgotten Feature of Early Disease

Another under-recognized feature of early amyloid deposition is hemispheric asymmetry. In preclinical Alzheimer's:

• Amyloid is often lateralized
• Asymmetry decreases as disease progresses
• Later stages appear more symmetric and "diffuse"

This suggests a clear temporal pattern:

Focal - asymmetric - network spread - global involvement

The "diffuse amyloid" model may therefore describe late disease, not early disease.

Why Global Metrics Fail Early Disease

Global SUVR and Centiloid measures are optimized for widespread cortical involvement. They fail when:

• Only a small number of regions are affected
• Signal is spatially concentrated rather than distributed

As a result:

Early disease can be systematically underdetected by global metrics.

Recent work, such as the Mayo Clinic 2024 study, shows that:

• Regional PET analysis detects amyloid earlier than CSF biomarkers
• Early-region ROIs outperform standard global meta-ROIs
• PET-positive / CSF-negative cases are common when using regional approaches

This fundamentally challenges the assumption that CSF becomes abnormal first. Instead:

Regional PET may be the most sensitive early detector of cortical amyloid deposition.

From Localization to Prediction

Regional amyloid is not just descriptive - it is predictive. Longitudinal studies show:

• Regional accumulation predicts episodic memory decline
• Regional staging predicts conversion to MCI and dementia
• Spatial extent of amyloid predicts disease timing

This reframes amyloid PET from:

• a binary diagnostic tool

to:

• a temporal and spatial disease-mapping instrument

Revisiting the Amyloid-Tau-FDG Hierarchy

The field often teaches:

• Amyloid = early but nonspecific
• Tau = symptom-correlated
• FDG = functional

But this oversimplifies the role of amyloid. A more accurate model:

Amyloid defines where the system becomes vulnerable.
Tau defines where the system is injured.
FDG defines where the system is failing.

In this framework:

• Regional amyloid is the earliest localization signal
• Tau refines and amplifies that signal
• FDG reflects downstream dysfunction

Dismissing early amyloid because it doesn't yet correlate perfectly with symptoms ignores the origin point of the disease process.

Clinical Phenotype Already Supports This Model

We already accept that Alzheimer's disease presents as regional syndromes:

• Posterior cortical atrophy -> visuospatial network
• Logopenic aphasia -> temporoparietal language network
• Executive variants -> frontal systems

These syndromes imply:

The disease begins regionally.

It is inconsistent to accept regional clinical phenotypes while assuming initial pathology is globally diffuse.

Implications for Clinical Practice

1. Stop Treating Amyloid as Binary

A "negative" global scan does not exclude early disease.

2. Evaluate Spatial Patterns

Look for:

• Posterior cingulate / precuneus involvement
• Temporal asymmetry
• Focal associative cortex signal

3. Recognize the Gray Zone as Actionable

Low Centiloid + regional positivity =

• Early-stage Alzheimer's biology
• Not incidental finding

4. Integrate with Longitudinal Risk

Regional amyloid provides:

• Prognostic signal
• Disease staging insight
• Early intervention opportunity

Conclusion: The Leading Edge of Disease

The field has been asking:

"Is amyloid present?"

But the more important question is:

"Where is amyloid present first?"

Because that location:

• predicts where tau will accumulate
• predicts which network will fail
• predicts how the disease will present

Regional amyloid positivity is not an incomplete form of Alzheimer's disease. It is the first visible imprint of it. If we continue to collapse that signal into a binary framework, we are not simplifying the disease - we are missing its beginning.

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