Knowledge, attitudes and practices regarding prevention of diabetic eye complications among people living with diabetes in Limpopo province of South Africa: A cross-sectional study.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by Amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and neurodegeneration, which are widely recognized as the hallmarks of the disease (DeTure & Dickson, ; Iaccarino et al., ; Jack et al., ). In recent years, vascular factors are increasingly implicated. Reduced cerebral blood flow (CBF) and increased white matter hyperintensity (WMH) volumes are common in the early stages of AD and may contribute to cognitive decline (Korte et al., ; Prins & Scheltens, ). However, studies on the relationship of CBF and WMH with Aβ and tau have yielded inconsistent findings, with some showing significant associations of higher WMH (Cha et al., ; Graff-Radford et al., ) and lower CBF (Mattsson et al., ) with elevated levels of Aβ, but not tau, whereas others finding their associations with tau only (McAleese et al., ; Visser et al., , ). There were also studies showing that WMH volumes (Garnier-Crussard et al., ) and CBF (Bangen et al., ) were not associated with Aβ or tau, and that lower CBF was associated with both higher Aβ and tau levels (Rubinski et al., ; Weigand et al., ). The longitudinal Korean Brain Aging Study demonstrated that baseline Aβ burden, but not tau, was associated with subsequent increases in WMH volume over a two-year period, particularly among females (Cha et al., ). A longitudinal study using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data showed that increases in within-session intraindividual cognitive variability—defined as dispersion across neuropsychological tests administered at a single visit—from baseline to 12-month follow-up were significantly associated with concurrent reductions in CBF in the entorhinal and hippocampal regions, but only in individuals classified as Aβ-positive based on cerebrospinal fluid (CSF) pTau/Aβ42 ratios at the cut-off of 0.0198 (Holmqvist et al., ). The Baltimore Longitudinal Study of Aging (BLSA) and ADNI datasets showed that Aβ status was not associated with changes in CBF, glucose metabolism, or volumes of the inferior temporal gyrus, highlighting limited vascular impact of Aβ accumulation in this region (Bilgel et al., ). Notably, current literature investigating the relationships of cerebrovascular biomarkers with tau and Aβ usually focuses on AD-vulnerable regions. Whole brain patterns of these associations have not been well documented. The Aβ cascade model of AD posits the primacy of Aβ deposition preceding tau-mediated neurofibrillary tangle formation (Hardy, ). However, emerging evidence suggests that tau pathology may develop independently of Aβ. A PET imaging study using ADNI data found that 46% of non-demented older adults exhibited tau accumulation in Braak stage I/II regions without cortical Aβ positivity (A−/T+). Individuals in the A−/T+ group showed worse cognitive performance compared to A−/T− individuals, and cognitive decline was associated with tau burden even in the absence of Aβ (Weigand et al., ). The underlying mechanisms driving WMH formation and CBF reduction may differ. Moreover, they appear at different stages during cerebrovascular dysfunction. The aetiology of WMH is diverse and may include neuroinflammation, cerebral microvascular damage, demyelination, and genetic influence (Sachdev et al., ; Wardlaw et al., ). The reduction of CBF, which is the primary cause for subsequent ischaemic vascular lesions, can stem from more systemic vascular factors such as blood pressure dysregulation (Korte et al., ). Given these distinct pathophysiological pathways, examining the associations of WMH and CBF with tau and Aβ will provide insights into how cerebrovascular dysfunction interacts with AD. As a result, the present study aims to examine both cross-sectional and longitudinal associations of CBF and WMH with Aβ and tau levels, using MRI and PET imaging data from the ADNI Phase 3 (ADNI3). We hypothesized that tau and Aβ pathology are differentially associated with vascular dysfunction, and the associations may be region specific.