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

Genetic susceptibility to Alzheimer's due to the APOE*E4 gene can be fought with Omega 3s. This is suggested in a study published in JAMA Network Open by a group of researchers led by Lynne H. Shinto, an expert at the NIA-Layton Aging and Alzheimer's Disease Center at Oregon Health & Science University in Portland, US. According to Gene Bowman, coordinator of the study and now on staff at Harvard Medical School in Boston, "This is the first dementia prevention study that using modern prevention tools, such as blood tests and brain scans, has identified not only people at high risk for dementia, but also those who benefit most from a specific nutritional intervention."

Canfish oil-one of the best sources of the biologically active Omega 3s: EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid)-really improve brain function in those who manifest memory problems? There is no shortage of clues to its usefulness, and any doubts may vanish by focusing on people genetically predisposed to develop Alzheimer's. In particular, Omega 3 in fish oil would be beneficial to elderly people who carry the APOE*E4 gene, which increases their risk of finding themselves struggling with a diagnosis of the condition.

The study suggesting this was conducted at Oregon Health & Science University between 2014 and 2019, but the data analysis was not finished until 2022 and the results were published in 2024. At the beginning of the research, the individuals involved were all at least 75 years old, blood Omega 3 levels less than 5.5 percent by weight, and brain white matter lesions at least 5 cm3 in size. Such lesions can impair the arrival of nutrients to the brain-a situation that increases the risk of dementia. At this early stage, however, no participants had signs or symptoms of dementia.

All 102 of the individuals involved underwent brain MRIs at the beginning of the study and 3 years later; this allowed the progression of white matter lesions to be assessed. Meanwhile, only half of them took an Omega 3-rich fish oil (975 mg EPA and 650 mg DHA), while the others took a soybean oil placebo. MRI scans revealed a slight slowing of lesion progression among those who had taken the Omega 3; however, the difference compared with those who had taken soybean oil did not appear significant.

The really interesting effect turned out to be another: among APOE*E4 carriers, fish oil had greatly reduced brain cell damage already after one year of intake, a significant difference from what was observed among those who had taken soybean oil. This effect, Bowman commented, "is remarkable and warrants a future larger clinical study in more diverse populations."

Who is most at risk for Alzheimer's disease?

Alzheimer's disease is the most common form of dementia. It is a neurodegenerative condition caused by the death of neurons for which there is currently no cure; therefore, any strategy that helps to effectively prevent it is important and welcome.

The factors that promote its occurrence are more than one. The most significant is undoubtedly age: starting at age 65, the prevalence of the disease doubles every 5 years. Other important risk factors are cardiovascular disease, obesity and diabetes; smoking and above-normal homocysteine levels also seem to come into play.

All of those named so far are modifiable factors. Other predisposing characteristics to the onset of Alzheimer's disease, however, cannot be modified. These include genetics.

In fact, Alzheimer's has a hereditary character. Having a first-degree relative affected by the disease increases the risk of developing it by 10-30%; in the case of having 2 or more siblings with a late-onset form of Alzheimer's disease (i.e., appearing after age 65), the risk is 3 times higher than in the general population. There are also genetic tests to assess susceptibility to Alzheimer's. But how is the disease transmitted genetically? The cases where genes come into play can be different. 

The first is that of trisomy 21 (also known as Down syndrome), in which the presence of an extra copy of chromosome 21 corresponds to the presence of an additional copy of the APP (Amyloid Precursor Protein) gene. The latter increases the production of the disease-associated beta-amyloid protein.

There are, in addition, inherited forms of Alzheimer's disease due to mutations. There may be 3 genes involved: PSEN1 (Presenilin 1) on chromosome 14, PSEN 2 (Presenilin 2) on chromosome 1-both responsible for the aggregation of beta-amyloid proteins in the brain-or, again, APP. Alzheimer's-associated mutated versions are rare and are responsible for 5-10% of cases, but they result in early forms.

Variants in the SORT1 (Sortilin 1) gene have also been associated with Alzheimer's disease. The process they interfere with is the transport of the APP gene product.

Finally, the E4 variant of the APOE gene (APOE*E4) is a significant risk factor for late-onset forms of Alzheimer's disease. APOE (Apolipoprotein E) is a regulator of lipid metabolism characterized by high affinity for beta-amyloid protein. Carriers of one copy of the APOE*E4 variant have a 3-fold higher risk of developing Alzheimer's than the general population, and for those with 2 copies, the risk increases as much as 15-fold.

In APOE*E4 carriers, the microstructural changes in the white matter associated with the decline in cognitive ability are clearly visible with the techniques used by Shinto and colleagues. On the other hand, when Omega 3 is present in the blood in high concentrations, the risk of white matter injury in the elderly is reduced. "Plasma concentrations of Omega 3 above 11.0 mg/dL," Shinto and colleagues explain in the pages of JAMA Open Network, "are associated with less executive function-dependent decline in white matter lesions in the elderly without dementia, and, clinically, 1.65 g per day of Omega 3 has been shown to eliminate this hypothetical neuroprotective threshold in mild-to-moderate forms of Alzheimer's disease. Therefore, we decided to enroll elderly people with white matter lesions and suboptimal Omega 3 levels to see if Omega 3 treatment could prevent the progression of white matter lesions and loss of neuronal integrity."

Omega 3: allies of the brain at any age

About the role of Omega 3 as allies of the brain there is no longer any doubt. Proof of this is the fact that the European Food Safety Authority (the Efsa) has authorized the statement that, in particular, "DHA contributes to the maintenance of normal brain function." No food supplement manufacturer can put such a statement on the packaging without prior authorization; this means that, in the case of Omega 3, enough evidence of its benefits to the brain is available to be sure of the benefits of taking it.

Such benefits know no age and begin as early as the womb, so much so that in addition to the one already mentioned, there is another statement authorized by Efsa: "the mother's intake of DHA contributes to the normal brain development of the fetus and breastfed baby."

This study points out, however, how some more specific effects might affect population subgroups. In the case of Alzheimer's prevention, genetic predisposition to develop the disease could be the condition in which it is actually beneficial to increase EPA and DHA intake by taking advantage of highly concentrated Omega 3 supplements. On the other hand, the authors of this study themselves point out that including more individuals in the trials could bring out significant benefits for the entire population.

Finally, the work of Shinto and colleagues emphasizes how much the specific composition of the supplement can also make a difference on the benefits that can be obtained from its intake. Previous studies involving DHA alone or higher doses of DHA than EPA had found no benefits in terms of Alzheimer's prevention. On the other hand, intake of DHA alone has been associated with slowing disease progression in individuals who do not carry the APOE*E4 gene. All this suggests that formulations richer in EPA might be useful in preventing Alzheimer's in elderly carriers of the APOE*E4 gene who have not yet shown signs of dementia and without white matter lesions, while formulations richer in DHA might be useful for people not carriers of APOE*E4 but with mild-to-moderate forms of Alzheimer's already diagnosed.

"The daily doses used in the studies ranged from 0.650 to 2 grams for DHA and 0 to 0.975 grams for EPA," Shinto and colleagues finally point out, adding that "the duration of treatment ranged from 6 months to 3 years." Given this wide heterogeneity of treatment protocols, only further studies will allow definitive conclusions to be drawn about the most appropriate prevention supplementation strategy according to individual characteristics.

Bibliographic references:

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

Kumar A, Sidhu J, Lui F, et al. Alzheimer's 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