Goodbye, APOE4. Hello, Healthy Brain?

Would carrying a muted version of APOE4, the strongest genetic risk factor of sporadic Alzheimer’s disease, protect against the disorder? Perhaps. Scientists led by Michael Greicius at Stanford University and Chang-En Yu at the VA Puget Sound Health Care System, Seattle, described two such cases in a medRxiv preprint uploaded July 24.

• Scientists found two men with APOE4 loss-of-function variants.
• At 70+ and 90+, both were cognitively sharp, with no signs of amyloid plaques.
• This may bode well for future therapeutics aiming to knock down APOE4.

Both men, who were APOE3/4, had an aberrant stop codon in their E4 allele. One stayed sharp into his 90s, the other until his most recent doctor’s visit at 79. The former had no amyloid plaques in his brain postmortem and the latter had no amyloid markers in his cerebrospinal fluid. “The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option,” the authors concluded. In contrast, a woman who was ApoE3/4 carried a deletion in her E3 allele, rendering it inactive. She developed AD at 75, about average for people with one copy of E4.

Loss-of-function (LoF) variants in APOE are rare. Eight have been reported, but only one, a frameshift in exon 4, was studied for its effects on cognition. A man in his early 40s with both copies of APOE silenced by the frameshift had blood choked with lipids, but his cerebrospinal fluid (CSF) was devoid of AD markers and he seemed cognitively normal, according to his global Mini-Mental State Exam score. Even so, he scored slightly below average for his age on verbal memory and language tasks, leaving it unclear whether the lack of APOE was helpful or harmful to his brain (Aug 2014 news).

To find others like him, co-first authors Augustine Chemparathy and Yann Le Guen, both at Stanford, analyzed whole-genome and whole-exome sequencing data from 20,850 people with AD and 26,600 controls ages 64 to 90 in the Alzheimer’s Disease Sequencing Project (ADSP), a compilation of genetic data from more than 40 cohorts worldwide. They looked for single nucleotide polymorphisms (SNPs) or structural variants in APOE predicted to quash protein levels. Four mutations fit the bill: two SNPs in exon 2, p.W5* and p.L8*, one in exon 3, p.Q39*, and a deletion. The SNPs create a premature stop codon leading to a truncated protein predicted to have no function. The 1,798bp deletion cuts out part of the promoter through to exon 2, preventing transcription.

Read the full article on the Alz Forum – https://www.alzforum.org/news/research-news/goodbye-apoe4-hello-healthy-brain