Alzheimer’s Disease is a More Heterogeneous Condition Than Previously Considered

Four distinct patterns of Alzheimer's disease that lead to different symptoms with different prognoses of the affected individuals has been discovered by an international team of scientists at the Lund University, as published in the journal Nature Medicine. Alzheimer's disease (AD) is a neurodegenerative disease that leads to gradual memory loss and behavioral changes. It is characterized by the formation of beta-amyloid plaques and the tau proteins in the brain tissues, years before the actual symptoms occur.

The progression of this abnormal tau protein accumulation in the brain is a key marker for Alzheimer's. With the aid of an advanced medical imaging technique – PET technology, monitoring of toxic protein accumulation in the brain has become possible in recent times.

Heterogeneity of the Alzheimer’s Disease

"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 re-evaluate 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 Vo-gel from McGill University, and the lead author of the study.

The usage of a single model for the description of Alzheimer’s pathology over the past thirty years has unanswered many questions as to why different patients may develop different symptoms. Since different regions of the brain are affected differently in the four subtypes of Alzheimer's, different symptoms and prognoses develop in patients.

This helps clinicians anticipate whether the four subtypes of Alzheimer's might respond differently to various treatments that focus on reducing the amount of tau in the brain. The present study included 3 groups of participants – those who had not yet developed any symptoms (pre-symptomatic), those with mild memory difficulties, and those with fully developed Alzheimer's dementia, to examine the entire clinical picture of Alzheimer's disease.

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Alzheimer’s Disease and its Subtypes

Long-term data was compiled from 1,612 individuals within five independent multicenter studies in a first sample. Among them, 1,143 individuals were identified to be cognitively normal or have developed Alzheimer's in various stages.

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The tau PET images data from the 1,143 individuals were utilized to apply the so-called SuStaIn (Subtype and Staging Inference) algorithm, to be able to distinguish subtypes and patterns as impartially as possible.

The imaging data 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 that became distinct over time were identified with the prevalence of the subgroups between 18 and 30%.

• Variant one in 33% of all cases : tau spreads mainly within the temporal lobe and primarily affects memory.
• Variant two in 18% of all cases: Tau spreads in the rest of the cerebral cortex, characterised by has lesser memory problems than in the first variant. However, greater difficulties with executive functions, that is, the ability to plan and perform an action was found.
• Variant three in 30% of all cases: Tau accumulation in the visual cortex, i.e. in the part of the cerebrum where information from the optic nerve is processed and classified. Defective visuospatial processing of sensory impressions in the brain along with difficulty in orienting oneself, distinguishing shapes and contours, distance, movement, and the location of objects concerning other objects.
• Variant four in 19% of all cases: Tau spreads asymmetrically in the left hemisphere and primarily affects the individual's language ability.

"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, professor of neurology at Lund University, who supervised the study.

The study thereby provides a new dimension to the knowledge on Alzheimer’s disease, which can give patients more individualized treatment methods in the future.

Source-Medindia