# Systemic complement factors in aging, Alzheimer’s disease and other dementias: a longitudinal study over 10 years

## TL;DR

This study identifies a unique pattern of complement factors in Alzheimer’s disease, distinguishing it from aging and other dementias over a 10-year period.

## Contribution

The study reveals an AD-specific complement profile detectable before clinical symptoms and differentiates AD from other dementias.

## Key findings

- Complement factors like C4 and Factor D show distinct changes with aging and in Alzheimer’s disease.
- The complement profile is specific to AD and not observed in other dementia subtypes.
- These changes are detectable during preclinical and clinical phases of AD.

## Abstract

Complement dysregulation is increasingly recognized in Alzheimer’s disease (AD). However, the temporal profile of complement alterations preceding AD onset and their distinction from age-related immune changes remain poorly defined. Clarifying these dynamics could provide insights into AD pathogenesis and identify systemic factors that predict disease onset and progression.

We conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson’s disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.

In the longitudinal cohort, aging was accompanied by gradual reductions in C4, C4b, Factor I, and Properdin and by increases in Factor D. These changes were more pronounced in individuals who subsequently developed AD. Importantly, this pattern of complement alterations was detectable during the preclinical and clinical phases of AD but was not observed in other dementias. In the cross-sectional cohort, the same complement profile was specific to AD and distinguished it from other dementia subtypes.

The results of this study indicate an AD-specific peripheral complement signature associated with disease development, highlighting complement factors as critical immune mediators that link aging and AD. This signature implicates complement factors as promising systemic markers for early detection and potential therapeutic targeting in preclinical AD.

The online version contains supplementary material available at 10.1186/s13024-026-00927-3.