Amyloid and Tau Predominance Subtyping Identifies CI Patients With Different Clinical Phenotypes
Authors: Zalzale Hussein , Povala Guilherme , Ferreira Pamela C.L. , Bellaver Bruna , Ferrari‐Souza João Pedro , Soares Carolina , Lussier Firoza Z , Aguzzoli Cristiano Schaffer , Lemaire Peter Charles , Abbas Sarah , Rohden Francieli , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Stevenson Alyssa , Pallen Vanessa , Ashton Nicholas J. , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

Background

The ATN classification system assumes a sequential model of disease progression. However, there are groups of individuals in the same ATN category that exhibit a predominance of abnormality (higher burden) of one of the biomarkers, creating heterogeneous ATN groups regarding pathological predominance. Thus, we tested the hypothesis that individuals clustered by ATN biomarker abnormality predominance may offer an alternative to groups defined using biomarkers cut‐offs.

Method

We assessed 103 cognitively impaired individuals(CDR> = 0.5) from the TRIAD cohort with available measures of plasma phosphorylated tau‐181, brain MRI, amyloid PET, and tau PET. We used the K‐means algorithm to stratify participants into three clusters. We compared the clusters on composite measures of memory, executive functioning, language, and visuospatial processing. To examine the utility of the discovered clusters, we compared them to traditional ATN categories in the prediction of neuropsychological measures. We did so by creating three categories: patients positive on all three ATN biomarkers, patients positive on two of the three biomarkers, and patients positive on either one or none. Additionally, we created an inflammation, amyloid and tau deposition probabilistic map anchored on young controls(n = 51, mean age = 23.74).

Results

We uncovered 3 clusters: an amyloid predominant (AP) cluster, a tau/phosphor‐tau predominant cluster (TP), and a cluster showing no predominance with low levels on all biomarkers (CN)(figure 1). Notably, levels of neurodegeneration and inflammation were similar between the AP and TP clusters. The AP cluster significantly differed from the CN cluster in memory only. Participants in the TP cluster had significantly lower scores in memory, executive functioning, language, and visuospatial processing than the other two clusters. In comparison, using threshold‐based ATN groups showed milder differences in memory and executive functioning, and no differences in language and visuospatial processing(figure 2). Furthermore, cluster membership moderated the relationship between various biomarkers, to the point of reversing the direction of correlation(figure 3).

Conclusion

Our results highlight the biological heterogeneity present within the Alzheimer’s disease continuum and that the pathological predominance of amyloid and tau is associated with different disease phenotypes. Approaching dementia patients with an eye on the predominance of pathology rather than cutoffs for abnormality may provide a better understanding of AD pathological subtypes.