Is Alzheimer's disease (AD) an alpha-synucleinopathy and can it be associated with parkinsonism?

Alzheimer's Disease and Parkinsonism: Pathological Relationship

Alzheimer's disease (AD) is not an alpha-synucleinopathy, but it can be associated with parkinsonism, particularly in cases where there is co-existing alpha-synuclein pathology or mixed pathology.

Pathological Classification of Alzheimer's Disease

Alzheimer's disease is primarily characterized by two hallmark pathological features:

1. Amyloid-beta (Aβ) plaques: Extracellular deposits of Aβ protein 1
2. Tau pathology: Intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein 1

These two pathological features form the basis of the "ABC score" used in the neuropathological diagnosis of AD, which includes:

• A: Aβ plaque score
• B: Braak NFT (neurofibrillary tangle) stage
• C: CERAD neuritic plaque score 1

Alpha-Synucleinopathies vs. Alzheimer's Disease

Alpha-synucleinopathies are a distinct group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein protein in neurons or glial cells 2. The primary alpha-synucleinopathies include:

• Parkinson's disease (PD)
• Dementia with Lewy bodies (DLB)
• Multiple system atrophy (MSA) 3

Unlike these conditions, AD is not classified as an alpha-synucleinopathy because its primary pathological features are Aβ plaques and tau tangles, not alpha-synuclein aggregates.

Co-Pathology and Mixed Dementia

Despite being distinct pathological entities, there is significant overlap between AD and alpha-synucleinopathies:

• Co-existing pathologies: The International Working Group guidelines note that "Alzheimer's disease in its so-called pure form is a model that is unlikely to apply to most cases of Alzheimer's disease, especially those in people with late-life dementia, in whom multiple proteinopathies are increasingly common" 1

• Mixed pathology prevalence: Pure AD pathology is found in only 3-30% of neuropathological examinations of people with dementia of the Alzheimer type 1

• Alpha-synuclein in AD: Lewy bodies (alpha-synuclein aggregates) are frequently observed in the setting of moderate-to-severe levels of AD neuropathologic change 1

Parkinsonism in Alzheimer's Disease

Parkinsonism (motor symptoms resembling those seen in Parkinson's disease) can occur in AD through several mechanisms:

1. Co-existing alpha-synucleinopathy:

   • Lewy bodies are frequent in the setting of moderate-to-severe AD pathology 1
   • This co-pathology can manifest clinically as parkinsonism

2. Clinical phenotype overlap:

   • A significant percentage of AD patients exhibit extrapyramidal features 4
   • Many PD patients develop dementia, with most demented PD patients showing widespread neurofibrillary tangles and senile plaques in addition to Lewy bodies 4

3. Pathological subtypes of dementia with parkinsonism: Research has identified pathological subgroups of dementia associated with parkinsonism:

   • Predominant synucleinopathy
   • Predominant synucleinopathy with Aβ deposition
   • Synucleinopathy and Aβ deposition with neocortical tauopathy 5

Clinical Implications

The relationship between AD pathology and parkinsonism has important clinical implications:

• Diagnostic challenges: The presence of parkinsonism in a patient with cognitive decline may indicate mixed pathology rather than pure AD 1

• Prognostic significance: Patients with synucleinopathy plus Aβ deposition have significantly shorter survival than patients with synucleinopathy only 5

• Treatment considerations: Recognition of mixed pathology may influence treatment approaches, as medications for AD may have different effects in patients with co-existing alpha-synucleinopathy

Conclusion

While Alzheimer's disease is not an alpha-synucleinopathy by definition, it frequently co-exists with alpha-synuclein pathology, particularly in older adults. This co-pathology can manifest clinically as parkinsonism in patients with AD. The extensive overlap between these conditions suggests they may represent different manifestations along a spectrum of neurodegeneration rather than entirely distinct entities.