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Sustained vigorous exercise might have slowed disease progression in two patients with positive Alzheimer's biomarkers and mild cognitive impairment, two case reports suggested.

At age 64, patient 1 was diagnosed with amnestic mild cognitive impairment. More than 15 years later, at age 80, he had minimal cognitive and functional decline and was diagnosed with mild Alzheimer's disease.

Patient 2 was diagnosed with amnestic mild cognitive impairment at age 72. At age 80, he showed no clinical progression.

Mini-Mental State Examination (MMSE) declines averaged 0.3 points per year for patient 1 and 0.125 points per year for patient 2, compared with the average 2-point MMSE annual decline in patients with mild to moderate Alzheimer's disease.

Why the "strikingly benign, atypical clinical course"?

Of all the possible contributors, intense physical activity was the likely disease-modifying factor, Davangere Devanand, MD, of Columbia University Irving Medical Center in New York City, and co-authors wrote in .

Both patients regularly exercised vigorously for hours a day and increased their participation after they either retired or reduced their work hours.

"We know that mild to moderate exercise is associated with a lower risk of developing dementia, including Alzheimer's disease, but the effects of vigorous, regular exercise have been poorly studied," Devanand told 麻豆传媒.

"The two patients in this report had Alzheimer's brain pathology based on established biomarkers and clinical features but showed little cognitive decline for 16 years and 8 years, respectively," he said. "Vigorous, regular exercise was the most likely explanation for their lack of deterioration, because they had multiple medical problems and did not focus on diet or cognitively-stimulating activities beyond what they did earlier in life."

Physical exercise has been linked with a reduced risk of cognitive decline, and daily movement including step counts have been tied to lower dementia risk. In the EXERT trial, moderate-intensity aerobic training for 12 months did not differ from stretching and balance exercises in cognitive outcomes among people with mild cognitive impairment. Meta-analyses also have found some evidence of a for Alzheimer's cognitive symptoms.

"Nearly all published studies have evaluated mild to moderate exercise for a few months to 2 years without regular exercise being required during the entire follow-up period," Devanand and colleagues observed.

The two patients in the case reports were evaluated at NYU Langone Health in New York City. During recent follow-ups, they both participated in the National Institute on Aging (NIA)-supported clinical trial, which is led by Columbia University.

VALAD is a randomized, double-blind, placebo-controlled clinical trial in patients with clinical Alzheimer's dementia who are seropositive for herpes simplex virus-1 (HSV-1) or HSV-2. Blinding will be maintained until the end of 2023.

Patient 1

Patient 1 was a lawyer and a judge who presented at age 64 with memory complaints. Testing showed impairment in visual memory and executive function. Neuropsychological testing at 1- to 3-year intervals consistently uncovered cognitive deficits with extremely slow cognitive decline.

Cerebrospinal fluid (CSF) biomarkers at age 69 supported an Alzheimer's etiology. MRIs over time showed atrophy in several brain regions and progressive left temporal atrophy, mild cerebrovascular disease, and a small, stable meningioma. His MMSE score fell from 28/30 to 25/30 during his last 10 years of follow-up.

He had treated atrial fibrillation, thyroid disease, hypertension, and hyperlipidemia. He retired at age 75 and played bridge regularly. His exercise regimen involved general physical activity and playing tennis, which increased after retirement to 4 to 6 times per week, averaging 2 hours each session. Both he and his wife said he was an intense, competitive tennis player.

Patient 2

Patient 2, an engineering management consultant, presented with memory complaints at age 72. MRI showed atrophy and a likely venous malformation in the superior lateral aspect of the right intraconal orbit. Fluorodeoxyglucose-PET (FDG-PET) showed bilateral temporoparietal hypometabolism consistent with an Alzheimer's disease etiology.

At age 76, testing showed marked anterograde memory impairment with initial encoding followed by rapid forgetting. Amyloid PET scans at ages 73 and 75 were positive for Alzheimer's disease. Over 8 years, his clinical diagnosis remained amnestic mild cognitive impairment and his MMSE scores changed from 27 to 26. His Montreal Cognitive Assessment (MoCA) scores were in the normal range at age 77 (26/30) and age 79 (27/30).

He had gout, atrial fibrillation, hyperlipidemia, and a history of Lyme disease that had been treated successfully with doxycycline. At age 75, he shifted from full-time to part-time work. His exercise regimen included daily workouts on an elliptical trainer, treadmill, or Peloton cycle, plus tennis and golf when possible. After he started working part-time, he participated in intense physical exercise 3 to 4 hours daily, which his wife confirmed.

Factors in Common

At recent follow-ups, MoCA scores for both patients were in the normal range for age and both patients showed minimal to no functional decline.

Both patients had the most common apolipoprotein E variant, APOE3, which does not appear to influence Alzheimer's risk or progression.

Both patients also had a high level of education and an active social life. "These factors may have contributed to the lack of disease progression," the researchers noted. "However, with the increased time available after retirement and reduction in work schedule, respectively, both patients did not increase their cognitive activities but rather became more engaged in vigorous, regular physical exercise."

Diet was unremarkable in both patients and unlikely to have contributed to slow disease progression, they added.

"If this initial report leads to future prospective, controlled studies that confirm that vigorous, sustained exercise can slow disease progression, widespread adoption of this approach is likely with major public health implications," Devanand and colleagues suggested. "Delaying Alzheimer's disease progression by even a few years will lead to enormous health care and societal cost savings."

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