Is Alzheimer's Disease (AD) associated with Parkinsonism?

Alzheimer's Disease and Parkinsonism: Association and Clinical Implications

Alzheimer's disease (AD) is not an alpha synucleinopathy but is frequently associated with parkinsonism through various mechanisms, including co-existing Lewy body pathology in up to 36% of cases. 1

Pathological Basis of AD and Its Relationship to Parkinsonism

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

• Amyloid-beta (Aβ) plaques
• Tau pathology (neurofibrillary tangles)

These form the basis of the "ABC score" used in the neuropathological diagnosis of AD 2, 1:

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

Co-existing Pathologies

Pure AD pathology is relatively uncommon, especially in late-life dementia:

• Only 3-30% of neuropathological examinations of people with dementia of the Alzheimer type show pure AD pathology 1
• Multiple proteinopathies are increasingly common in older patients 1
• Lewy bodies (alpha-synuclein aggregates) are frequently observed alongside moderate-to-severe AD neuropathologic changes 2, 1

Parkinsonism in Alzheimer's Disease

Parkinsonism occurs in AD patients through several mechanisms:

1. Co-existing alpha-synucleinopathy: Many AD patients develop Lewy bodies, which are the hallmark of Parkinson's disease 1, 3

2. Direct effects of AD pathology:

   • Neuronal loss with neurofibrillary tangles and amyloid plaques in the brainstem, substantia nigra, and locus coeruleus can contribute to parkinsonism features 4
   • Some cases show parkinsonism without alpha-synuclein pathology 5

3. Clinical prevalence:

   • The frequency of parkinsonism in AD ranges from 9% to 100% depending on the sample, assessment methods, and disease stage 3
   • Rigidity and hypokinesia are the most commonly observed parkinsonian signs in AD
   • Resting tremor is less common in AD-associated parkinsonism 3

Clinical Implications

Diagnostic Considerations

• The presence of parkinsonism in a patient with cognitive decline may indicate mixed pathology rather than pure AD 1
• In rare cases, parkinsonism can be an initial and sustained manifestation of pathologically confirmed AD, even mimicking idiopathic Parkinson's disease for years 4

Prognostic Significance

• Patients with parkinsonism show more rapid progression to advanced stages of dementia 3, 5
• Patients with both synucleinopathy and Aβ deposition have significantly shorter survival than those with synucleinopathy alone 1
• Parkinsonism in AD is associated with more global (rather than selective) cognitive impairment 5

Treatment Implications

• Rivastigmine is FDA-approved for both Alzheimer's disease and Parkinson's disease dementia 6
• Patients with AD-associated parkinsonism may show only mild improvement with standard treatments for PD motor symptoms 4
• Psychiatric symptoms such as depression and delusion are frequently associated with parkinsonism in AD 3

Conclusion

While AD is not an alpha synucleinopathy (it is primarily characterized by amyloid-beta and tau pathology), it is frequently associated with parkinsonism. This association reflects the complex overlap between neurodegenerative disorders and suggests potential common pathogenic mechanisms affecting vulnerable neuronal populations 7. The presence of parkinsonian features in AD patients has important implications for diagnosis, prognosis, and treatment approaches.