Epidemiological: Systematic review and meta-analysis (Singh et al., 2014) found 33-40% reduced risk of cognitive impairment with higher Mediterranean diet adherence. Consistent across multiple cohorts but subject to residual confounding from socioeconomic and lifestyle factors.

Mechanistic: Plausible anti-inflammatory effects via polyphenols, omega-3, and fibre. Gut microbiome diversification reduces dysbiosis and systemic LPS translocation.

RCT evidence: The PREDIMED trial showed cardiovascular benefit; cognitive endpoints were secondary and not pre-specified. No large RCT has shown significant cognitive benefit as a primary outcome in the general population.

Caveat: Observational benefit likely reflects healthy-user confounding in part. Cannot be recommended as a proven dementia prevention strategy on current evidence.

Epidemiological: Morris et al. (2015) found high MIND diet adherence associated with cognitive age approximately 7.5 years younger and 53% lower rate of AD over 4.7 years. Strong observational signal.

RCT evidence: The MIND trial (Bhupathiraju et al., 2023) found that intensive MIND diet counselling did not significantly slow cognitive decline compared to a healthy diet control over 3 years in adults without dementia at baseline. This is the primary result and should temper confidence in the observational findings.

Interpretation: The gap between observational and RCT evidence likely reflects residual confounding in cohort studies. The intervention benefit, if real, may require longer follow-up or higher-risk populations to be detectable.

Epidemiological: Gonçalves et al. (2023; JAMA Neurology) found each 10% increase in ultra-processed food consumption associated with 16% higher rate of cognitive decline over 8 years (n=10,775). Consistent with other large cohort analyses.

Mechanistic: Multiple plausible pathways: postprandial glucose/insulin dysregulation, advanced glycation end-products, gut barrier disruption via emulsifiers, systemic LPS translocation from dysbiosis.

Limitation: No intervention trial; observational data vulnerable to reverse causation and confounding from overall dietary quality and socioeconomic factors.

Epidemiological: Consistent prospective association between higher oily fish intake and reduced cognitive decline in older adults across multiple cohorts.

Mechanistic: EPA and DHA are structural components of neuronal membranes; anti-inflammatory via resolution pathways (resolvins, protectins); reduce microglial activation.

RCT evidence: Cochrane review found no significant effect of omega-3 supplementation on cognitive function in cognitively healthy older adults. Some trials in mild cognitive impairment show modest benefit on specific memory outcomes. Effect may be population-specific (those with low baseline DHA status).

Conclusion: Dietary adequacy from oily fish is supported. Therapeutic supplementation as a dementia prevention strategy in the general population is not established.

Mechanism: B vitamins are required for homocysteine methylation. Elevated homocysteine is an independent risk factor for cognitive decline and accelerated brain atrophy on neuroimaging.

RCT evidence: Smith et al. (2010; PLOS ONE) found B vitamin supplementation in older adults with mild cognitive impairment significantly slowed brain atrophy rates on MRI versus placebo. This is a biomarker outcome, not a clinical dementia endpoint.

Limitation: Benefit appears specific to those with elevated homocysteine at baseline and possibly to those with adequate omega-3 status. Clinical dementia endpoint data from longer trials are lacking.

Population note: Deficiency is common in older adults, vegans, and those on metformin or PPIs. Testing homocysteine and B12 status is clinically justified.

Epidemiological: Leira et al. meta-analysis (2017): pooled OR 1.67 for dementia in periodontitis. 12-year cohort: 38% lower observed dementia incidence with treatment (HR 0.62). Schwahn et al. (2022): reduced AD-related brain atrophy on MRI with treatment.

Important caveat: All intervention data are observational. Healthy-user bias, differential healthcare access, and residual confounding cannot be excluded. These are associations within treatment patterns, not proven treatment effects.

Mechanistic: Pg and gingipains detected in AD brain tissue (Dominy et al., 2019). Multiple plausible inflammatory pathways established in animal models.

RCT status: PETAL trial (NCT04120831) ongoing. No completed RCT demonstrating cognitive benefit from periodontal treatment. GAIN trial (gingipain inhibitor) did not meet primary endpoints in ITT population.

Clinical implication: Justified on established oral and systemic health grounds. Not yet evidence-based as a dementia prevention strategy.

Epidemiological: Deficiency associated with higher rates of cognitive decline and dementia in prospective cohort studies. Association consistent but potentially confounded by reduced outdoor activity and dietary variety in those with early cognitive decline (reverse causation).

Mechanistic: Vitamin D receptors expressed in microglia and neurons; modulates neuroinflammation and amyloid clearance in experimental models.

RCT evidence: Limited. The VITAL trial found no significant cognitive benefit of vitamin D supplementation in the general population over 5 years. No large RCT in deficient populations with cognitive outcomes as a pre-specified primary endpoint.

Conclusion: Deficiency correction is clinically justified on established musculoskeletal and immune grounds. Cognitive benefit of supplementation is not established.

Mechanistic: Anti-inflammatory and antioxidant properties relevant to neuroinflammation are well-characterised in cell and animal models. Curcumin inhibits NF-kB; resveratrol activates SIRT1 and may reduce amyloid aggregation in preclinical models.

Human evidence: Most clinical trials are small, short in duration, and use biomarker rather than clinical endpoints. Bioavailability is a significant issue for both curcumin and resveratrol in standard formulations.

Conclusion: Mechanistically plausible but human clinical evidence for cognitive benefit is insufficient to support supplementation recommendations. Dietary intake from food sources is reasonable; therapeutic supplementation is not established.