Dementia Treatment – Lower Homocysteine Levels

Posted by: Kevin Flatt

Good food sources of folate. Photo courtesy of USDA, ARSAn elevated blood level of homocysteine is a risk factor for cognitive impairment and dementia.

This article relates to 7 case reports regarding the administration of the antioxidant N-acetylcysteine together with folate (folic acid) and vitamin B to cognitively impaired patients with elevated levels of homocysteine.

A link between high blood folate (folic acid) levels and relatively lower homocysteine levels has long been known. Scientists have also long known that being seriously deficient in vitamin B12 leads to impaired cognitive function due to neurological complications.

Therefore, homocysteine can be lowered by folate (folic acid) and/or vitamin B12 supplementation. (See Cognitive Function – Folic Acid and Vitamin B12 Deficiency and Homocysteine )

Andrew McCaddon, an Honorary Research Fellow of the Wales College of Medicine in the UK, presented clinical and radiological findings from administering the antioxidant N-acetylcysteine together with B vitamins to cognitively impaired patients with elevated levels of homocysteine.

Note: N-acetylcysteine was used in conjunction with folate (folic acid) and vitamin B12 as antioxidants might also be required for optimal reduction of homocysteine in both nerves and blood vessel tissue.

N-acetylcysteine increases urinary excretion of homocysteine, leading Ventura and colleagues to suggest that this approach may be an important associative or alternative therapy for elevated levels of homocysteine. (Pharmacology 2003, 68:105-114).

Case presentations

Case 1

A 78 year old lady presented with fatigue, anxiety and depression. She had angular cheilosis (inflammation and cracking of the lips which may occur secondary to a vitamin C or B-complex or mineral deficiency) but was not anaemic, despite a profound vitamin B12 deficiency with normal blood and red cell folate. She had parietal cell antibodies but a normal Schilling test. She “…felt better” after monthly injections of B12 (1,000 micrograms) were commenced, but nevertheless remained anxious.

A year later she developed memory impairment, with difficulty remembering names. She scored 21/30 on Mini-mental state examination. It was felt that she had a dementia, perhaps with associated depression, and she was commenced on an antidepressant (a selective serotonin reuptake inhibitor). Her depression slowly resolved but her cognitive decline continued.

A year later she scored 18/30 on Mini-mental state examination and 28/70 on the Alzheimer’s disease assessment scale. In view of her persistent dementia despite regular B12 injections, she was commenced on oral N-acetylcysteine (NAC) (600 mg) daily.

Two weeks later her husband reported a noticeable improvement in her memory. She now remembered names and faces she previously would have struggled to recall. Her Mini-mental state examination improved to 21/30 and Alzheimer’s disease assessment scale to 20/70. The areas of improvement were in scores of orientation, copying skills, word-recall, naming and commands.

Case 2

An 84 year old lady presented with a three year history of short-term memory impairment and early Parkinsonism for which she took L-dopa. She was otherwise well. She scored 12/28 on the 6 Item Cognitive Impairment Test. Investigations revealed an above normal total blood homocysteine level, but normal serum vitamin B12, folate and red cell folate. She was not anaemic, but had borderline hypothyroidism.

In view of her elevated total homocysteine, and despite ‘normal’ serum B vitamin levels, she was commenced on daily oral B12 (1000 mg), folic acid (5 mg) and N-acetylcysteine (NAC) (600 mg). Within one month her total homocysteine fell to 7.5 μmol/L.

She was assessed by a Psychogeriatrician three months after her initial presentation. She now showed no significant cognitive deficits; she scored 28/30 on Mini-mental state examination.

The psychogeriatrician was “…particularly impressed that she could provide the Christian names of all her five children and twelve grandchildren without any problems” and it was felt that she now had no obvious diagnosis of a dementia.

Case 3

A 77 year old lady presented with a six month history of confusion and memory loss. An aunt had early-onset Alzheimer’s Disease. On examination she was disorientated to time and had demonstrable memory impairment. She was vitamin B12 deficient but with normal serum and red cell folate.

She commenced monthly intramuscular B12 injections (1,000 mg) but continued to deteriorate.

She became fatigued and developed visual hallucinations and persecutory ideas. She had naming difficulties, her repetition was poor, and she had constructional dyspraxia.

It was felt she had probable Alzheimer’s Disease. She was admitted for care, scoring only 13/30 on Mini-mental state examination. She was commenced on an acetylcholinesterase inhibitor with slight initial improvement (15/30). Nevertheless her condition continued to deteriorate. She developed dysphagia (a condition in which swallowing is difficult or painful) and weight loss due to a grade III oesophagitis (inflammation of the esophagus).

Oral N-acetylcysteine (NAC) (600 mg daily) was added to her treatment and her family and carers noticed a significant improvement. She became more alert and recognised her close family; a formal cognitive assessment was not performed in view of the severity of her dementia and associated physical condition. Sadly she died from a bronchopneumonia several weeks later.

Case 4

An 87 year old retired school headmistress presented with a three year history of gradually deteriorating short-term memory and general ‘confusion’; she frequently mislaid things and often wandered, forgetting her way home. She had a past medical history of diverticular disease (a herniation through the muscular wall of a tubular organ, especially the colon) and an osteoarthritic hip, but was otherwise well.

On examination it was felt she was suffering from a senile dementia of moderate severity although no formal cognitive scores were recorded. Routine investigations were normal other than a highly elevated total homocysteine.

She was commenced on folic acid 5 mg daily and oral hydroxo-B12 1,000 mcg daily, together with N-acetylcysteine (NAC) 600 mg daily. Her total homocysteine fell to 6.6 μmol/L six-months later, at which time she felt generally well although she remained mildly confused.

Her daughter commented on a marked improvement in her general behaviour, although she remained forgetful at times. Three years later she remains very well and continues to be cared for at home with no major difficulties.

Case 5

An 84 year old lady presented with a two year history of increasing forgetfulness and confusion and no significant previous illnesses. She was cared for at home by her daughter. On formal examination she was disorientated in time and place with demonstrable short-term memory impairment.

It was felt she had a moderate dementia; she scored 55 out of 70 on an Alzheimer’s disease assessment scale. Blood investigations were normal other than an elevated total homocysteine and low red cell folate (157mg/l). She was not anaemic.

She was commenced on daily oral cyano-B12 (150 mg daily) folic acid (5 mg) and NAC (600 mg) daily. One month later she had gained ten points on Alzheimer’s disease assessment scale score. Her daughter also reported that she was “…generally more settled and content, and less likely to wander.”

Case 6

A 71 year old retired engineer presented with a ten year history of gradually progressive short-term memory impairment. His wife had become concerned because he had recently lost his way driving to a regular address. He complained of losing objects and forgetting people’s names.

His father had died of senile dementia aged 74, with symptoms developing at aged 60 years. The patient himself had a past medical history of hypertension controlled by beta-blocker. On cognitive examination he scored poorly on 6 Item Cognitive Impairment Test (12/28). Routine blood investigations revealed elevated total homocysteine with normal serum vitamin B12, folate and red cell folate.

He was commenced on daily oral cyano-B12 (1,000 mg) folate (5 mg) and NAC (600 mg). His wife reported a “…definite and immediate improvement” within two weeks of commencing treatment.

His total homocysteine fell to 9.6 μmol/L. He was seen by a Psychogeriatrician one month later. He now scored 28/30 on Mini-mental state examination with a CAMCOG of 115/125, indicating only a mild cognitive deficit.

A diagnosis of “age-related cognitive impairment” was made. He has continued on this treatment for the last two years and continues to score well on cognitive assessments. He scored 27/30 on his most recent assessment and has now commenced an acetylcholinesterase inhibitor in addition to B vitamins and NAC supplementation.

Case 7

A 75 year old retired College Lecturer presented with a four year history of increasing forgetfulness. In particular he frequently mislaid things, and had occasional difficulty remembering people’s names. His wife had become concerned about his ability to drive. He had a past medical history of prostatic carcinoma treated with radiotherapy, anxiety/depression, and gastro-oesophageal reflux, but was generally well in himself.

On cognitive examination he was disorientated in time and had demonstrable short term memory impairment. He scored 8/28 on 6 Item Cognitive Impairment Test and 16/39 on TICS-m. An MRI scan showed several foci consistent with small vessel disease. Blood investigations revealed raised total homocysteine of 14.6 μmol/L, borderline low serum B12, but normal folate and red cell folate.

He was commenced on daily oral cyano-B12 (1000 mg), folic acid (5 mg) and NAC (600 mg). After one month he had gained five points on TICS-m (21/39). His total homocysteine
fell to 8.3 μmol/L.

He was personally delighted with the treatment. His wife commented that “…he was becoming very forgetful, quite retiring, quiet, sleepy all the time, not interested in his food or in life. Now, there’s a marked improvement. We can discuss the news without any problem. He’s reading again. He’s interested in life once more.”

One year later, he remains well and has successfully regained his driving license following a formal assessment. A repeat MRI scan showed no significant progression in the extent or size of the focal areas of abnormality in the deep white matter, and no change in ventricular configuration.

Andrew McCaddon concluded: These reports demonstrate the apparent clinical efficacy of the addition of N-acetylcysteine (NAC) to B vitamin regimes in elevated homocysteine level patients with cognitive impairment. NAC was well-tolerated in all patients; there were no reported side-effects.

There is now strong evidence that elevated blood levels of homocysteine are associated with dementia in general, including both vascular dementia and Alzheimer’s Disease. However, the mechanism underlying this association remains unclear. The clinical responses to N-acetylcysteine (NAC) in these cases suggest that homocysteine might also be a surrogate marker for the effects of oxidative stress on neurovascular tissues (both nerves and blood vessel tissues).

The radiological findings in Case 7 are notable. Elevated homocysteine levels are associated with brain atrophy and white matter lesions. The annual estimate of progression of white matter lesions in cognitively intact elderly individuals is approximately 0.6 mL/year.

Though not formally quantified, the apparent halting of disease progression in Case 7 is of significance. Follow-up scans were not performed in the earlier cases.

A notable feature in all cases was the complete absence of anaemia. Indeed, despite the clear association between metabolic evidence of B12 and/or folate deficiency and dementia, anaemia and macrocytosis are invariably absent in these patients.

Elevated homocysteine levels in these patients potentially arises from oxidative depletion of vitamin B12 and folate. Such depletion is, of course, subtly different from our current concepts of classical deficiency due to malnutrition or malabsorption.

The epidemiological evidence (the branch of medical science dealing with the transmission and control of disease) is now of sufficient strength that elevated levels of homocysteine should be considered a potential risk factor for dementia in elderly patients. At the very least, clinicians should determine the folate and vitamin B12 status of these patients, irrespective of whether or not there is a macrocytic anaemia.

Derived and adapted from: Andrew McCaddon. Homocysteine and cognitive impairment; a case series in a General Practice setting. Nutrition Journal 2006, 5:6 (15 February 2006) doi:10.1186/1475-2891-5-6.
© 2006 McCaddon; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (

Photo courtesy of USDA, ARS

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