# Accrual of Alzheimer's disease pathology as a function of proximity to parental dementia onset

## TL;DR

The study finds that being close in age to when a parent developed dementia can predict amyloid buildup in the brain, especially in people with a specific genetic risk.

## Contribution

The study shows that proximity to parental dementia onset predicts amyloid accumulation in a gene-dependent manner.

## Key findings

- Shorter proximity to parental dementia onset predicts lower amyloid levels in carriers of APOE-ε4.
- APOE-ε2 carriage appears to provide protection against amyloid accrual.
- Proximity to parental dementia onset does not predict further progression of Alzheimer's pathology.

## Abstract

Whether temporal proximity to parental onset of dementia (PPO) can be used to estimate timing of the preclinical stage of sporadic Alzheimer's disease (AD) remains uncertain.

We investigated cross‐sectionally adults aged > 50 without dementia included in the European Prevention of Alzheimer's Dementia (EPAD) study. PPO was tested as a predictor of quantitative levels of cerebrospinal fluid (CSF) β‐amyloid (1‐42) (Aβ1‐42) in those with a parental history of dementia (n = 688) and of phosphorylated tau (p‐tau) and EPAD neuropsychological examination (ENE) subscores in an amyloid positive subgroup (n = 226). Possible interactions were explored.

Shorter PPO predicted lower CSF Aβ1‐42 level (β = 9.357; T = 4.161; p < 0.001), interacting with apolipoprotein E (APOE) ‐𝜀4 carriage in a dose‐dependent manner. Concomitant APOE‐𝜀2 carriage appeared to provide protection. PPO did not predict p‐tau levels or cognitive performance.

PPO may provide a valid method of stratifying risk of early AD pathologic change in APOE‐𝜀4 carriers, with empirical and clinical applications.

Proximity to age of parental dementia onset can predict amyloid accrualThe effect is APOE‐𝜀4 dose‐dependent and APOE‐𝜀2 appears to provide protectionPPO does not appear to predict further advancement along the AD continuumIn the era of anti‐amyloid treatments, this may inform timing of amyloid screeningUsed as an empirical metric, PPO could help elucidate the natural history of LOAD

Proximity to age of parental dementia onset can predict amyloid accrual

The effect is APOE‐𝜀4 dose‐dependent and APOE‐𝜀2 appears to provide protection

PPO does not appear to predict further advancement along the AD continuum

In the era of anti‐amyloid treatments, this may inform timing of amyloid screening

Used as an empirical metric, PPO could help elucidate the natural history of LOAD