Amyloid-Beta Pathology Negatively Affects Cognition

Accumulation of amyloid-beta pathology should not be considered a benign consequence of aging, according to findings published in JAMA Neurology.

Researchers conducted a longitudinal cohort study using cross-sectional data from self-reported cognitively healthy Dutch centenarians to evaluate the association between amyloid-beta pathology and cognitive performance. They compared amyloid-beta pathology between centenarians (n=95) and patients with Alzheimer disease (n=38). Krusal-Wallis tests, Chi-square tests, and linear regression models were employed for statistical analysis.

Among the centenarians, 75% were women, and the median age at death was 103.5 (IQR, 102.3-104.7) years. All Thal phases were represented (median, 3 [IQR, 1-4]); 91% had amyloid-beta pathology, while 9% had Thal phase 0. Cerebral amyloid angiopathy was observed in 77% of patients, while 57% had neuritic plaques (median Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] neuritic plaques score, 1 [IQR, 0-2]).

In amyloid-beta–positive centenarians, amyloid-beta load was highest and most frequent in the frontal cortex, followed by the parietal, temporal, and occipital cortices. Amyloid-beta loads were an average of 10 times lower in the medial temporal lobe compared with the neocortex. When compared with individuals with Alzheimer Disease, centenarians had lower amyloid-beta loads across all neocortical and medial temporal lobe regions except cornu ammonis 2.

More than half (56%) of the centenarians had a low amyloid-beta load. APOE genotype was similar between centenarians with low and high amyloid-beta loads, but those with no amyloid-beta load were enriched for protective APOE ε2 genotypes.

Among 72 centenarians with cognitive performance data, those with no (n=7) or low (n=45) amyloid-beta load showed better executive functioning and global cognition than those with high amyloid-beta load in the frontal cortex (n=20). Higher amyloid-beta load across neocortical regions was associated with poorer executive functioning and global cognition. In addition, higher Thal phase was associated with lower clock drawing scores, higher cerebral amyloid angiopathy stage was associated with lower clock-drawing and digit spin backward scores, and higher CERAD neuritic plaques scores were associated with lower Mini-Mental State Examination scores.

Among 20 centenarians with high amyloid-beta load, 5 scored among the top 25% of all 72 centenarians on the digit spin backward, clock drawing, Mini-Mental State Examination, or composite global cognition. These individuals had significantly less tau pathology vs centenarians with high amyloid-beta loads and low cognitive performance.

Study limitations include missing cognitive data and lack of consideration for specific amyloid-beta isoforms.

“Overall, our findings indicate that accumulation of [amyloid-beta] pathology should not be considered a benign consequence of aging, and that keeping [amyloid-beta] load within limits is a hallmark of maintained cognitive health until extreme ages,” the authors wrote.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.