Markers of Vitamin B12 Status in Relation to Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Cognitive Performance.

BACKGROUND: The association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), which precede cognitive impairment, has been investigated by only a few small studies and results have been inconsistent. AIM: The aim of this study was to investigate the associations of vitamin B12-related markers with CSF biomarkers of AD and cognitive performance. METHODS: Data included 462 patients aged 40 to 94 years referred to the Memory Clinic of the Ulm University Hospital, Ulm, Germany. Vitamin B12, holotranscobalamin (HoloTC), homocysteine (tHcy), and methylmalonic acid (MMA) have been measured. CSF values of amyloid ß42 (Aß42 ) and total-tau have been assessed in 227 participants. CERAD battery was administered to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations. RESULTS: In the multi-adjusted model, higher levels of MMA were associated with raised CSF total-tau values: the odds ratios (ORs) 95% confidence intervals (CIs) were 3.25 (95% CI = 1.35-7.76) for the highest quartile of MMA compared to the lowest. Furthermore, moderately increased MMA were related to lower Aß42 levels: the ORs and 95% CIs were 3.06 (95% CI = 1.22-7.67) for the third quartile of MMA compared to the lowest. All B12 indicators except B12 itself were related to several cognitive domains, such as episodic memory and executive functioning. CONCLUSIONS: Markers of vitamin B12 may be independent predictors of CSF biomarkers of AD and cognitive functioning, with MMA showing the most consistent effects. Randomized controlled trials are needed to determine the importance of vitamin B12 supplementation on slowing structural brain changes and cognitive decline. ANN NEUROL 2023;94:223-231.

Cerebrospinal fluid BACE1 activity and brain amyloid load in Alzheimer's disease.

The secretase BACE1 is fundamentally involved in the development of cerebral amyloid pathology in Alzheimer's disease (AD). It has not been studied so far to what extent BACE1 activity in cerebrospinal fluid (CSF) mirrors in vivo amyloid load in AD. We explored associations between CSF BACE1 activity and fibrillar amyloid pathology as measured by carbon-11-labelled Pittsburgh Compound B positron emission tomography ([¹¹C]PIB PET). [¹¹C]PIB and CSF studies were performed in 31 patients with AD. Voxel-based linear regression analysis revealed significant associations between CSF BACE1 activity and [¹¹C]PIB tracer uptake in the bilateral parahippocampal region, the thalamus, and the pons. Our study provides evidence for a brain region-specific correlation between CSF BACE1 activity and in-vivo fibrillar amyloid pathology in AD. Associations were found in areas close to the brain ventricles, which may have important implications for the use of BACE1 in CSF as a marker for AD pathology and for antiamyloid treatment monitoring.

Amyloid clearance as a treatment target against Alzheimer's disease.

An imbalance between production and clearance of the amyloid-ß peptide (Aß) is a key momentum of the complex pathological cascade of Alzheimer's disease (AD). It is caused by overproduction of Aß or, more frequently, by impaired clearance from brain. Clearance can be reduced by increased aggregation, defective degradation, disturbed balance of transport across the blood-brain barrier, or inefficient peripheral removal of the peptide. In recent years these mechanisms have become targets of pharmacological interventions. Although several compounds have been discarded on the grounds of limited clinical efficacy, all major clearance-related approaches still hold promise. Some drug candidates have advanced to Phase III trials including anti-Aß antibodies, metal complexing agents, ginseng extracts, and intravenous immunoglobulins. Data are currently not available from these studies that might allow an evaluation of efficacy and safety. Phase II trials on active and passive immunization have demonstrated a striking discrepancy between significant neurobiological effects regarding the removal of Aß deposits and minor clinical outcomes. This does not preclude the possibility that clearance-related strategies have the potential of saving neurons and synapses via reducing the levels of soluble and particularly toxic Aß species in brain. It may take longer than projected in ongoing trials for such neurobiological effects to translate into measurable changes of clinical progression.