Alzheimer’s proteins predict early brain shrinkage before dementia symptoms appear

An analysis of the AMYPAD Prognostic and Natural History Study data found that, in older individuals with preserved cognition, amyloid-beta accumulation in the brain can predict future brain atrophy. In women, the association was stronger for predicting atrophy of the temporal region of the brain. It was also stronger in the frontal and lateral-temporal regions as well as the hippocampus in carriers of at least one version (allele) of the APOE-ε4 gene, a gene associated with increased risk of Alzheimer’s disease. The paper was published in NeuroImage: Clinical.

As people reach advanced age, their memory, attention, and mental processing speed tend to gradually worsen. This is a normal part of aging. However, in some people these changes can be more severe, indicating that some type of dementia or neurodegenerative disease might be developing.

Alzheimer’s disease is the most common cause of dementia. It gradually disrupts memory, reasoning, language, and the ability to function independently. Other forms of dementia, such as vascular dementia, Lewy body dementia, and frontotemporal dementia, produce similar symptoms but arise from partly different biological processes.

One of the hallmark features of Alzheimer’s disease is the accumulation of amyloid-beta protein into plaques between brain cells. Another important change is the buildup of abnormal tau protein inside neurons, which is closely associated with neuronal damage and brain atrophy. These pathological processes can begin many years before noticeable cognitive symptoms appear.

Study author Leonard Pieperhoff and his colleagues wanted to explore the influence of global accumulation levels of amyloid-beta in the brain on regional brain atrophy. To do this, they examined regional changes in brain volume and thickness in a large research sample composed of older adults without dementia.

They also explored whether the relationship between amyloid-beta accumulation and subsequent brain atrophy depends on an individual’s sex and on whether the person is a carrier of the APOE-ε4 gene. APOE-ε4 is a gene variant that increases a person’s genetic risk of developing Alzheimer’s disease. People with this gene variant also tend to develop Alzheimer’s disease earlier in life.

These researchers analyzed data from the Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic Natural History Study (PNHS). The study included 1,329 participants who were all required to have no history of dementia and be above 50 years of age at the start. Participants’ average age was 68.2 years. 56% were women. 40% had at least one version of the APOE-ε4 gene.

All participants completed magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging of their brains. A subgroup of 684 participants completed these scans at least once again in the years after the start. The median follow-up time for these scans was 3.4 years later.

Results showed that participants’ brain volumes generally shrank over time, suggesting that there was widespread atrophy of the brain due to aging-related factors. This effect was the most prominent in temporal and parietal regions of the brain as well as in the hippocampus and amygdala. Similar reductions were seen in cortical thickness, although the posterior and anterior cingulate cortices showed thickening over time.

Higher amyloid-beta concentrations were associated with lower volumes of multiple regions of the brain including the lateral-temporal lobes, precuneus, posterior cingulate, amygdala, and hippocampus. Cortical thickness of these regions was also associated with amyloid-beta concentrations in the same way.

Across time, higher amyloid-beta concentrations in the cortex were associated with widespread decrease of volume and thickness at follow-up scans, across different brain regions. The strongest effects were observed in the posterior cingulate, fusiform, and parahippocampal gyri, as well as the hippocampus and amygdala. Notably, atrophy in the fusiform gyrus was predicted by amyloid-beta independently of tau protein levels. This association was stronger in women when temporal regions of the brain were concerned. For carriers of at least one variant of the APOE-ε4 gene, these associations were stronger in frontal and lateral-temporal regions and the hippocampus.

“Our findings suggest that in older adults with mostly preserved cognition, baseline Aβ-PET [amyloid-beta concentrations assessed using PET] predicts future brain atrophy, with fusiform atrophy showing independence from tau pathology [accumulation of tau proteins in the brain] and Aβ-dependent atrophy being exacerbated in region-dependent manners in females and APOE-ε4 carriers. Regional cortical volume and thickness may serve as sensitive markers for early Aβ-related neurodegeneration and aid in stratifying risk in AD [Alzheimer’s disease] prevention trials,” the study authors concluded.

The study contributes to the scientific understanding of the neural correlates of dementia and age-related brain atrophy. However, it should be noted that the design of the study does not allow any causal inferences to be derived from the results.

The paper, “Amyloid PET predicts atrophy in older adults without dementia: Results from the AMYPAD Prognostic & Natural History study,” was authored by Leonard Pieperhoff, Luigi Lorenzini, Sophie Mastenbroek, Mario Tranfa, Mahnaz Shekari, Alle Meije Wink, Robin Wolz, Sylke Grootoonk, Craig Ritchie, Mercè Boada, Marta Marquié, Wiesje van der Flier, Rik Vandenberghe, Bernard J. Hanseeuw, Pablo Martínez-Lage, Pierre Payoux, Pieter Jelle Visser, Michael Schöll, Giovanni B. Frisoni, Andrew Stephens, Christopher Buckley, Gill Farrar, Frank Jessen, Oriol Grau-Rivera, Juan Domingo Gispert, David Vállez García, Henk Mutsaerts, Frederik Barkhof, and Lyduine E. Collij, on behalf of the AMYPAD consortium.