Reversal of cognitive decline in Alzheimer's disease

Patient 1

A 66-year-old professional man presented with what he described as “senior moments” (for example, forgetting where his keys were or forgetting appointments) of two-years duration, and difficulty performing his work. There was a positive family history of dementia in both parents. He was an ApoE4 heterozygote (3/4), his amyloid PET scan was markedly positive, and his fluorodeoxyglucose (FDG) PET scan showed temporoparietal reduced glucose utilization indicative of Alzheimer's disease. An MRI showed hippocampal volume at only 17^th percentile for his age. His neuropsychological testing was compatible with a diagnosis of MCI. His hs-CRP was 9.9mg/l, albumin: globulin ratio was 1.6, homocysteine 15.1μmol/l, fasting glucose 96mg/dl, hemoglobin A1c 5.5%, fasting insulin 32mIU/l, 25-hydroxychole-calciferol 21ng/ml, TSH 2.21mIU/l, and testosterone 264ng/dl.

He began the MEND protocol [3], lost 18 pounds, and after three months his wife reported that his memory had improved. He noted that his work came more easily to him. However, after five months, he discontinued the majority of the program for approximately three weeks. His wife came home to find his car in the driveway, idling with the keys in the ignition, while he was inside the house, working and unaware that he had left the car idling in the driveway. He re-initiated the program, and had no further such episodes.

After 10 months on the program, he returned for a follow-up MRI, which was subjected to volumetric analyses by both Neuroquant [7] and Neuroreader [8] programs. The former indicated an increase in hippocampal volume from 17^th percentile to 75^th percentile, with an associated absolute increase in hippocampal volume of 11.7%. The Neuroreader program showed an absolute increase from 7.65cc to 8.3cc, which represents an 8.5% absolute increase in size. The associated Z-scores were −4.6 and +1.6, respectively, disclosing an increase from <5^th percentile to the 90^th percentile. Thus although the Neuroquant and Neuroreader analyses differed somewhat in the amplitude of the effect detected, they were in agreement that a relatively large magnitude increase in hippo-campal volume had occurred.

Follow-up metabolic analysis also disclosed improvement, with hs-CRP having decreased from 9.9mg/l to 3mg/l, fasting insulin having decreased from 32mIU/l to 8mIU/l, homocysteine having decreased from 15.1μmol/l to 8μmol/l, and 25-hydroxychole-calciferol having increased from 21ng/ml to 40ng/ml. See Table 1 for a summary of the responses of all patients to the treatment program.

Patient 2

This is a follow-up on patient 2 from a previous publication [3]. A 69-year-old entrepreneur and professional man presented with 11 years of slowly progressive memory loss, which had accelerated over the past one to two years. In 2002, at the age of 58, he had been unable to recall the combination of the lock on his locker, and he felt that this was out of the ordinary for him. In 2003, he had an FDG PET scan, which was read as showing a pattern typical for early Alzheimer's disease, with reduced glucose utilization in the parietotemporal cortices bilaterally and left > right temporal lobes, but preserved utilization in the frontal lobes, occipital cortices, and basal ganglia. In 2003, 2007, and 2013, he had quantitative neuropsychological testing, which showed a reduction in CVLT (California Verbal Learning Test), a Stroop color test at 16^th percentile, and auditory delayed memory at 13^th percentile. In 2013, he was found to be heterozygous for ApoE4 (3/4). He noted that he had progressive difficulty recognizing the faces at work (prosopagnosia), and had to have his assistants prompt him with the daily schedule. He also recalled an event during which he was several chapters into a book before he finally realized that it was a book he had read previously. In addition, he lost an ability he had had for most of his life: the ability to add columns of numbers rapidly in his head.

He was advised that, given his status as an Alzheimer's disease patient and his clear progression, as well as his poor performance on the 2013 test, he should begin to “get his affairs in order.” His business was in the process of being shut down due to his inability to continue work.

His laboratory values included a homocysteine of 18 μmol/l, CRP <0.5mg/l, 25-hydroxycholecalciferol 28ng/ml, hemoglobin A1c 5.4%, serum zinc 78mcg/dl, serum copper 120mcg/dl, copper:zinc ratio of 1.54, ceruloplasmin 25mg/dl, pregnenolone 6ng/dl, testosterone 610ng/dl, albumin:globulin ratio of 1.3, cholesterol 165mg/dl (on atorvastatin), HDL 92mg/dl, LDL 64mg/dl, triglycerides 47mg/dl, AM cortisol 14mcg/dl, free T3 3.02pg/ml, free T4 1.27ng/l, TSH 0.58mIU/l, and BMI 24.9.

He began on the MEND therapeutic program, and after six months, his wife, co-workers, and he all noted improvement. He lost 10 pounds. He was able to recognize faces at work unlike before, was able to remember his daily schedule, and was able to function at work without difficulty. He was also noted to be quicker with his responses. His life-long ability to add columns of numbers rapidly in his head, which he had lost during his progressive cognitive decline, returned. His wife pointed out that, although he had clearly shown improvement, the more striking effect was that he had been accelerating in his decline over the prior year or two, and this had been completely halted.

After 22 months on the program, he returned for follow-up quantitative neuropsychological testing, which revealed marked improvement: his CVLT-IIB had increased from 3^rd percentile to 84^th percentile (3 standard deviations), total recognized hits from <1^st percentile to 50^th percentile, CVLT-II from 54^th percentile to 96^th percentile, auditory delayed memory from 13^th percentile to 79^th percentile, reverse digit span from 24^th percentile to 74^th percentile, and processing speed from 93^rd percentile to 98^th percentile. His business, which had been in the process of termination, was reinvigorated, and a new site was added to the previous sites of operation.

Patient 3

A woman late in her fifth decade began to note episodes of forgetfulness, such as returning home from shopping without the items she had purchased. She also placed household items in the wrong locations repeatedly, and frequently failed to recognize previously familiar faces. She had difficulty remembering which side of the road on which to drive. A male cousin had developed Alzheimer's disease in his fifth decade. She was found to be an ApoE4 homozygote. On-line cognitive evaluation showed her to be at the 35^th percentile for her age, despite her having been an excellent student earlier in her life.

She began various parts of the MEND protocol, and slowly added protocol features over several months. She began to note improvement, and her on-line cognitive evaluation improved to the 98^th percentile, where it has remained to the current time, with her having been on the protocol for 3.5 years.

Patient 4

A 49-year-old woman noted progressive difficulty with word finding, and noted that her vocabulary had become more limited. She also began to feel unsure about her navigation during driving. She also complained of difficulty with facial recognition (prosopagnosia). Her recall was affected, and she described the requirement of “more energy” for recall of events. She had difficulty with remembering scheduled events. She also noted that her clarity and sharpness were reduced, leading to difficulties assisting her children with schoolwork. She had difficulty with complex conversations, and with reading comprehension. She also lost the ability she had had to speak two foreign languages.

Her family history was positive for Alzheimer's disease in her father, and her ApoE genotype was 2/4. Her MRI was read as normal, but volumetrics were not included. She underwent quantitative neuropsychological testing at a major university center, and was told that she was in the early stages of cognitive decline and therefore ineligible for the Alzheimer's prevention program, since she was already too late in the disease course for prevention. Her homocysteine was 10μM, hs-CRP 0.6mg/l, hemoglobin A1c 5.2%, fasting insulin 7mIU/l, TSH 1.6mIU/l, and 25-hydroxycholecalciferol 35ng/ml.

She began on the MEND protocol, and over the next several months she noted a clear improvement in recall, reading, navigating, vocabulary, mental clarity, and facial recognition. Her foreign language abilities returned. Nine months after her initial neuro-psychological testing, the testing was repeated at the same university site, and she was told that she no longer showed evidence of cognitive decline. Immediate and delayed recall, as well as semantic knowledge, executive function, and processing speed, had all shown improvement.

Patient 5

A 55-year-old woman presented with memory concerns of two-years duration. She had a positive family history of dementia in an aunt and a grandmother. She was an ApoE4 homozygote and a TOMM40 homozygote (G/G).

She experienced difficulties with word recall several times a day, either being unable to recall the word at all or substituting the wrong word in its place. For example, she would say a word like “tweezers” when she meant to say “tongs” (semantic paraphasic errors). She also experienced an increase in spelling errors as she typed on her computer. As a professional writer and editor with a master's degree in English, she found these issues very troubling. She often lost her train of thought while speaking, requiring her to ask others what she had just said. In addition, she would misplace items and forget why she had walked into a room. She would also forget some things her husband had told her or asked her to do.

She began the MEND protocol, and after four months her husband reported that her memory had improved. She noted that her word recall was as good as it had ever been, and she was no longer experiencing an increase in spelling errors. She also reported that she rarely lost her train of thought, but if she went off on a tangent or if someone interrupted her, that issue might return. However, if she paused and gave herself a few seconds, she could find her way back to her original train of thought without asking for help. In addition, she no longer forgot why she had entered a room, and only rarely misplaced items.

Her primary care provider noted that, in her professional opinion, her cognition had returned to normal after four months on the protocol, and an on-line cognitive test (CNS Vital Signs), performed prior to the start of the protocol and then again after five months on the protocol, confirmed this opinion: her overall cognitive assessment (neurocognitive index) had increased from 16^th percentile to 73^rd percentile; composite memory from 1^st percentile to 61^st percentile; verbal memory from 3^rd percentile to 93^rd percentile; visual memory from 5^th percentile to 14^th percentile; executive function from 14^th percentile to 58^th percentile; and processing speed from 37^th percentile to 81^st percentile. Improvement had occurred in all sub-tests.

Patient 6

A 74-year-old attorney presented with a five-year history of memory loss and word-finding difficulty. His family history was positive for dementia in his mother, beginning at the age of 75 years. He had been evaluated at an Alzheimer's disease center at the onset of his memory loss, and was found to be ApoE4/4, with MRI showing ventricular enlargement and temporal lobe atrophy, right > left, and FDG-PET showing reduced glucose utilization in the temporal lobes and the precuneus, compatible with Alzheimer's disease. Neuropsychological testing was compatible with a diagnosis of amnestic MCI. He was treated with donepezil, memantine, and intravenous immunoglobulin, and his MMSE fell from 27 to 23 over three years. He noted no improvement with the treatment.

He began the MEND protocol, and after six months, his MFI (phagocytosis index) was measured at 1260, with normal being >500 and most Alzheimer's patients scoring <500 [11, 12]. His MMSE was 29. He returned three months later, his MMSE was 30, and his MFI was 1210. He then returned three months after that, complaining that he had taken a trip, gone off much of the protocol, come under stress, and he felt that his memory had declined. His MFI at that visit had dropped to 230, a typical score for a patient with Alzheimer's disease, and his MMSE was 28. He was placed back on the protocol, and returned two months later, with MFI of 1100 and MMSE of 30. Over the ensuing 12 months, his MFI remained >1000 and his MMSE remained at 30.

Patient 7

A 57-year-old man began to have difficulty with memory and in work performance as a computer programmer, leading to dismissal from his job. Over the next five years his cognition continued to decline, he developed navigational difficulties, had difficulty with attention and multi-tasking, and became quieter and less self-assured. He had been a superb guitarist, and he lost both the chord progression memory and the nuance in his playing. Family history was positive for dementia in his mother, in her ninth decade. Evaluation by a neurologist included an unremarkable brain MRI without volumetrics, and he was placed on Aricept, which he discontinued after two months.

Seven years after his symptom onset, he was again evaluated, and found to be homozygous for ApoE4. An FDG PET scan was strongly suggestive of Alzheimer's disease, with reductions in glucose utilization in the temporal, parietal, posterior cingulate, and frontal regions, with some asymmetry. He scored 22/30 on the mini-mental state examination, having lost points for failing to know the date or day, location, and failing tasks of attention and short-term recall. His BMI was 23.

A diagnosis of Alzheimer's disease was made. His laboratory evaluation included an hs-CRP of 0.2mg/l, homocysteine 9.5μmol/l, albumin:globulin ratio of 1.6, hemoglobin A1c 5.7%, fasting insulin 4.9mIU/l, free T3 2.8pg/ml, free T4 1.3ng/l, TSH 2.1mIU/l, testosterone 281ng/dl, pregnenolone 44ng/dl, 25-hydroxychole-calciferol 38ng/ml, total cholesterol 145mg/dl (on atorvastatin), RBC magnesium 4.7mg/dl, serum copper 93mcg/dl, serum zinc 76mcg/dl, copper:zinc ratio 1.22, and AM cortisol 6.8mcg/dl. His Cyrex Array 2 was positive for gastrointestinal hyperpermeability, Cyrex Array 3 (for gluten sensitivity) was negative, and Cyrex Array 20 (for blood-brain barrier disruption) was negative.

He was placed on the MEND protocol, and his MMSE increased to 26 after four months, and to 29 after 10 months. His wife noticed clear improvement in his memory and navigation. His guitar skills improved, both his chord progressions and the nuances of his playing, such that he was able to play several pieces for the neurologist.

Patient 8

A 68-year-old business executive presented with a five-year history of progressive memory loss, forcing him to retire from his company. He had difficulty navigating while driving, as well. Family history was positive in his mother. He underwent amyloid PET imaging, which was positive. His ApoE genotype was 3/4.

After six months on the MEND protocol, his BMI improved from 27.7 to 24.6, and his hemoglobin A1c improved from 5.9% to 5.7%. Both he and his family noted improvement in memory and navigation. His improvement was documented by on-line neuropsychological testing (Brain HQ), which showed increase from 0 (baseline) to 2221, which represented 52^nd percentile for his age.

Patient 9

This is a follow-up description of a patient presented in a previous publication [13]. A 50-year-old woman developed depression following a hysterectomy. She received hormone replacement therapy, but the depression continued. At the age of 54, she began to have word-finding difficulty, disorientation, difficulty driving, difficulty following recipes and other instructions, and memory complaints, and these problems progressed. She became quieter and slower to respond. Her depression deepened when her son left home.

She underwent neuropsychological testing, which disclosed frontal, temporal, and parietal abnormalities. A PET scan was typical for Alzheimer's disease, with temporoparietal decreases in glucose utilization as well as a modest frontal decrease. She was placed on duloxetine, which reduced her depression, and donepezil, which improved her cognition. However, she continued to decline.

At the age of 57, she was again evaluated. Her ApoE genotype was 3/3, MoCA was 19/30, BMI was 18, hs-CRP 0.2mg/l, homocysteine 8μM, fasting insulin 4.2uIU/ml, hemoglobin A1c 5.1%, free T3 2.1pg/ml, free T4 1.33ng/dl, reverse T3 23ng/dl, fT3:rT3 9, TSH 1.16uIU/ml, progesterone 0.3ng/ml, AM cortisol 7.2mcg/dl, pregnenolone 19ng/dl, 25-hydroxycholecalciferol 37ng/ml, vitamin B12 799pg/ml, alpha-tocopherol 12.5mg/l, zinc 82mcg/l, copper 99mcg/l, copper:zinc ratio 1.2, ceruloplasmin 20mg/dl, total cholesterol 221mg/dl, HDL cholesterol 67mg/dl, non- HDL cholesterol 167mg/dl, triglycerides 82mg/dl, urinary mercury:creatinine < 2.8, Lyme antibodies negative, C4a 5547ng/ml, TGF-β1 7037pg/ml, and VEGF (vascular endothelial growth factor) 56pg/ml (normal range 31-86pg/ml). VIP (vasoactive intestinal peptide) was not evaluated. HLA-DR/DQ was 13-6-52A (mycotoxin sensitive) and 15-6-51 (Borrelia sensitive). MARCoNS (multiple-antibiotic-resistant coagulase-negative Staph) culture was negative. Anti-thyroglobulin antibodies were strongly positive at 2076IU/ml (normal range 0-0.9IU/ml) and anti-thyroid peroxidase antibodies positive at 58IU/ml (normal range 0-34IU/ml).

She was placed on the MEND protocol, and intranasal VIP (vasoactive intestinal peptide) was administered. After three months, she showed improvement. She was able to babysit her grandchildren. She was able to follow written and verbal instructions without any problems, which had not been possible prior to treatment. She was able to read and remember overnight, and discuss her reading with her husband, which she had not been able to do prior to treatment. She also routinely remembered events of the previous day, which had not occurred in the few years prior to treatment. She had a follow-up MoCA test, and scored 21/30.

Patient 10

A 54-year-old woman presented with a two-year history of memory loss. She noted that she did not retain new information the way she formerly had, she had to re-read information a number of times to remember it, especially technical or scientific information, and noted that her reading speed had decreased. She also noted a reduction in vocabulary, word-finding problems, and repeated use of the same word instead of using synonyms. She also noted increased difficulty with grammar and spelling, as well as loss of names of friends and of famous people. Her writing declined, her typographical errors increased, and she had difficulty remembering passwords. She had increasing difficulty driving, organizing, and with her motivation. Activities of daily living were preserved.

Her ApoE genotype was 4/4, homocysteine 7.5μmol/l, hs-CRP 0.26mg/l, albumin:globulin ratio 2.0, hemoglobin A1c 5.3%, fasting insulin 2.7mIU/l, fasting glucose 81mg/dl, alpha-tocopherol 18.3mg/l, and 25-hydroxycholecalciferol 188ng/ml.

On-line quantitative neuropsychological testing disclosed a composite memory score at the 32^nd percentile, visual memory at 10^th percentile, and verbal memory at 73^rd percentile. This testing was repeated after four months on the protocol, at which time the composite memory score was at the 61^st percentile, visual memory score at the 25^th percentile, and verbal memory score at the 84^th percentile.