Alzheimer's Disease, Alpha-Synucleinopathy, and Parkinsonism
Alzheimer's disease (AD) is NOT primarily an alpha-synucleinopathy, but it can be associated with parkinsonism due to co-existing pathologies or advanced disease progression. 1
Pathological Classification of Alzheimer's Disease
Alzheimer's disease is pathologically defined by two primary hallmark features:
- Amyloid-beta (Aβ) plaques
- Tau pathology (neurofibrillary tangles)
These form the basis of the "ABC score" used in neuropathological diagnosis of AD 1:
- A: Aβ plaque score
- B: Braak NFT (neurofibrillary tangle) stage
- C: CERAD neuritic plaque score
Alpha-Synuclein in Alzheimer's Disease
Alpha-synuclein pathology (characteristic of synucleinopathies like Parkinson's disease) is not the primary pathological feature of AD. However:
- Lewy bodies (alpha-synuclein aggregates) are frequently observed alongside moderate-to-severe AD neuropathologic changes 1
- Pure AD pathology is found in only 3-30% of neuropathological examinations of people with dementia of the Alzheimer type 1
- Recent evidence suggests that alpha-synuclein may be involved in the pathophysiology of AD, potentially interacting with tau hyperphosphorylation and Aβ pathology 2
Parkinsonism in Alzheimer's Disease
Parkinsonism (motor symptoms resembling those seen in Parkinson's disease) can occur in AD through several mechanisms:
- Co-existing alpha-synucleinopathy: Many AD patients have concomitant Lewy body pathology 1
- Advanced AD pathology: Neuronal loss with neurofibrillary tangles and amyloid plaques in the brainstem, substantia nigra, and locus coeruleus can contribute to parkinsonian features 3
- Mixed pathology: The presence of parkinsonism in a patient with cognitive decline often indicates mixed pathology rather than pure AD 1
Clinical Implications
- A significant percentage of AD patients exhibit extrapyramidal features 4
- Patients with both synucleinopathy and Aβ deposition have significantly shorter survival than patients with synucleinopathy only 1
- The co-occurrence of neocortical alpha-synuclein, tau, and amyloid pathologies suggests potential synergistic interaction of these pathologies 5
Diagnostic Considerations
When evaluating a patient with cognitive decline and parkinsonian features:
- Consider the possibility of mixed pathology
- Recognize that the presence of parkinsonism does not exclude an AD diagnosis
- Be aware that some rare cases of pathologically confirmed AD may present initially with a syndrome clinically indistinguishable from Parkinson's disease 3
Pitfalls to Avoid
- Diagnostic oversimplification: Avoid assuming that parkinsonian features automatically indicate a primary synucleinopathy
- Therapeutic nihilism: Don't assume that patients with mixed pathology won't respond to treatment; they may still benefit from therapies targeting both cognitive and motor symptoms
- Overlooking biomarkers: With the emergence of blood-based biomarkers for AD, these should be considered in the diagnostic workup of patients with mixed cognitive and motor symptoms 6