黃柏仁醫師 Po-Jen Huang, M.D.: Traditional Methods for Preventing and Treating Dementia

Previously, we introduced the basic concepts of dementia and discussed hypotheses regarding the causes of Alzheimer's disease.

Now, let's provide an overview of methods for preventing and treating dementia.

The saying "prevention is better than cure" holds true.

Let's first examine the current medical methods of prevention based on a review of extensive literature, primarily relying on evidence-based data from UpToDate.

I. Lifestyle and Activity

a. Physical Exercise:

1. Negatively correlated with dementia risk, but protective effects are not confirmed.

2. Aerobic exercise does not improve cognitive outcomes in any area, even with improved cardiovascular health.

3. Exercise levels start declining nine years before dementia diagnosis — the relationship between exercise and dementia may be reverse causation (meaning that individuals without dementia may have better physical abilities, and not exercising is not a cause of dementia).

b. Cognitive Training:

1. Short-term benefits, long-term effects are unclear (no differences observed).

2. ACTIVE trial: Inductive reasoning training program conducted for five years with no significant differences observed.

3. MAPT(Multidomain Alzheimer Preventive Trial): Conducted for three years involving physical activity, cognitive training, and nutritional advice with no significant differences in outcomes.

c. Education and Cognitive Reserve:

⁃ Higher education reduces dementia risk, and symptoms appear later.

⁃ Higher education contributes to higher cognitive reserve, reducing the impact of degenerative pathology on cognitive function rather than protecting against the accumulation of amyloid proteins or other pathological changes.

II. Risk Factor Modification

a. Cardiometabolic Risk Factors:

• Diabetes, high cholesterol, hypertension, metabolic syndrome, obesity, smoking, vascular diseases. b. Seven Potentially Modifiable Risk Factors for Alzheimer's Disease (Lancet Neurol. 2011;10(9):819):

b. Seven Potentially Modifiable Risk Factors for Alzheimer's Disease (Lancet Neurol. 2011;10(9):819):

• Diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, physical inactivity.

These results are derived from analyzing big data and identifying factors related to dementia. Lowering the risk of dementia may be possible by addressing these factors.

However, in the real world, these factors are often considered "established facts" for many patients and are challenging to change.

III. Diet, Health Foods, Vitamins, etc.

All Unproven benefits:

a. Dietary adjustments – Omega-3 fatty acids (from fish or supplements), Mediterranean diet.

• The most studied ways, but the evidence is insufficient to conclude that they can reduce the risk of dementia.

b. Antioxidant vitamins (Vitamin E, β-carotene, flavonoids, Vitamin C).

• ─Multiple large randomized clinical trials->No effect on cognitive changes or dementia, with follow-up times ranging from 7 to 10 years

c. Vitamins B6, B12, and folic acid.

• ─Deficiency may be associated with cognitive impairment and risk of dementia, but there is no convincing evidence that supplementation prevents dementia.

d. Vitamin D.

• ─Same as B

e. Isoflavone-rich soy protein

• – No improvement in cognitive outcomes in a randomized trial involving 350 postmenopausal women over 2.5 years.

IV. Ineffective Therapies

a. Cholinesterase Inhibitors: Provide some symptom improvement in confirmed patients but do not delay the progression of dementia in mild cognitive impairment patients; not recommended for preventive purposes.

b. Hormone Therapy: Not recommended for preventing dementia.

c. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cannot prevent dementia, potential harm (Naproxen – risk of heart attack); should not be used for treating or preventing dementia or cognitive impairment.

d. Ginkgo Biloba: Multi-center, randomized, double-blind, median six-year follow-up study found no significant reduction in Alzheimer's or all-type dementia incidence, and it did not slow cognitive decline in individuals with normal or mild cognitive impairment.

The above summarizes the preventive methods outlined in traditional treatment guidelines along with the relevant evidence. Now, let's discuss the primary treatment approaches for dementia, particularly Alzheimer's disease (AD).

Currently, there are three major categories of medications for Alzheimer's disease:

I. Mild to Moderate Alzheimer's Disease: Cholinesterase Inhibitors

• Symptomatic treatment medication

• Recommended for new diagnosis cases

• Expected benefits are limited

• Not recommended for patients with no improvement or significant side effects to continue treatment indefinitely

• No evidence of neuroprotection or altering the underlying disease trajectory

II. Moderate to Severe Alzheimer's Disease: NMDA Antagonists

• Neuroprotective effects

• No significant side effects reported

• Combined with cholinesterase inhibitors: Moderately improves cognition and overall outcomes in late-stage patients

• Some studies show slight improvement in cognition and overall assessment, but not all studies demonstrate significant differences

• No difference in outcomes between patients with mild to moderate Alzheimer's who were already taking cholinesterase inhibitors and those who received a combination with a placebo

• Treatment decisions should be individualized, considering drug tolerance and costs

III. Anti-Amyloid Monoclonal Antibodies (MABs)

a. Aduhelm/Aducanumab: Temporarily approved by the FDA in 2021

- Severe side effects and high cost led to rejection of market applications by the EU and Japan

b. Lecanemab: FDA approved in 2023

- Phase III clinical trial (18 months): Slows cognitive decline by 27%

- Severe side effects reported in 14% (126/898) of participants

c. Donanemab: Market application submission completed in the second quarter of 2023, under FDA review

- 2022 partial Phase III results (vs Aduhelm): Plaque reduction of 65.2% for Donanemab vs. 17% for Aduhelm

- Phase II clinical trial (18 months): Slows cognitive and daily functional decline by 60% (iADRS) in mild patients

- Side effects: ARIA-E in 24%, severe leading to discontinuation in 13%

d. Gantenerumab: Phase 3 results announced in November 2022, showing no significant improvement in slowing cognitive decline

As mentioned earlier, anti-amyloid monoclonal antibodies effectively remove plaques but fall short of expectations in improving cognitive function. There is also a risk of severe side effects (brain edema and hemorrhage) and high costs (tens of thousands of dollars annually).

According to the integrated information presented above, it becomes evident that the current available methods for both prevention and treatment of dementia have limited effectiveness.

This is particularly true for health foods and dietary supplements, which, in many cases, have not demonstrated significant benefits.

The few methods that have shown some effectiveness, such as increasing cognitive reserve and modifying risk factors, primarily aim to reduce the occurrence and impact of dementia.

However, these strategies may not be easily applicable to individuals where these factors are considered "established facts" and are challenging to change.

So, is there truly no better way to prevent dementia?

In fact, there is.

The next article will introduce the only evidence-based health food that effectively prevents dementia: highly bioavailable curcumin!

References:

Uptodate:

Epidemiology, pathology, and pathogenesis of Alzheimer disease

Treatment of Alzheimer disease

Prevention of dementia

Risk factors for cognitive decline and dementia

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