Researchers published a study “Four distinct trajectories of tau deposition identified in Alzheimer’s disease”in Nature Medicine that shows how the tau protein spreads in AD according to four distinct patterns that lead to different symptoms with different prognoses of the affected individuals.

“Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%,” write the investigators.

“We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes.

“Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging.”

“In contrast to how we have so far interpreted the spread of tau in the brain, these findings indicate that tau pathology in the brain varies according to at least four distinct patterns. This would suggest that Alzheimer’s is an even more heterogeneous disease than previously thought. We now have reason to reevaluate the concept of typical Alzheimer’s, and in the long run also the methods we use to assess the progression of the disease,” says Jacob Vogel from McGill University, and the lead author of the study.

Key marker for Alzheimer’s

The spread of tau in the cerebral cortex is a key marker for Alzheimer’s. In recent years, it has become possible to monitor the accumulation of the toxic protein in the brain of AD patients with the help of PET technology.

For the past thirty years, many researchers have described the development of tau pathology in AD using a single model, despite recurring cases that do not fit that model. However, the current findings explain why different patients may develop different symptoms.

“Because different regions of the brain are affected differently in the four subtypes of Alzheimer’s, patients develop different symptoms and also prognoses. This knowledge is important for doctors who assess patients with Alzheimer’s, and it also makes us wonder whether the four subtypes might respond differently to different treatments. Right now, research on various drugs that reduce the amount of tau in the brain is very active, and it will be exciting to see if they vary in efficacy depending on the subtype of Alzheimer,” notes Oskar Hansson, MD, PhD, professor of neurology at Lund University, who supervised the study.

The current study is a collaboration between sites in Sweden, Canada, US, and Korea. Together, the researchers say they have examined the largest and most diverse population in the world to date with tau PET, which spans the entire clinical picture of AD. The study included participants who had not yet developed any symptoms, so-called pre-symptomatic AD, participants with mild memory difficulties, and those with fully developed AD dementia.

In a first sample, long-term data was compiled from 1,612 individuals within five independent multicenter studies. Among these, the researchers identified a total of 1,143 individuals who were either cognitively normal or individuals who had developed AD in various stages.

An algorithm was applied to the data from the tau PET images from the 1,143 individuals, the so-called SuStaIn (Subtype and Staging Inference) algorithm. The material was processed with machine learning in an automated process, in order to be able to distinguish subtypes and patterns as impartially as possible.

Many individuals did not show any abnormal tau PET signal, and these were therefore automatically assigned to a tau-negative group. By then cross-validating the tau PET images with a sixth independent cohort, and following up the individuals for about two years, the researchers were able to develop four patterns that best represented the data from the remaining individuals.

Four clear patterns of tau pathology

Although the number of subgroups varied in relation to the individuals, all were represented in all cohorts.

“We identified four clear patterns of tau pathology that became distinct over time. The prevalence of the subgroups varied between 18 and 30 percent, which means that all these variants of Alzheimer’s are actually quite common and no single one dominates as we previously thought,” explains Hansson.

* Variant one: tau spreads mainly within the temporal lobe and primarily affects memory. Variant one occurred in 33% of all cases.

* Variant two: In contrast to variant one, this variant spreads in the rest of the cerebral cortex. The individual has less memory problems than in the first variant, but on the other hand has greater difficulties with executive functions, i.e., the ability to plan and perform an action. Variant two occurred in 18% of all cases.

* Variant three: The accumulation of tau takes place in the visual cortex, i.e., in the part of the cerebrum where information from the optic nerve is processed and classified. The visuospatial processing of sensory impressions in the brain is affected in individuals with this pattern. They have difficulty orienting themselves, distinguishing shapes and contours, distance, movement, and the location of objects in relation to other objects. Variant three occurred in 30% of all cases.

* Variant four: Tau spreads asymmetrically in the left hemisphere and primarily affects the individual’s language ability. Variant four occurred in 19% of all cases.

“The varied and large databases of tau PET that exist today, along with newly developed methods for machine learning that can be applied to large amounts of data made it possible for us to discover and characterize these four subtypes of Alzheimer’s,” says Hansson.

“However, we need a longer follow-up study over five to ten years to be able to confirm the four patterns with even greater accuracy.”

The researchers believe that this new knowledge can give patients more individualized treatment methods in the future.

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