# ALZHEIMER'S BIOMARKER EVIDEN

ALZHEIMER'S BIOMARKER EVIDENCE ATLAS

Multi-Modal Investigation: Genomics, Fluid Proteomics, Molecular Imaging & Clinical Therapeutics

This evidence canvas maps the causal and diagnostic relationships across core Alzheimer's Disease (AD) biomarkers based on the NIA-AA Revised Diagnostic Criteria and recent Phase 3 clinical trial readouts (Clarity AD, TRAILBLAZER-ALZ 2).

How to read: Trace left-to-right from genetic risk and molecular initiators through fluid/imaging biomarkers, neurodegeneration cascades, and disease-modifying therapies.

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01 / GENETICS & INITIATORS

02 / CORE PATHOLOGY (A & T)

03 / NEURODEGENERATION (N)

04 / CLINICAL PHENOTYPES

05 / TARGETED THERAPIES

Gene

APOE-ε4 Allele

Risk: 1 copy = 3x risk; 2 copies = 12x lifetime risk
Category: Genetics
Mechanism: Impairs Aβ lipid clearance & promotes amyloid seeding

Gene Mutations

APP / PSEN1 / PSEN2

Category: Autosomal Dominant
Mechanism: Alters gamma-secretase cleavage favoring Aβ42 peptide
ClinicalOnset: Early-onset AD (<65 years)

Microglia Receptor

TREM2 / CD33 Pathway

Variant: R47H loss-of-function confers 2-4x AD risk
Category: Innate Immunity
Function: Microglial phagocytosis of fibrillar plaques & barrier formation

Biomarker Amyloid

Plasma & CSF Aβ42/40

Specimen: Plasma / CSF (LC-MS/MS & Immunoassays)
Concordance: ~88-92% with Amyloid PET
DiagnosticSignificance: Decreased ratio indicates brain plaque sequestration

Biomarker Tau

Plasma p-Tau217

Benchmark: Gold standard blood biomarker for early AD
Performance: AUC > 0.95 vs Amyloid/Tau PET
ClinicalUtility: Triages patients for anti-amyloid infusion therapy

Molecular Imaging

Amyloid PET (Centiloids)

Metric: Centiloid Scale (0 = normal, >30 = significant plaque burden)
Tracers: 11C-PiB, 18F-Florbetapir, 18F-Florbetaben

Molecular Imaging

Tau PET (Flortaucipir)

Tracer: 18F-Flortaucipir (Tauvid)
BraakStaging: Tracks spatial spread from transentorhinal to neocortex
ClinicalCorrelation: Directly correlates with immediate cognitive decline

Biomarker Neurodegeneration

Neurofilament Light (NfL)

Nature: Non-specific to AD, but tracks rate of brain atrophy
Source: Large myelinated axonal breakdown
Utility: Monitoring disease progression velocity

Biomarker Inflammation

Astrocytic GFAP

Origin: Reactive astrogliosis responding to amyloid deposition
Synergy: Combines with p-tau217 for heightened risk stratification
Detection: Spikes very early in plasma before clinical symptoms

Biomarker Microglia

CSF Soluble TREM2 (sTREM2)

Pathway: Shedding of microglial receptor during neuroinflammation
ProtectiveRole: Higher sTREM2 levels correlate with slower tau spread

Clinical Stage

Preclinical AD (Stage 1-2)

Status: Cognitively Unimpaired (CU)
Window: Optimal window for preventative intervention (10-20 years pre-symptoms)
Biomarkers: A+ / T- or A+ / T+

Clinical Stage

Mild Cognitive Impairment (MCI)

Status: Objective memory impairment; functional independence preserved
Biomarkers: A+ / T+ / N+
TherapeuticWindow: Primary population in FDA-approved mAb trials

Clinical Stage

AD Dementia (Mild / Moderate)

Status: Loss of activities of daily living (ADLs)
Pathology: Widespread cortical tangle propagation and neurodegeneration

Therapeutic Antibody

Lecanemab (Leqembi)

Target: Soluble Aβ protofibrils
Efficacy: 27% slowing of CDR-SB decline at 18 months
Regulatory: Traditional FDA & PMDA Approval
ClinicalTrial: Clarity AD (Phase 3, 1,795 patients)

Therapeutic Antibody

Donanemab (Kisunla)

Target: N3pG-modified Aβ (insoluble core of plaques)
Efficacy: 35% slowing of decline in low/medium tau; complete plaque clearance allows stopping therapy
ClinicalTrial: TRAILBLAZER-ALZ 2 (Phase 3)

Pipeline Therapeutics

Next-Gen Anti-Tau & Microglia

Hypothesis: Halting tau propagation after amyloid removal to stabilize cognition
Modalities: Tau aggregation inhibitors, antisense oligonucleotides (ASO), TREM2 agonists

Impairs Clearance

Drives Aβ42 Generation

Sheds Receptor Into CSF

Induces Hyperphosphorylation

Concordant With Imaging

Precedes Spatial Spread

Triggers Astrogliosis

Drives Axonal Loss

Defines Early Stage

Stratifies Conversion Risk

Tracks Functional Decline

Delays Progression

Robust Plaque Clearance

## CLINICAL & DIAGNOSTIC INTER

CLINICAL & DIAGNOSTIC INTERPRETATION

The ATN Biomarker Matrix

A (Amyloid): Decreased CSF Aβ42/Aβ40 or Plasma Aβ42/40 ratio; elevated Amyloid PET tracer uptake.
T (Tau): Elevated p-Tau (specifically p-tau217), followed by cortical Tau PET ligand retention.
N (Neurodegeneration): Elevated NfL (reflecting axonal trauma) and structural MRI hippocampal atrophy.

Clinical Utility of Blood-Based Biomarkers (BBBM)

Plasma p-tau217 has revolutionized clinical trial enrollment and diagnostic triage. Prior to blood tests, trial screening required invasive lumbar punctures or $5,000 PET scans with a 50% screen failure rate. Blood p-tau217 triages up to 80% of patients without secondary imaging.

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## KEY SCIENTIFIC LITERATURE &

KEY SCIENTIFIC LITERATURE & CLINICAL EVIDENCE

Clarity AD (Lecanemab Phase 3): van Dyck CH, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023; 388:9-21.
TRAILBLAZER-ALZ 2 (Donanemab Phase 3): Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease. JAMA 2023; 330(6):512-527.
Revised Diagnostic Criteria 2024: Jack CR Jr, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement 2024.
Plasma p-tau217 Diagnostic Accuracy: Ashton NJ, et al. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology. JAMA Neurol 2024; 81(3):255-263.
NfL Dynamics in Neurodegeneration: Mattsson N, et al. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol 2017; 74(5):557-566.

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Alzheimer's Biomarker Evidence AtlasPublic · Read-only

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