What’s happening in the brain in Alzheimer’s disease and dementia?

Abnormal amyloid-beta and phosphorylated tau protein deposits

Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer’s disease

Characteristic changes are seen in the brains of people with Alzheimer’s disease, explained Professor Thal. These changes are:

• Neurofibrillary tangles, which are intraneuronal aggregates of abnormal phosphorylated tau protein
• Senile plaques, which are extracellular aggregates of amyloid-beta (Aβ) protein¹

The presence of Aβ protein plaques in the brain follows a distinct hierarchical sequence with gradual progression into regions that receive neuronal projections from regions already containing Aβ plaques.

Amyloid-beta deposition follows a distinct hierarchical sequence

Five phases can be identified as the plaques spread throughout the brain,² said Professor Thal.

• In phase 1, one or more Aβ plaques are found in the frontal, occipital, parietal and/or temporal neocortex
• In phase 2, Aβ plaques are seen in the allocortex—the entorhinal cortex, the hippocampus, and the cingulate gyrus
• In phase 3, the distribution of Aβ plaques includes the thalamus, the hypothalamus, and the basal ganglia, and by this phase, the entire neocortex is filled with Aβ plaques

Only the final two phases of amyloid-beta deposition are associated with dementia

• In phase 4, Aβ plaques are present in the midbrain and in the medulla oblongata
• In phase 5, Aβ plaques are seen in the pons and cerebellum

Dementia is only seen in patients with phase 4 or 5 Aβ plaques, added Professor Thal. It is not usually seen patients with phase 1, 2, or 3 Aβ plaques.

Other brain pathologies contributing to the Alzheimer’s dementia phenotype

Alzheimer’s dementia is a heterogeneous disease

Professor Thal highlighted that the brains of many elderly people show changes not only of Alzheimer’s disease, but also many other pathologies, including:

• Cerebral amyloid angiopathy³
• Small vessel disease³
• Atherosclerosis of the circle of Willis³
• Granulovacuolar degeneration⁴
• Limbic-associated age-related transactive response DNA-binding protein (TDP)-43 encephalopathy (LATE)⁵
• Lewy body disease⁶

These brain pathologies can all contribute to the dementia phenotype, explained Professor Thal.

A diagnosis of dementia should include all brain pathologies

In addition, specific brain pathologies such as argyrophilic grain disease, which affects 5% of all patients with dementia, has additive effects on the cognitive symptoms associated with Alzheimer’s disease.⁷

A diagnosis of dementia should therefore include all pathologies, and combined treatment strategies may be more effective than a treatment strategy targeting a single pathology, concluded Professor Thal. This has implications for the design of clinical trials investigating drugs targeting Alzheimer’s disease.