Co‐ and Multi‐Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review

Movement Disorders (Wiley) · 2026-05-22 · open original →

Movement Disorders, EarlyView.

Connects: Dementia & MCI ↔ Alpha-synuclein biology · Alpha-synuclein biology ↔ Neuroinflammation · Dementia & MCI ↔ Genetics

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by xavier.grehant on 2026-05-24

Co-pathologies in PD Alpha-synuclein biology Dementia & MCI Genetics Biomarkers & diagnosis Trial design & recruitment Neuroinflammation

Most people think of Parkinson's as a single brain disease caused by one thing — the buildup of a protein called alpha-synuclein into clumps called Lewy bodies. But when researchers examine PD brains after death, they almost never find Lewy bodies alone. This expert review, commissioned by the International Parkinson and Movement Disorder Society's Scientific Issues Committee (a body of leading international specialists), synthesises decades of autopsy studies, genetic analyses, animal models, and observational cohort data to map what those extra pathologies are, how common they are, and what difference they make. The most frequent additions are Alzheimer-type changes (tau tangles and amyloid plaques), damage from small blood-vessel disease, and deposits of a third protein called TDP-43. Many patients carry two or three of these on top of their Lewy body pathology. This type of paper — an expert consensus review — does not generate new data; it authoritatively distils existing evidence to guide the field.

The central finding is that Alzheimer-type pathology does not just sit passively alongside PD: tau and alpha-synuclein appear to promote each other's clumping, and patients who carry significant amounts of both tend to develop memory and thinking problems earlier and more severely. This interaction — not alpha-synuclein burden alone — may explain much of the striking variation between people who have the same PD diagnosis yet follow completely different courses. Shared genetic risk factors (especially the APOE ε4 gene variant, already known in Alzheimer's disease, and the MAPT gene region) increase the chance that a person with PD will also accumulate Alzheimer-type pathology.

For someone living with Parkinson's, this review matters on several levels. It helps explain why cognitive trajectories differ so much from one patient to another. It also signals that biomarkers built entirely around alpha-synuclein — blood tests, spinal fluid assays, imaging — can give misleading readings when undetected Alzheimer or vascular pathology is also present. And it argues that clinical trials testing new PD drugs need to screen for co-pathologies in their participants, because an undetected layer of Alzheimer pathology in half the trial group could easily mask a real benefit from a PD therapy. The practical takeaway for patients is to ask their neurologist whether their cognitive screening or family history warrants evaluation for Alzheimer-type risk alongside PD management — the two conditions are more intertwined than the separate diagnoses suggest.

What this article adds

Co-pathologies in PD (topic pending review): This MDS Scientific Issues Committee review establishes the conceptual framework of co-pathologies (one additional pathology) and multi-pathologies (several at once) as the norm — not the exception — in PD brains, identifying Alzheimer-type changes, cerebrovascular disease, and TDP-43 deposits as the most prevalent companions to Lewy body pathology and arguing that the specific mix largely determines each patient's individual disease course.
Alpha-synuclein biology: The review synthesises evidence that tau, amyloid-β, and TDP-43 do not merely coexist with alpha-synuclein but interact with it synergistically — altering its aggregation pattern, accelerating its spread through the brain, and intensifying neurodegeneration beyond what alpha-synuclein pathology alone would produce.
Dementia & MCI: The review documents that Alzheimer-type co-pathology (tau tangles and amyloid plaques) is among the strongest independent predictors of dementia in PD, above and beyond Lewy body burden itself; patients with higher Alzheimer co-pathology develop cognitive impairment faster and more severely, which this review frames as one of the most clinically important implications of the co-pathology picture.
Genetics: The review highlights how APOE ε4 and the MAPT H1 haplotype — genetic variants originally characterised in Alzheimer's disease — increase susceptibility to Alzheimer-type co-pathology in PD, helping explain why cognitive decline risk varies so dramatically between individuals who share the same PD diagnosis; LRRK2 variants are also discussed as a bridge between PD and multiple co-pathologies via immune function.
Biomarkers & diagnosis: A key practical message of this MDS SIC expert review is that co-pathologies can confound biomarker readings: alpha-synuclein seed-amplification assays, amyloid PET, DAT-SPECT, and blood-based markers can all be affected by concurrent Alzheimer or vascular pathology, making single-biomarker diagnostic strategies unreliable in the large proportion of PD patients who carry co-pathologies — the review argues for multi-modal biomarker approaches.
Trial design & recruitment: The review explicitly argues that uncharacterised co-pathology burden is a major but largely unaddressed source of heterogeneity in PD trial populations — a patient's response to an alpha-synuclein-targeting therapy could be masked or confounded by concurrent Alzheimer or vascular pathology — and calls for routine multi-pathology biomarker screening as part of standard PD trial design.
Neuroinflammation: The review identifies shared neuroinflammatory mechanisms as a key driver of the synergistic interaction between alpha-synuclein and co-pathologies: oligomeric forms of tau, amyloid-β, and alpha-synuclein each activate microglia and astrocytes, and this shared inflammatory response then feeds back to accelerate aggregate formation across all protein types simultaneously.

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