Alzheimer’s Disease with DLB Co-Pathology

Improving Diagnostic Confidence for Complex Clinical Presentations

Accurate identification of Lewy body co-pathology in patients with Alzheimer’s disease (AD) is crucial. Mixed pathology accelerates cognitive decline, increases neuropsychiatric symptoms, and heightens sensitivity to antipsychotics. While amyloid and tau biomarkers define AD neuropathologic change (ADNC), they do not detect misfolded alpha-synuclein aggregates.

The SAAmplify-ɑSYN clinically validated seed amplification assay (SAA) enables in vivo detection of misfolded ɑ-synuclein in cerebrospinal fluid (CSF). When combined with traditional AD biomarkers, SAAmplify-ɑSYN provides diagnostic clarity in ambiguous cases and guides safer, more personalized treatment strategies. Incorporating SAAmplify-ɑSYN into diagnostic approaches can help:

• Identify ɑ-synuclein co-pathology in AD patients with hallucinations, motor signs, or rapid progression
• Improve diagnostic confidence when clinical presentations are atypical or mixed
• Avoid adverse outcomes from antipsychotic sensitivity in DLB-spectrum pathology
• Stratify patients for individualized prognosis and therapeutic selection
• Support clinical trial enrollment targeting specific proteinopathies

AD/DLB Mixed Pathology Stages and Clinical Characteristics

Alzheimer’s disease with Lewy body mixed pathology (AD/DLB) is prevalent but often underdiagnosed. Pathologically, overlap is substantial. Autopsy studies reveal that over 50% of older individuals with a diagnosis of AD also harbor cortical ɑ-synuclein aggregates. This mixed pathology is associated with

• Earlier and more rapid cognitive decline
• Neuropsychiatric symptoms, including visual hallucinations and delusions
• Idiopathic REM sleep behavior disorder
• Extrapyramidal motor signs
• Severe antipsychotic sensitivity

AD/DLB co-pathology exists along a biological continuum of disease progression. In contrast to pure AD, patients with mixed pathology demonstrate earlier neuropsychiatric features and a more aggressive trajectory.

• Stage A: Amyloid pathology only (A+T-S-), preclinical AD, often asymptomatic or subtle memory complaints
• Stage B: Emergence of tau pathology (A+T+S-), typical amnestic or executive dysfunction, mild cognitive impairment (MCI)
• Stage C: Added ɑ-synuclein pathology (A+T+S+), onset of hallucinations, cognitive fluctuations, iRBD or parkinsonism
• Stage D: Advanced co-pathology (A+T+S+ with severe tau burden), rapid decline, functional loss, and multi-domain deficits

The presence of ɑ-synuclein pathology accelerates decline and increases clinical complexity, often requiring treatment modifications and caregiver support earlier in the disease course.

AD/DLB Mixed Pathology Diagnostic Criteria and Tools

The 2024 Alzheimer’s Association revised diagnostic framework¹ defines AD biologically, requiring evidence of amyloid and tau pathology irrespective of clinical symptoms. Biomarker-based definitions include:

• Amyloid PET positive
• CSF assays: AB42/40 ratio, p-tau/AB42, or t-tau/AB42
• Plasma biomarkers: p-tau217

However, these markers do not capture ɑ-synuclein pathology. The SAAmplify-ɑSYN test complements the AT(N) framework by detecting the third key proteinopathy (S+), enabling identification of mixed AD/DLB phenotypes.

Additional Tools for Differential Diagnosis:

• Tau PET, CSF MTBR-tau243, p-tau205
• MRI and FDG-PET for regional atrophy and hypometabolism
• DAT SPECT for nigrostriatal dopaminergic deficits in patients with parkinsonism

Clinical Use Cases

• Atypical Progression in Mild Alzheimer’s Disease: A patient with biomarker-confirmed AD (A+T+) develops visual hallucinations, iRBD, and mild parkinsonism. SAAmplify-ɑSYN result is “Detected” (S+), confirming evidence of underlying synucleinopathy. Diagnosis is updated to AD/DLB, and treatment is adjusted accordingly, avoiding antipsychotics.
• Rapid Functional Decline: A patient with early AD exhibits abrupt cognitive decline, attentional fluctuations, and parkinsonian gait. SAAmplify-ɑSYN result is detected (S+), and DAT SPECT confirms dopaminergic loss. The revised diagnosis of AD/DLB informs prognosis and qualifies the patients for dual-pathology clinical trials
• Therapy Stratification and Risk Management: In a patient with A+T+ profile being considered for anti-amyloid therapy, the emergence of hallucinations and iRBD raises concerns. A “Detected” SAAmplify-ɑSYN result (S+) highlights the presence of co-pathology. Treatment planning is re-evaluated due to limited efficacy and safety data for S+ individuals and payer requirements for additional justification.

ɑ-Synuclein Pathology and Its Role in AD/DLB Mixed Pathology

ɑ-synuclein aggregation is central to Lewy body diseases and plays a critical modifying role in AD when present. Its presence is associated with accelerated cognitive and functional decline, early neuropsychiatric and motor symptoms, and exacerbation of amyloid and tau toxicity through synergistic mechanisms. ɑ-synuclein cannot be detected via PET imaging clinically, although research and development are ongoing. SAAmplify-ɑSYN is currently the only clinically available assay for the detection of misfolded ɑ-synuclein in CSF.

Diagnostic Innovation

The SAAmplify-ɑSYN assay is a highly sensitive, autopsy-validated assay for detecting misfolded ɑ-synuclein in CSF. The principle of the assay is similar to prion amplification technologies: if misfolded ɑ-synuclein “seeds” are present in the patient’s CSF, they induce aggregation of the recombinant protein in vitro. These aggregates incorporate fluorescent dye and emit a signal that can be read over time. The readout is binary (“Detected” or “Not Detected”). Samples are run in triplicate with stringent controls.

In Practice: Incorporating Alpha-Synuclein as a Biomarker for AD/DLB Co-Pathology

AD with Lewy body co-pathology is common, underrecognized, and associated with unique clinical challenges. Misfolded ɑ-synuclein modifies disease course, increases treatment risk, and impacts therapeutic eligibility. As the revised 2024 diagnostic framework¹ shifts toward biologic classification, the need for accurate identification of co-pathology becomes increasingly important. The SAAmplify-ɑSYN assay fills this diagnostic gap, offering reliable detection of underlying synucleinopathy and enabling clinicians to tailor care based on disease biology. For any AD patient with hallucinations, motor symptoms, sleep disturbances, or rapid progression, SAAmplify-ɑSYN testing should be considered to determine ɑ-synuclein status for informed and more personalized management.

References:

¹Jack CR, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimer's Dement. 2024; 20: 5143–5169. https://doi.org/10.1002/alz.13859

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