Dennis N Crouse PhD

Discussion of 2024 paper by Fortea, et al. on ApoE 4/4

Does APOE4 homozygosity represent a distinct genetic form of AD?

Dennis N. Crouse      May 11, 2024

This question remains unanswered but new data has been recently (2024) presented by Fortea, et al. in a study that compares AD biomarkers of autosomally dominate AD (ADAD a.k.a. familial AD), Down syndrome AD (DSAD) and APOE3/3 and APOE4/4 carriers [Fortea, J., et al.; Nature Med.; https://doi.org/10.1038/s41591-024-02931-w (2024)].

In order for APOE4 homozygosity (i.e. two APOE4 alleles) to be a distinct genetic form of AD the penetrance must be close to 100%. In this regard, the AD penetrance is the percentage of people with APOE4 homozygosity who exhibit signs and symptoms of AD. In 1990-1991 a population of 638 people aged 70 and older were both interviewed and checked for APOE genotype and then reinterviewed in 1994. The estimated AD penetrance by age 90 for APOE4 homozygosity was found to be 50% [Henderson, A.S., et al.; Lancet 346(8987):1387-90(1995)].

The percentage of people who will get AD in their lifetime is called lifetime risk (LTR). In 2011 an estimate of LTR was made based upon 7,351 AD cases and 10,132 controls all of Caucasian ancestry. The estimated LTR at age 85 of homozygous APOE4 males was 51% and females was 60% [Genin, E., et al.; Mol. Psychiatry; 16(9):903-7 (2011)]. Genin, et al., defined the APOE4 gene as semi-dominant and moderately penetrant. 

 In May of 2024 Fortea et al. reported a study of two populations: 3,297 brain doners from the National Alzheimer’s Coordinating Center (NACC) cohort and 10,039 individuals from five large multicenter clinical cohorts. The first population leaned in favor of brains from symptomatic patients and the second leaned in favor of cognitive health.

In the first population there were 273 brains from people who were APOE4 homozygous and 240 (88%) of these people had been diagnosed with AD dementia prior to death with an average age of 65 at onset of symptomology, 74 at onset of dementia, and they died on average at age 80. From the postmortem data the Alzheimer’s disease neuropathological change (ADNC) was profiled along the age range and “nearly all” APOE4 homozygotes exhibited high or intermediate ADNC scores. The AD penetrance for this population is 88%. But the NACC cohort is a skewed population of brains autopsied from symptomatic patients. Therefore, the AD penetrance is potentially skewed being higher than Henderson’s and Genin’s populations that estimated penetrance at age 85 to 90 at 50-60%.  

In the second population of 519 APOE4 homozygous people with an average age of 69 only 22%  had MCI and 21% had AD. This population was used to study AD biomarker development. It has been found and confirmed by this study that APOE4 heterozygotes and homozygotes have a gene dose response on AD biomarkers supporting Genin’s concept of the APOE4 gene being semi-dominant [Jensen, JAMA; 313:1924-38 (2015) and Saddiki, H., et al.; PLoS Med. https://doi.org/10.1371/JOURNAL.PMED.1003289 (2020)]. The biomarkers for AD increase with age reaching a biological penetrance of 88% for Ab-42 PET and p-tau biomarkers at age 80. This was in spite of the skewed selection bias of this population toward cognitively unimpaired individuals.

But as suggested by Fortea et al., the expected age for symptom onset, including the appearance of biomarkers for AD, are influenced by lifestyle factors. One such factor is the accumulation of aluminum in the brain that increases with age impacting almost everyone in the second population of APOE4 homozygous people as they had a mean age of 69.

In addition, people with autosomally dominate AD (ADAD, a.k.a. familial AD) have higher than normal levels of aluminum in their brains [Mirza, A., et al.; J. Trace Elements in Med. Biol.; 40:30-36 (2017) and Mold, M., et al.; J. Alz. Dis.; 73(4):1627-35 (2020)]. Those with Down syndrome absorb 4 to 6-fold more aluminum in their gut than normal, have 3 to 7-fold higher than normal levels of aluminum in their brains, and have a 50% penetrance for AD (DSAD) at age 60-69 [Moore, P.B., et al.; Biol. Psychiatry; 15:41(4):488-92 (1997) and penetrance from National Down Syndrome Society].

Aluminum accumulation impacts the same biomarkers as AD. For example, the AD biomarker p-tau-181 is modulated by the body burden of accumulated aluminum. Occupational aluminum exposure increases p-tau-181 levels [Lu, X., et al.; JOEM;56(2):155-60 (2014)] making the second population of 519 APOE4 homozygous people have an exaggerated  biological penetrance of 88% for p-tau-181 biomarker at age 80.

In addition, the AD biomarker Ab-42 PET is also modulated by the body burden of accumulated aluminum making the second population of 519 APOE4 homozygous people have an exaggerated biological penetrance of 88% for Ab-42 PET biomarker at age 80.

Both aluminum accumulation and ApoE e4 allele work together additively and synergistically to cause cognitive impairment in workers occupationally exposed to aluminum [Wang, S., et al.; Chemosphere; 323:138282 (2023)] in the following ways:

• ApoE e4 allele weakens blood-brain barrier causing more aluminum to enter the brain [Montagne, A., et al.; Nature; 71-6 (2020)]. 
• Aluminum increases Ab-42 peptide levels in a human neuroblast cell line and aluminum plus ApoE e4 allele increases Ab-42 peptide levels even more [Wang, Y., et al.; J. Trace Elem. Biol.; 64:126700 (2021)].
• Aluminum increases Ab-42 peptide in the brain by both increasing gene expression of APP, BACE1, and g-secretase and by reducing neprilysin mRNA expression [Luo, Y., et al.; Mech. Ageing Dev.; 130(4):248-52 (2009) and Liang, R.F., et al.; Biomed. Environ. Sci.; 26(6):445-52 (2013) and Zhang, T., et al.; Neurotoxicity Res.; 35:931-44 (2019)].
• ApoE e4 allele increases oligomerization of Ab-42 peptide and thereby increases Ab-42’s neurotoxicity⁴⁸². AD patients with ApoE e4 have 2.7 times the level of oligomerized Ab-42 compared to AD patientswith ApoE e2 or e3 [Wang, Y., et al.; J. Trace Elem. Biol.; 64:126700 (2021)].
• Aluminum aggregates Ab-42 peptide into Ab-42 oligomers more efficiently as compared with other metal ions [Drago, D., et al.; Int. J. Biochem. Cell Biol.; 40:731-46 (2008)].
• Aluminum containing Ab-42 oligomers (0.5mM) are 50% more neurotoxic than aluminum-free Ab-42 oligomers (0.5mM) [Drago, D., et al.; Int. J. Biochem. Cell Biol.; 40:731-46 (2008)].

Modulation of p-tau-181and Ab-42 PET biomarkers by the lifestyle factor aluminum accumulation makes questionable the higher-than-expected biological penetrance suggested by the Fortea, et al. paper. Instead of showing  that APOE4 homozygosity represents a distinct form of AD, this paper shows that autosomally dominate AD (ADAD), Down syndrome AD (DSAD) and APOE3/3 and APOE4/4 carriers all have p-tau-181 and Ab-42 PET biomarkers that are being impacted by both genetics and the lifestyle factor aluminum accumulation in the population of 519 APOE4 homozygous people chosen for this study.

Aluminum accumulation is a lifestyle factor because the amount of aluminum ingested depends upon diet and the amount of aluminum excreted in urine and sweat depends upon the amount of silica rich water or silica rich beverages consumed [Crouse, D.N.; Prevent Alzheimer’s, Autism, and Stroke (2016)]. Lifestyle choices can be made to avoid aluminum ingestion and drink silica rich water and beverages daily.  

In conclusion Fortea et al. have overestimated the AD penetrance of APOE4 homozygosity:

• Using a population of 273 brains from people who were APOE4 homozygous with 240 (88%) of these people having been diagnosed with AD dementia prior to death results in an overestimate of AD penetrance.
• Using p-tau-181 and Ab-42 PET biomarkers to predict biological penetrance in a population of 519 APOE4 homozygous people also results in an overestimate of biological AD penetrance. Because there are lifestyle factors, such as consuming aluminum and not drinking silica rich water and silica rich beverages to facilitate the elimination of aluminum, that increases these biomarkers.