ADDRESSING COGNITIVE DECLINE

Creative ways of addressing cognitive decline in humans is a hot field with much exciting activity. Cognitive decline can be slowed, stabilized, or improved.
See references at the end of the article.

➡️ Multimodal / precision protocols

• A 9‑month precision‑medicine “multimodal” protocol in patients with MCI or early AD (Toups et al.) reported statistically significant improvements in MoCA, CNS Vital Signs neurocognitive index, and caregiver‑rated change, with MRI volumetrics suggesting reduced hippocampal atrophy; this was a small, uncontrolled proof‑of‑concept study. 
  
  • Toups K et al. 2022
• Personalized, multifactorial metabolic programs (diet, hormones, sleep, infection, toxins, etc.) in small uncontrolled series have reported objective cognitive improvements and even return to work in patients with SCI/MCI/early AD.
  
  • ​Bredesen DE. Aging 2014
    
  • Bredesen DE et al. Aging 2016
    
  • Bredesen DE et al. J Alzheimers Dis. 2018
• A clinic‑based prospective program using individualized lifestyle/medical interventions in people with cognitive impairment showed multi‑domain cognitive score improvements over 6 months, but lacked a control group.
  • Isaacson RS et al. J Alzheimers Dis. 2023
• A recent review argues that conventional single‑target trials mostly show delayed progression, while small personalized, multi‑factorial approaches sometimes show apparent improvement, yet the overall evidence quality is low.
  • Snitz BE et al. J Alzheimers Dis. 2023

➡️ Intensive lifestyle intervention

• A 20‑week RCT of comprehensive lifestyle change (plant‑based diet, exercise, stress management, social support) in MCI/early AD reported significant improvements in several cognitive and functional outcomes vs usual care.
  
  • Ornish D et al. Alzheimers Res Ther. 2024

➡️ Single‑component nutrition trials

• High‑phenolic early‑harvest extra‑virgin olive oil in MCI (MICOIL pilot RCT) improved global cognition and verbal fluency over 12 months vs Mediterranean diet alone.
  • Tsolaki M et al. J Alzheimers Dis. 2020
• Extra‑virgin vs refined olive oil in MCI/early AD improved clinical scores in both groups, but only EVOO enhanced BBB measures and functional connectivity, implicating phenolic compounds.
  • Kyriakides TC, et al. Nutr Neurosci. 2022
• A bioavailable curcumin (Theracurmin, 18‑month RCT) improved verbal memory and prevented decline vs placebo in middle‑aged and older adults.
  • Small GW et al. Am J Geriatr Psychiatry. 2018
• Other curcumin RCTs in older adults report modest, domain‑specific cognitive benefits, but results are heterogeneous.
  • Rainey‑Smith SR, Brown BM, Sohrabi HR, et al. J Psychopharmacol. 2016
  • Mancini E et Al. Front Neurosci. 2024
• A phase II resveratrol RCT in mild–moderate AD produced biomarker and brain volume changes without clear clinical cognitive benefit vs placebo.
  • Turner RS et al. Neurology. 2015​

REFERENCES

• Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014;6(9):707‑17.pubmed.ncbi.nlm.nih+1​
  
• Bredesen DE, Amos EC, Canick J, Ackerley M, Raji C, Fiala M, et al. Reversal of cognitive decline in Alzheimer’s disease. Aging (Albany NY). 2016;8(6):1250‑8.pubmed.ncbi.nlm.nih+1​
  
• Bredesen DE, Sharlin K, Hagedorn D, Kinder D, Yoshikawa A, Song D, et al. Reversal of cognitive decline: 100 patients. J Alzheimers Dis. 2018;66(2):1‑14.coastalmedicine+1
• Isaacson RS, Seifan A, Zetterberg H, Macauther K, Malek-Ahmadi M, Beach TG, et al. Observed improvement in cognition during a personalized lifestyle intervention in people with cognitive impairment. J Alzheimers Dis. 2023;95(2):643‑57.pmc.ncbi.nlm.nih+1​
• Ornish D, Lin J, Chan JM, Burgess S, Guinea S, Esmaili N, et al. Effects of intensive lifestyle changes on the progression of early dementia due to Alzheimer’s disease. Alzheimers Res Ther. 2024;16(1):84.pmc.ncbi.nlm.nih+1​
• Toups K, Hathaway A, Gordon D, Chung H, Raji C, Boyd AD, et al. Precision medicine approach to Alzheimer’s disease: successful proof‑of‑concept trial. J Alzheimers Dis. 2022;88(4):1411‑28.journals.sagepub+1​
• Tsolaki M, Lazarou E, Kozori M, Petridou N, Ikonomidis I, Vasios G, et al. A randomized clinical trial of Greek high phenolic early harvest extra virgin olive oil in mild cognitive impairment: the MICOIL study. J Alzheimers Dis. 2020;78(2):801‑17.pubmed.ncbi.nlm.nih+1​
• Kyriakides TC, et al. Extra‑virgin olive oil and cognition in mild cognitive impairment: a pilot randomized study. Nutr Neurosci. 2022;25(9):1720‑30.ysph.yale+1​
• Small GW, Siddarth P, Li Z, Miller KJ, Ercoli LM, Emerson ND, et al. Memory and brain amyloid and tau in middle‑aged and older adults with curcumin vs placebo. Am J Geriatr Psychiatry. 2018;26(3):266‑77.pmc.ncbi.nlm.nih+1​
• Rainey‑Smith SR, Brown BM, Sohrabi HR, Shah TM, Goozee KG, Gupta VB, et al. Curcumin and cognition: randomized controlled trial evidence. J Psychopharmacol. 2016;30(12):e1‑e9.sciencedirect​
• Mancini E, Beglinger C, Drewe J, Zanchi D. Curcumin and cognitive function: a systematic review of randomized controlled trials. Front Neurosci. 2024;18:1388737.pmc.ncbi.nlm.nih​
• Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double‑blind, placebo‑controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383‑91.pmc.ncbi.nlm.nih+1​
• Katayama Y, Shimamura N, Sato S, Yamaguchi M, Naraoka M, Niizuma K, et al. Long‑term resveratrol and cognition in patients with asymptomatic carotid stenosis. J Stroke Cerebrovasc Dis. 2020;29(9):105047.frontiersin+1​
• Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, et al. A 2‑year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at‑risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255‑63.thelancet+1​
• Snitz BE, Isaacson RS, Mosconi L, Soininen H, Ngandu T, Kivipelto M, et al. Multidomain interventions for prevention of dementia: rationale, evidence, and future directions. J Alzheimers Dis. 2023;91(2):391‑408.pubmed.ncbi.nlm.nih+1​​