Are Alzheimer's disease associated with tau and beta-amyloid, Parkinson's disease with alpha-synuclein, Dementia with Lewy bodies (DLB) with tau and alpha-synuclein, Frontotemporal lobar degeneration (FTLD) with tau and Pick bodies, and Chronic traumatic encephalopathy (CTE) a tauopathy?

Proteinopathies in Neurodegenerative Diseases: Clarifying the Pathological Hallmarks

Your understanding is mostly correct, but requires important clarifications: Alzheimer's disease is characterized by both beta-amyloid and tau pathology; Parkinson's disease features alpha-synuclein; DLB (Dementia with Lewy Bodies) is primarily an alpha-synucleinopathy that frequently has co-existing Alzheimer's pathology (beta-amyloid and tau), not a primary tauopathy; FTLD encompasses multiple subtypes including tau-positive variants (like Pick's disease with Pick bodies); and CTE is indeed a tauopathy with a distinctive pattern of phosphorylated tau deposition. 1

Alzheimer's Disease (AD)

• AD pathology requires both beta-amyloid (Aβ) deposition in plaques AND tau deposition in neurofibrillary tangles for definitive pathological diagnosis 1
• The current pathological criteria mandate evidence of both proteins, as their combined buildup is associated with neuronal injury 1
• Aβ deposition appears to precede tau pathology temporally, with amyloid changes occurring 25-30 years before symptom onset 1
• Tau pathology correlates more strongly with clinical symptoms and neurodegeneration than amyloid alone 1

Parkinson's Disease (PD)

• PD is characterized by alpha-synuclein aggregation, not tau or beta-amyloid as primary pathology 2, 3
• Alpha-synuclein forms the core pathological lesions in Parkinson's disease 2

Dementia with Lewy Bodies (DLB)

Your statement about DLB needs significant correction:

• DLB is primarily an alpha-synucleinopathy (Lewy bodies and Lewy neurites contain aggregated alpha-synuclein), NOT primarily a tauopathy 2, 3, 4
• However, most DLB cases have co-existing Alzheimer's pathology: approximately 66% show Braak neurofibrillary tangle stage ≥III (tau pathology) 5
• All sporadic DLB cases demonstrate abundant beta-amyloid (Aβ42) deposits similar in quality and quantity to AD 2
• This represents pathological overlap rather than DLB being defined by tau—the defining feature remains alpha-synuclein 2, 4
• Higher tau burden in DLB reduces diagnostic accuracy (RR 0.49) and is associated with reduced visual hallucinations (RR 0.56) and parkinsonism (RR 0.62) 5

Frontotemporal Lobar Degeneration (FTLD)

• FTLD is heterogeneous and includes multiple pathological subtypes, not solely tau pathology 1, 3
• Tau-positive FTLD variants include Pick's disease (which features Pick bodies—tau-positive inclusions) 6
• However, many FTLD cases are TDP-43 proteinopathies, not tauopathies 1
• Other FTLD subtypes may show FUS protein aggregation 1
• Pick bodies specifically refer to tau-positive inclusions in Pick's disease, a subset of FTLD 6

Chronic Traumatic Encephalopathy (CTE)

• CTE is definitively a tauopathy characterized by a unique pattern of phosphorylated tau (p-tau) deposition 1
• Diagnosis requires neuropathological examination demonstrating this distinctive p-tau pattern 1
• Associated with repetitive head impacts from contact sports or military service 1
• Cannot be definitively diagnosed during life—only suspected clinically as traumatic encephalopathy syndrome (TES) 1

Critical Clinical Pitfalls

Pathological Overlap is Common

• Most older adults with dementia have multiple co-existing pathologies, not pure single-protein diseases 1, 3
• These proteins can co-exist in the same brain and may have additive effects on neurodegeneration 3
• Patients over age 80 with cognitive impairment typically harbor more than one type of brain pathological change 1

Diagnostic Implications

• Elevated p-tau217 is highly specific for AD pathology and not significantly elevated in other tauopathies like progressive supranuclear palsy, corticobasal degeneration, or Pick's disease 6
• When p-tau217 is normal but cognitive impairment exists, actively consider non-AD diagnoses like frontotemporal dementia 6
• The presence of one pathology doesn't exclude others—mixed pathology is the rule rather than exception in elderly patients 1, 3

Understanding Disease Specificity

• Tau elevation is not specific to AD—it occurs in prion diseases, CTE, and some FTLD variants 1
• Alpha-synuclein defines synucleinopathies (PD, DLB) but these frequently have co-existing AD pathology 2, 4, 5
• Beta-amyloid deposition occurs in non-AD conditions including amyloid angiopathy 1