Greater burden of Alzheimer's Co-pathology in women with Parkinson's disease dementia.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that typically manifests in later life, with most individuals developing symptoms after the age of 65 years. In the United Kingdom, a diagnosis of dementia is suspected with evidence of cognitive impairment, often accompanied by behavioural changes or difficulties performing activities of daily living (). Diagnostic assessment is supported by biomarkers of AD pathology, classified within the A/T/N framework according to the presence of amyloid-β deposition (A), tau neurofibrillary tangle formation (T), and neurodegeneration (N) (). These biomarkers are measured using amyloid-β or tau positron emission tomography (PET), blood- or cerebrospinal fluid-based assays, or structural magnetic resonance imaging (MRI) to examine the extent of atrophy and neurodegeneration. Together these methods allow identification of AD-specific pathology, biomarker progression over time, and in some cases, differentiate AD from other types of dementia (). However, these overt symptoms reflect advanced macrostructural degeneration and are likely preceded by disease-specific neurobiological alterations occurring years or decades before diagnosis (; ). Evidence from clinical trials suggests therapeutic interventions initiated during symptomatic stages of AD confer minimal cognitive or structural benefit (). This has led to increasing emphasis on identifying AD-related pathology at earlier, preclinical stages, where interventions may be more effective in delaying or preventing disease progression. Accordingly, some clinical trials target preclinical or Mild Cognitive impairment (MCI) populations, evaluating the efficacy of treatments such as lecanemab in reducing amyloid-β deposition over 18 months () or in preventing the onset of tau pathology before the appearance of any measurable cognitive deficits (). Apolipoprotein E (APOE) is the most well-established genetic risk factor for sporadic AD and exists in three common isoforms: ε2, ε3, and ε4. The least common isoform is thought to be neuroprotective and has been associated with reduced AD-related histopathology () while the allele is the most prevalent and generally considered risk-neutral. Previous literature associated the -allele with increased amyloid-β deposition (), potentially mediated through impaired clearance via low-density lipoprotein receptor–related protein 1 (), increased microglial immunoreactivity surrounding amyloid plaques (), and elevated levels of phosphorylated tau (). Consistent with these mechanistic findings, the allele confers the greatest known genetic risk for AD; -homozygotes have a ∼ 40% higher likelihood of developing AD by 85 years compared with APOE ε3/ε3 carriers (). Together, these findings suggest that influences multiple pathological pathways central to AD pathogenesis.