APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson’s disease

Why this matters for people with Parkinson’s

Cognitive problems such as slowed thinking, trouble with planning, or memory lapses are among the most feared complications of Parkinson’s disease, but they do not affect everyone in the same way. This study asks a practical question with big implications for patients, families, and future treatments: which biological factors best predict who with Parkinson’s is most likely to experience serious thinking decline over time?

Different kinds of Parkinson’s, different risks

Parkinson’s disease is not a single condition. It can appear without a known cause (often called sporadic Parkinson’s) or be linked to inherited changes in certain genes, including GBA1 and LRRK2. Earlier work showed that people with GBA1-related Parkinson’s tend to have more cognitive problems, while those with LRRK2 changes may be relatively protected. The new study followed more than 2,300 adults—people with sporadic Parkinson’s, GBA1-Parkinson’s, LRRK2-Parkinson’s, and healthy volunteers—over several years. Everyone took repeated tests of thinking and memory, and many provided spinal fluid samples so the researchers could measure protein markers linked to Alzheimer’s disease.

How genes tied to Alzheimer’s shape thinking in Parkinson’s

The team focused on a gene called APOE, long known to influence risk for Alzheimer’s disease. One version of this gene, called ε4, tends to raise Alzheimer’s risk, while another, ε2, tends to be protective in the general population. In this study, however, APOE’s impact depended strongly on the type of Parkinson’s. Among people with sporadic Parkinson’s, carriers of APOE ε4 experienced a much steeper drop in thinking scores over ten years than those with other APOE versions. In contrast, APOE type made little difference for people with GBA1- or LRRK2-related Parkinson’s, or for healthy controls, suggesting that the same gene can have very different effects depending on the underlying form of Parkinson’s.

Alzheimer’s proteins as common drivers of decline

The researchers then examined two spinal fluid markers that mirror changes seen in Alzheimer’s disease: Aβ42, related to amyloid buildup, and phosphorylated tau (pTau), linked to tangles inside nerve cells. Lower baseline levels of Aβ42 signaled faster cognitive decline across every group studied—sporadic Parkinson’s, GBA1-Parkinson’s, LRRK2-Parkinson’s, and healthy volunteers. In other words, this Alzheimer’s-related change appeared to add an extra push toward decline on top of whatever risk each Parkinson’s subtype already carried. Tau told a more selective story: higher pTau levels at the start predicted faster decline mainly in sporadic Parkinson’s and, to a lesser extent, LRRK2-Parkinson’s, but not in GBA1-Parkinson’s or healthy people. This suggests that tau-related damage matters more for some forms of Parkinson’s than others.

Untangling how these factors interact

To understand how these pieces fit together, the investigators asked whether the harmful effect of APOE ε4 in sporadic Parkinson’s was explained by its link to Aβ42 levels. Their analysis suggested that about one-third of the extra cognitive decline seen in ε4 carriers was indirectly related to having lower Aβ42, a sign of greater amyloid burden. The remaining two-thirds could not be explained by this marker alone, hinting that APOE ε4 also promotes decline through other, yet-to-be-clarified pathways. Tau levels, in contrast, did not meaningfully mediate APOE’s effect. The study also confirmed the influence of familiar clinical factors: older age, less education, male sex, and longer-standing disease were all tied to worse thinking outcomes.

What this means going forward

For people living with Parkinson’s, these findings reinforce that cognitive decline is not inevitable and that risk is shaped by both the kind of Parkinson’s they have and the presence of Alzheimer’s-related changes. In sporadic Parkinson’s, APOE ε4 and higher tau seem to make thinking problems more likely, while low Aβ42 is a warning sign across all groups. For researchers and clinicians, this means that future drug trials aimed at protecting cognition will likely be more powerful if they account for Parkinson’s subtype, APOE status, and these spinal fluid markers when selecting participants and interpreting results. Ultimately, a more personalized understanding of risk may help tailor monitoring and, one day, preventive treatments for those most vulnerable to losing cognitive abilities.

Citation: Botta, R., Locascio, J.J., Ye, R. et al. APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson’s disease. npj Parkinsons Dis. 12, 79 (2026). https://doi.org/10.1038/s41531-026-01290-2

Keywords: Parkinson’s disease, cognitive decline, APOE gene, amyloid and tau, genetic subtypes