Modifiable dementia risk factors associated with higher CSF tau and poorer cognition in middle‐aged adults

Abstract

AbstractBackgroundModifiable factors in domains such as mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep are associated with increased risk for dementia. These modifiable risk factors could promote Alzheimer’s disease (AD) related biological processes, such as beta‐amyloid (Aβ) or tau accumulation, but these associations remain poorly understood. This study aimed to determine associations between modifiable dementia risk factors with Aβ, tau, and cognition in cognitively unimpaired middle‐aged adults.MethodMiddle‐aged adults (n = 82) (age range 40‐70) enrolled in a biomarker sub‐study of the Healthy Brain Project completed self‐report questionnaires about their physical and psychological health and lifestyle. Cerebrospinal fluid (CSF) levels of Aβ42, total tau (t‐tau), and phosphorylated tau (p‐tau) (Roche Elecsys) were obtained. A comprehensive neuropsychological battery was administered to measure cognition, and composite scores were derived for memory, executive function, and the Preclinical Alzheimer’s Cognitive Composite (PACC). Participants were classified according to reporting normal modifiable risk (NMR) (risk in ≤1 domains; n = 34) or high modifiable risk (HMR) (risk in ≥2 domains; n = 48) across five domains (mood, lifestyle behaviours, cardiovascular health, cognitive and social engagement, and sleep).ResultCompared to those with NMR, those with HMR had increased t‐tau (d = 0.54, p = .021) and p‐tau (d = 0.47, p = .044) levels but did not differ on Aβ42 (d = 0.23, p = .319) after adjusting for age and sex. With age, sex, and education adjusted for, HMR participants showed worse performance on PACC (d = 0.69, p = .003), executive function (d = 0.55, p = .016), and episodic memory (d = 0.40, p = 0.076) compared to NMR participants. Differences in cognitive performance remained when levels of Aβ42, t‐tau and p‐tau levels were controlled in the models [PACC (d = 0.59, p = .011), memory (d = 0.64, p = .005) and executive function (d = 0.45, p = .049)].ConclusionModifiable dementia risk factors across multiple domains are related to higher total and phosphorylated tau levels and with subtle cognitive deficits, but not with Aβ, in middle‐aged adults. Together with the observation that differences in cognition across modifiable risk groups remained when Aβ and tau levels were controlled statistically, this suggests that modifiable dementia risk factors may increase risk through neurodegenerative processes non‐specific to AD, such as increased cerebrovascular burden, although this needs to be confirmed in future neuroimaging studies.