Higher CSF Ab38 levels protect against cognitive decline in high‐functioning individuals

Abstract

AbstractBackgroundThe amyloid cascade hypothesis proposes that Alzheimer’s disease (AD) pathology starts with accumulation of b‐amyloid (Ab) peptides, leading to plaque deposition. In this context, the spotlight has been pointed firmly onto Ab42, but evidence suggests that shorter isoforms may also play an important role in modulating AD pathophysiology. A recent report with individuals with mild cognitive impairment or subjective cognitive decline (Cullen et al., 2021) has shown that higher cerebrospinal fluid (CSF) levels of Ab38 were associated with less decline on the mini‐mental state exam (MMSE) score and reduced risk of conversion to AD. The aim of this study was to test whether CSF Ab38 levels also predicted change in MMSE scores in cognitively intact individuals.MethodData were obtained from 40 individuals (age = 67.3, 6.3), who had taken part in a study on late‐life major depressive disorder at the Nathan Kline Institute and New York University. Data were available for baseline examination as well as three‐year follow up. Twenty‐three individuals were depressed at baseline, and 17 were controls; all had an MMSE score of 28 or higher at baseline. To test our hypothesis, we carried out a Bayesian linear regression analysis with change in MMSE score from baseline to follow‐up as outcome; CSF Ab38, CSF Ab42, and CSF phosphorylated (p) tau as predictors; and controlling for age, sex, APOE e4‐status and depression diagnosis (null model).ResultThe results showed that the model combining CSF Ab38 and CSF p tau was the strongest, with moderate evidence (BFm = 4), carrying nearly double the odds of the model with all predictors (BF10 = 0.539), and 4.6 times the odds of the null model (BF10 = 0.219): higher baseline levels of CSF Ab38 were associated with less decline in MMSE score, while higher p tau levels were linked to more decline. When isolating depressed individuals, the pattern of results was unchanged, while the null model was strongest with controls.ConclusionThese findings confirm the importance of examining shorter Ab isoforms also in individuals with no cognitive impairment or subjective cognitive decline.