Alzheimer's disease is characterized by the abnormal accumulation and spread
of the tau protein in the brain. An international study can now show how tau
spreads according to four distinct patterns that lead to different symptoms
with different prognoses of the affected individuals. The study was
published in Nature Medicine.
“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.
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 Alzheimer’s patients with the help of PET
technology, an advanced medical imaging technique.
For the past thirty years, many researchers have described the development
of tau pathology in Alzheimer's 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”, says Oskar Hansson, professor of neurology at Lund University,
who supervised the study.
The current study is a collaboration between sites in Sweden, Canada, USA
and Korea. Together, the researchers have examined the largest and most
diverse population in the world to date with tau-PET, which spans the entire
clinical picture of Alzheimer's disease. The study included participants who
had not yet developed any symptoms, so-called pre-symptomatic Alzheimer's,
participants with mild memory difficulties and those with fully developed
Alzheimer's 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 Alzheimer's 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.
As expected, 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. 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”, says Oskar Hansson.
“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. 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”, says Oskar Hansson.
The researchers believe that this new knowledge can give patients more
individualized treatment methods in the future.
The four subtypes
• Variant one: tau spreads mainly within the temporal lobe and primarily
affects memory. Variant one occurred in 33 percent 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, that is, the ability to plan and perform an action. Variant two
occurred in 18 percent 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 percent 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 percent of all cases.
Reference:
Vogel, J.W., Young, A.L., Oxtoby, N.P. et al. Four distinct trajectories of
tau deposition identified in Alzheimer’s disease. Nat Med (2021).
https://doi.org/10.1038/s41591-021-01309-6