Pre-diagnostic manifestations of alzheimer's disease: a systematic review and meta-analysis of longitudinal studies

Alzheimer's disease (AD) is associated with a range of non-cognitive symptoms that can be early or even presenting features. Better recognition of pre-diagnostic symptoms of AD would support improved early detection and diagnosis. To identify possible prodromal symptoms of AD, we systematically searched electronic databases for prospective longitudinal studies to March 2023, that reported the risk of AD diagnosis associated with non-cognitive symptoms. We conducted random-effects meta-analyses to obtain pooled odds of subsequent AD. Thirty studies met eligibility criteria. Most studies (n=18) reported on the association of depression with subsequent AD diagnosis (pooled OR= 1.80; 95% CI: 1.29 to 2.50; I2=95.8%). Hearing loss, weight loss, spondylosis and hypotension also predicted a subsequent AD diagnosis. This evidence suggests that these features that may be recorded during routine healthcare encounters are risk markers for incident AD and could therefore support improved early detection and diagnosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was carried out within EQUATED (towards equality of opportunity for timely and equitable dementia diagnosis) study funded by the NIHR Three Schools' Dementia Research Programme. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Not relevant