Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study

Abstract

Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged ≥85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-β and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and α-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-β accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or α-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged ≥85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.

Homocysteine and cognitive function in Parkinson's disease

“…However, the effect of levodopa dosage was investigated in a mediation analysis which supports the hypothesis that elevated HC itself promotes cognitive decline in PD. This hypothesis is plausible in light of basic science evidence that elevated levels of HC are toxic to both neurons [23] and endothelial cells[24], and by clinical studies showing that elevated plasma HC predicts both neurofibrillary tangles and vascular pathology at brain autopsy [25], and that HC-lowering interventions slow cognitive decline in non-PD MCI patients[3] [4]. The hypothesis that HC is potentially harmful to PD patients is further supported by clinical studies showing that elevated HC predicts rate of brain atrophy in PD [26].…”

Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease

“…An autopsy study showed a clear association between Hcy levels and neurofibrillary tangles, a known hallmark of AD, with an odds ratio of having such deposits of 2.60 (95% confidence interval 1.28–5.28) when comparing the top with the bottom Hcy quartile [138]. A prospective study showed greater brain atrophy in AD patients with higher Hcy levels [116] and this association between Hcy and grey matter atrophy has been confirmed by a range of studies (See review by Smith and Refsum [16]).…”

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

“…The association with hippocampal atrophy appears to be independent of amyloid pathology [14]. White matter lesions reflect vascular damage [92] and it is therefore notable that white matter changes are associated with HHCy [47,49,64,94] and with low vitamin B 12 levels [21] and low folate [51,100]. Evidence supporting a causal relationship between HHCy and cerebrovascular injury includes: i) independent, graded association of HHCy with stroke in prospective and retrospective clinical studies [48,61]; ii) genetic association studies of genes regulating HCy metabolism, using Mendelian randomisation [9]; iii) HHCy-induced lesions in experimental animals [4,68,108,111].…”