Alzheimer's, Omega 3 for prevention in case of genetic predisposition

Genetic predisposition to Alzheimer's due to the APOE*E4 gene may be combated with Omega-3s. This suggestion comes from a study published in JAMA Network Open by researchers led by Lynne H. Shinto from the NIA-Layton Aging and Alzheimer's Disease Center at Oregon Health & Science University in Portland (USA). According to Gene Bowman, study coordinator now at Harvard Medical School in Boston, "this is the first dementia prevention study using modern prevention tools like blood tests and brain scans that has identified not only people at high risk of dementia, but also those who benefit most from a specific nutritional intervention."

Can fish oil - one of the best sources of biologically active Omega-3s EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) - actually improve brain function in people with memory problems? Evidence of its benefits exists, and all doubts might disappear by focusing on people genetically predisposed to Alzheimer's. Specifically, fish oil Omega-3s appear particularly beneficial for elderly carriers of the APOE*E4 gene, which increases Alzheimer's risk.

The study suggesting this was conducted at Oregon Health & Science University between 2014-2019, with data analysis completed in 2022 and results published in 2024. At study start, all participants were at least 75 years old with blood Omega-3 levels below 5.5% by weight and white matter brain lesions ≥5 cm³. Such lesions can impair nutrient delivery to the brain - increasing dementia risk. However, no participants showed signs or symptoms of dementia initially.

All 102 participants underwent brain MRIs at study start and 3 years later to assess white matter lesion progression. Meanwhile, only half received fish oil rich in Omega-3s (975 mg EPA + 650 mg DHA), while others received soybean oil placebo. MRIs showed slightly slower lesion progression in Omega-3 recipients, though the difference versus placebo wasn't statistically significant.

The truly interesting effect emerged elsewhere: among APOE*E4 carriers, fish oil strongly reduced brain cell damage after just one year, with significant difference versus soybean oil. Bowman commented this effect is "notable and warrants a future larger clinical trial in more diverse populations."

Who's Most at Risk for Alzheimer's?

Alzheimer's is the most common dementia form. This neurodegenerative condition caused by neuron death currently has no cure, making any effective prevention strategy important and welcome.

Multiple factors promote its development. The most significant is undoubtedly age: from age 65 onward, disease prevalence doubles every 5 years. Other major risk factors include cardiovascular disease, obesity and diabetes; smoking and elevated homocysteine levels also appear involved.

All aforementioned factors are modifiable. Other Alzheimer's predispositions can't be changed, including genetics.

Indeed, Alzheimer's has hereditary aspects. Having a first-degree relative with the disease increases personal risk by 10-30%; with ≥2 siblings having late-onset Alzheimer's (appearing after age 65), risk triples versus general population. Genetic tests can assess Alzheimer's predisposition. But how is it genetically transmitted? Several genetic scenarios exist.

First is trisomy 21 (Down syndrome), where an extra chromosome 21 copy means an extra APP (Amyloid Precursor Protein) gene copy. This increases beta-amyloid protein production linked to Alzheimer's.

There are also hereditary Alzheimer's forms from mutations. Three genes may be involved: chromosome 14's PSEN1 (Presenilin 1), chromosome 1's PSEN2 (Presenilin 2) - both affecting beta-amyloid brain aggregation - or APP again. Mutation-associated versions are rare (5-10% of cases) but cause early-onset forms.

SORT1 (Sortilin 1) gene variants also associate with Alzheimer's by interfering with APP gene product transport.

Finally, APOE gene's E4 variant (APOE*E4) significantly increases late-onset Alzheimer's risk. APOE (Apolipoprotein E) regulates lipid metabolism and strongly binds beta-amyloid. APOE*E4 carriers have triple the Alzheimer's risk versus general population; those with two copies face 15-fold higher risk.

In APOE*E4 carriers, white matter microstructural changes linked to cognitive decline are clearly visible using Shinto's team's techniques. Conversely, high blood Omega-3 concentrations reduce elderly white matter lesion risk. "Plasma Omega-3 concentrations >11.0 mg/dL," Shinto's team explains in JAMA Open Network, "associate with less white matter lesion-dependent executive function decline in dementia-free elderly, and clinically, 1.65 g/day Omega-3 eliminated this hypothetical neuroprotective threshold in mild-moderate Alzheimer's. Therefore we enrolled elderly with white matter lesions and suboptimal Omega-3 levels to determine if Omega-3 treatment could prevent white matter lesion progression and neuron integrity loss."

Omega-3s: Brain Allies at Any Age

There's no remaining doubt about Omega-3s as brain allies. The European Food Safety Authority (EFSA) authorizing the claim that "DHA contributes to maintenance of normal brain function" proves this. No supplement manufacturer can make such claims without pre-authorization, meaning sufficient evidence exists to confirm Omega-3 brain benefits.

These benefits span all ages, beginning in utero - EFSA also authorizes the claim that "maternal DHA intake contributes to normal fetal and breastfed infant brain development."

However, this study shows some effects may be subgroup-specific. For Alzheimer's prevention, genetic predisposition might indicate when increasing EPA/DHA intake via high-concentration Omega-3 supplements is truly useful. The authors note including more participants might reveal significant population-wide benefits.

Finally, Shinto's work highlights how specific supplement composition affects potential benefits. Previous studies administering DHA alone or DHA-dominant formulations detected no Alzheimer's prevention benefits. However, DHA alone slowed progression in non-APOE*E4 carriers. This suggests EPA-rich formulations may help prevent Alzheimer's in APOE*E4 carriers without dementia signs or white matter lesions, while DHA-rich formulations may benefit non-carriers with mild-moderate diagnosed Alzheimer's.

"Daily doses in studies range from 0.650-2 grams DHA and 0-0.975 grams EPA," Shinto's team specifies, adding that "treatment duration varies from 6 months to 3 years." Given this protocol heterogeneity, only further studies will determine ideal personalized prevention strategies.

References:

European Community. Food and Feed Information Portal Database. Last accessed 09/12/24

Kumar A, Sidhu J, Lui F, et al. Alzheimer Disease. [Updated 2024 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499922/

Science Daily. Study examines effect of fish oil in older adults' brains. August 1, 2024.

Shinto LH, Murchison CF, Silbert LC, Dodge HH, Lahna D, Rooney W, Kaye J, Quinn JF, Bowman GL. ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2024 Aug 1;7(8):e2426872. doi: 10.1001/jamanetworkopen.2024.26872