# Amyloid‐beta subspecies in individuals with Down Syndrome, sporadic Alzheimer's disease (sAD) and PS1 mutations ‐ comparison using IP‐Mass Spectrometry of plasma

## TL;DR

This study compares amyloid-beta subspecies in Down Syndrome, sporadic Alzheimer's disease, and PS1 mutations using mass spectrometry to understand differences in AD development.

## Contribution

The study identifies distinct plasma Aß subspecies patterns in Down Syndrome compared to sporadic Alzheimer's and PS1 mutations using IP-MS.

## Key findings

- DS individuals have higher Aß subspecies levels compared to CS adults, sAD, and PS1 mutations.
- DS pAD/AD shows increased Aß ratios compared to sAD but similar ratios to PS1 mutations.
- Changes in Aß subspecies precede neurodegeneration markers like NfL and pTau in DS.

## Abstract

Down Syndrome (DS) individuals develop Alzheimer's Disease (AD) neuropathology by the age of 40 due to the triplication of Chromosome 21 and the amyloid precursor protein gene. This genetic alteration leads to an overproduction of Aß, resulting in amyloid accumulation. However, triplication of other Chr21 genes may be involved in AD pathogenesis in DS, and affect amyloid processing and alter subspecies production. This study compares plasma Aß subspecies using mass spectrometry (MS) in DS, sAD and PS1 mutations.

Plasma from adults with DS who were cognitively stable (CS‐DS; n = 46; mean age 33.5), cognitive stable older adults from the general population (CS; n = 42; mean age 71.7), DS deemed prodromal or with AD (DS pAD/AD; n = 25; mean age 53.5), early onset sporadic pAD/AD (n = 27; mean age 63.9) and with presenilin 1 mutations (n = 6; mean age 50.5) were analysed using IP‐MS for Aß 1‐37, 1‐38, 1‐40, and 1‐42. In those with DS, Simoa assays for Aß 40 and 42, neurofilament light (Nfl), glial fibrillary protein (GFAP, pTau181 and pTau231 were also obtained, and an Event‐Based Model (EBM) was used to determine the sequence of changes associated with AD.

DS individuals had consistently higher levels of Aß1‐37, 1‐38, 1‐40, and 1‐42 compared to CS general population adults, sporadic pAD/AD, and those with PS1 mutations. DS pAD/ AD had increased Aß ratios for 1‐ 40/1‐37 and 1‐37/ 1‐38 compared to sporadic pAD/AD, but similar ratios when compared to those with PS1 mutations. Age‐related patterns of changes in Aβ1‐37 and 1‐38 subspecies in DS pAD/AD differed compared to sporadic pAD/AD, but changes in Aβ 1‐40 and 1‐42 levels were similar. APOE ε4 was associated with Ab 1‐37 levels in DS. Changes Aβ1‐42/1‐38, 1‐42/1‐37, and 1‐42/1‐40 were early events followed by changes in NfL, GFAP, pTau 181 and pTau 231.

All Aß subspecies are increased in DS compared to sAD, with higher 1‐40/1‐37 ratios and different age associated changes. Measurement of Aβ subspecies with IP‐MS may help to identify early AD in DS. Further work could determine the nature of differences in subspecies compared to sAD.