An Alzheimer’s-disease-protective APOE mutation

The reported patient displayed extremely high Aβ pathology but minimal Tau burden, hippocampal atrophy and neuroinflammation.

“This patient displayed extremely high Aβ pathology but minimal Tau burden, hippocampal atrophy and neuroinflammation36,43,44.”

Individuals carrying the PSEN1 p.E280A mutation typically develop mild cognitive impairment at a median age of 44 years and dementia at a median age of 49 years.

“Individuals carrying the PSEN1 p.E280A mutation typically develop mild cognitive impairment at a median age of 44 years (95% confidence interval [CI]: 43‒45 years) and dementia at a median age of 49 years (95% CI: 49‒50 years).”

The APOE Christchurch variant rs121918393 and the APOE Jacksonville variant rs199768005 are protective against Alzheimer's disease in Caucasians.

“The Christchurch variant rs121918393 (APOEChc: CGC > aGC, p.Arg[R]136Ser[S]) [19–21] and the Jacksonville variant rs199768005 (APOEJax: GTG > GaG, p.Val[V]236Glu[E]) [22, 23] have been identified as protective variants against AD in Caucasians”

The APOEChc variant reduces the effects of the pathogenic PSEN1 p.E280A mutation.

“with the APOEChc variant apparently reducing the effects of the pathogenic PSEN1 variant (GAA > GcA, p.Glu[E]280Ala[A]), which is a highly penetrant and causative mutation for dominantly inherited AD [20, 21]”

A woman with homozygous APOEChc variant and carrying the PSEN1 p.E280A mutation did not exhibit mild cognitive impairment until her 70s despite abundant amyloid-β accumulation in the brain.

“Surprisingly, a woman with homozygous APOEChc variant and carrying the PSEN1 p.E280A mutation did not exhibit mild cognitive impairment until her 70 s even though abundant accumulation of amyloid-β (Aβ) was seen in the brain.”