Table 3.

Cognitive decline and dementia; left column: relevant HCys-associated pathomechanisms; right column: correlation analyses and information on clinical studies; citation of other reviews or meta-analyses is marked as Rev [citation], followed by the reported findings, without individual quotations.

Hypo-methylation—Rev [52]; also see Figure 3: HCys ↑ → SAM/SAH ↓ → hypo-methylation of the presenilin 1 gene → increased β-amyloid formation. Hypo-methylation of the enzyme protein phosphatase 2A → loss of activity for phosphate cleavage of protein tau → accumulation of over-phosphorylated protein tau in neurofibrils → deposition of neurofibrillary tangles.	Clinical studies—Rev [73,74,75]: Plasma HCys negatively correlates with the thickness of the medial, inferior temporal lobe in normal subjects; equally in Alzheimer’s patients (already lower baseline values). Meta-analysis (77 case-control studies, 33 prospective studies, 46,000 subjects):
Neurotoxicity—Rev [73]; also see Figure 4E,F: HCys and oxidation products (homocysteic acid) activate NMDA receptors → excitotoxicity (cellular Ca2+ increase → activation of proteases and radical formation → cell death = neuronal degeneration). Increased formation of ROS → activation of NFκB → inflammatory reaction.	Plasma-HCys	Risk
	≥15 μM	3-fold for cognitive impairment
	≥14 μM	2-fold for Alzheimer’s dementia
	Of approx. 10 placebo-controlled intervention studies with the three B-vitamins (B6, B12, folate), only five meet the decisive criteria: primary preventive approach, increased HCys starting level, study duration of at least two years, adequate vitamin dosage, proven decline in cognitive parameters in the placebo group. Significant results of these studies in favor of the vitamins: reduction of the brain atrophy rate, mainly gray matter, significantly better values for dementia status, MMSE (mini mental state evaluation) and learning test. Positive influence of plasma omega-3 fatty acid level on the effect of the B-vitamins [76]. Patients in the Alzheimer’s prodromal stage benefit from multi-nutrients with B-vitamins and omega-3 fatty acids: significantly better dementia status. The effect correlates directly with the baseline MMSE value [77] → importance of early start of prevention!

Brain tissue: no HCys transsulfuration and no re-methylation of HCys to methionine by betaine (cf. Section 2.1) high sensitivity to folic acid and vitamin B12 deficiency.